# data[].attributes.headline
Complications of electrosurgery: mechanisms and prevention strategies

# data[].attributes.subject
Complications of electrosurgery: mechanisms and prevention strategies

# data[].attributes.attachment_link.title
Complications of electrosurgery: mechanisms and prevention strategies - Facts, views & vision in ObGyn

# data[].attributes.attachment_link.description
S.M. El-Sayed1, E. Saridogan2, M.M. El-Sayed3

# data[].attributes.headline
An examination of service user satisfaction in forensic mental health settings

# data[].attributes.subject
An examination of service user satisfaction in forensic mental health settings

# data[].attributes.attachment_link.title
An examination of service user satisfaction in forensic mental health settings - Al Adiya Khan, Victoria Stirrup, Douglas MacInnes, 2025

# data[].attributes.attachment_link.description
High levels of service user satisfaction are viewed as a reliable indicator of a service providing good care and treatment. There has been limited research look…

# data[].attributes.headline
How Does the Pre-Registration Midwifery Programme Prepare the Newly Qualified Midwives for Their Post-Registration Perinatal Mental Health Role? A Mixed Methods Study

# data[].attributes.subject
How Does the Pre-Registration Midwifery Programme Prepare the Newly Qualified Midwives for Their Post-Registration Perinatal Mental Health Role? A Mixed Methods Study

# data[].attributes.attachment_link.title
How Does the Pre-Registration Midwifery Programme Prepare the Newly Qualified Midwives for Their Post-Registration Perinatal Mental Health Role? A Mixed Methods Study

# data[].attributes.attachment_link.description
Objective: In the United Kingdom (UK) and most countries worldwide, midwives are professionally required to undertake an initial perinatal mental health (PMH) risk assessment at every maternity contact. However, studies have found that midwives feel that they are not well-equipped to provide effective care for women with PMH needs. This study explores how the newly qualified midwives (NQMs) are prepared through pre-registration midwifery education and placements to have sufficient confidence in their knowledge, attitude, skills, and habits (KASH) for their post-registration PMH role. Methods: This explanatory sequential mixed methods study collected survey data from two independent groups: NQMs (n = 50), who qualified from 10 UK universities, and senior specialist midwives (SSMs) (n = 32). Descriptive and inferential responses were analysed using SPSS. Statistical differences between the ranged Likert scale responses of the NQMs and SSMs were analysed using the Mann-Whitney U test. The p-value of <0.05 was considered statistically significant. The semi-structured interview phase comprised of NQMs (n = 12) and SSMs (n = 8). The qualitative data were thematically analysed using NVivo. Results: The pre-registration midwifery programme significantly prepared the NQMs to have sufficient confidence in their knowledge of the related PMH role, multidisciplinary team (MDT) role, and available services (p < 0.05) and good attitude towards women with varying PMH conditions (p < 0.0005). The NQMs had sufficient confidence in their skills in using the validated tool for PMH assessment, to build rapport to facilitate disclosure, and recognise deteriorating PMH (p < 0.01). They had regular habits of discussing PMH well-being at booking and made prompt referrals (p < 0.05). The NQMs were not prepared to have sufficient knowledge of PMH medications, perinatal suicide prevention, and the impact of maternal mental health on partners (p < 0.01) including children (p < 0.05); skills in managing PMH emergencies (p < 0.05), and to regularly discuss suicidal thoughts (p < 0.01), issues of self-harm, and debrief women following pregnancy or neonatal losses and traumatic births (p < 0.05). Some aspects were either confirmed or contradicted at the interviews. Conclusions and recommendations: The pre-registration midwifery programme prepares the NQMs to some extent for their post-registration PMH role. Perceived areas for improvement suggest implications for the development of educational, practice, policy, and preceptorship to facilitate the NQMs’ sustainable confidence in their KASH.

# data[].attributes.headline
Fusobacterium nucleatum-Induced Empyema Masquerading as Lung Cancer: A Diagnostic Challenge

# data[].attributes.subject
Fusobacterium nucleatum-Induced Empyema Masquerading as Lung Cancer: A Diagnostic Challenge

# data[].attributes.attachment_link.title
Fusobacterium nucleatum-Induced Empyema Masquerading as Lung Cancer: A Diagnostic Challenge

# data[].attributes.attachment_link.description
A 73-year-old man, an ex-smoker with a history of asbestos exposure and hypertension, presented with progressive shortness of breath, weight loss, loss of appetite, and fatigue. He was referred by a general practitioner for evaluation of a round lesion in the right lung. Chest computed tomography (CT) revealed a pleural-based mass and small right-sided pleural effusion that was not amenable to aspiration. Routine blood investigations revealed elevated levels of the inflammatory markers. He was discharged with a course of oral antibiotics, levofloxacin, and scheduled for a two-week follow-up on the lung cancer pathway. The patient returned with worsening shortness of breath and enlarged pleural effusion. Ultrasound-guided diagnostic aspiration yielded purulent fluid, with cultures identifying Fusobacterium nucleatum. Cytological examination of the pleural fluid yielded negative results for malignant cells. Further investigations ruled out septic thrombophlebitis of the internal jugular vein (Lemierre syndrome) and septic mediastinitis. After excluding all other possible infection sites and conducting an oral examination, the pleural infection was attributed to periodontal disease. Empyema was effectively managed with antibiotics and drainage. However, empyema resulted in a visceral pleural rind, leading to an unexpandable lung. Surgical intervention was not pursued because of the patient’s comorbidities and clinical and biochemical resolution of the infection. This case highlights the importance of considering rare pathogens, such as Fusobacterium nucleatum, in pleural infections, particularly when linked to oral sources.

# data[].attributes.headline
The National Joint Registry Data Quality Audit of elbow arthroplasty

# data[].attributes.subject
The National Joint Registry Data Quality Audit of elbow arthroplasty

# data[].attributes.attachment_link.title
The National Joint Registry Data Quality Audit of elbow arthroplasty | Bone & Joint

# data[].attributes.attachment_link.description
The National Joint Registry Data Quality Audit of elbow arthroplasty

# data[].attributes.headline
Atypical Motor-Predominant Presentation of Subacute Combined Degeneration of Spinal Cord Due to Vitamin B12 Deficiency: A Case Report of Stroke Mimicry in the Absence of Classic Symptoms

# data[].attributes.subject
Atypical Motor-Predominant Presentation of Subacute Combined Degeneration of Spinal Cord Due to Vitamin B12 Deficiency: A Case Report of Stroke Mimicry in the Absence of Classic Symptoms

# data[].attributes.attachment_link.title
Atypical Motor-Predominant Presentation of Subacute Combined Degeneration of Spinal Cord Due to Vitamin B12 Deficiency: A Case Report of Stroke Mimicry in the Absence of Classic Symptoms

# data[].attributes.attachment_link.description
Vitamin B12 deficiency is a prevalent condition that can lead to serious neurological disorders, including subacute combined degeneration (SCD) of the spinal cord, which can result in lasting damage if not promptly treated. This report discusses a unique case of a 53-year-old female patient who presented with a one-week history of gait instability and falls, ultimately diagnosed with SCD due to severe vitamin B12 deficiency. Notably, the patient exhibited an atypical presentation, lacking classic symptoms such as paraesthesia and hematologic abnormalities, which often accompany B12 deficiency. Clinical evaluation revealed no previous neurological deficits or hematological issues, suggesting an acute decline in B12 levels. Neuroimaging, particularly MRI of the spine, showed demyelination affecting the dorsal columns and corticospinal tracts, consistent with SCD while excluding ischemic causes. Laboratory tests confirmed low serum B12 levels, supporting the diagnosis. This case underscores the necessity for clinicians to maintain a high index of suspicion for vitamin B12 deficiency in patients presenting with unexplained neurological symptoms. Early intervention is crucial; in this case, immediate treatment with intramuscular B12 led to significant recovery in gait stability and neurological function. The findings highlight the importance of thorough assessments and ongoing education about the diverse presentations of B12 deficiency, especially in populations at risk, such as the elderly and those with malabsorption issues. Awareness of the neurological consequences of B12 deficiency is essential for effective management and improved patient outcomes.

# data[].attributes.headline
Complications Following Shoulder Arthroplasty: A Review of the Recent Literature

# data[].attributes.subject
Complications Following Shoulder Arthroplasty: A Review of the Recent Literature

# data[].attributes.attachment_link.provider_name
Journal of Clinical Orthopaedics & Trauma

# data[].attributes.attachment_link.title
Complications Following Shoulder Arthroplasty: A Review of the Recent Literature

# data[].attributes.attachment_link.description
Glenohumeral joint arthroplasty is a safe and effective treatment with osteoarthritis
being the most common indication. The incidence of shoulder arthroplasty has increased
over twofold in the last ten years (1) but increasing reoperation rates are also noted
(2). Revision surgery is associated with higher complication rates and poorer patient
outcomes (2).

# data[].attributes.headline
Comprehensive consent in urology using decision aids, leaflets, videos and newer technologies: empowering patient choice and shared decision-making

# data[].attributes.subject
Comprehensive consent in urology using decision aids, leaflets, videos and newer technologies: empowering patient choice and shared decision-making

# data[].attributes.body
decision aids, leaflets, videos and newer

technologies: empowering patient choice

and shared decision-making

# data[].attributes.headline
National Dermatological Surgery Sustainability Survey: An Evaluation of Healthcare Professional Beliefs and Practices

# data[].attributes.subject
National Dermatological Surgery Sustainability Survey: An Evaluation of Healthcare Professional Beliefs and Practices

# data[].attributes.headline
A Storm of Polyserositis: Unravelling Multisystem Effusions in Hypereosinophilic Syndrome

# data[].attributes.subject
A Storm of Polyserositis: Unravelling Multisystem Effusions in Hypereosinophilic Syndrome

# data[].attributes.attachment_link.title
A Storm of Polyserositis: Unravelling Multisystem Effusions in Hypereosinophilic Syndrome

# data[].attributes.attachment_link.description
Idiopathic hypereosinophilic syndrome (i-HES) is a rare disorder characterized by persistent eosinophilia and organ involvement, without an identifiable secondary cause. This case report describes a 42-year-old man with no significant medical history, who initially presented with symptoms resembling community-acquired pneumonia, including fever, shortness of breath, and pleuritic chest pain. Despite antibiotic treatment, his condition rapidly progressed to polyserositis, characterized by bilateral pleural effusions, pericardial tamponade, and ascites. Extensive diagnostic evaluation excluded the secondary causes of hypereosinophilia, leading to a final diagnosis of i-HES. Prompt initiation of high-dose corticosteroids resulted in dramatic clinical improvement, with resolution of the fever, pleural effusion, and pericardial effusion. This case highlights the diagnostic challenges associated with the atypical presentations of i-HES and emphasizes the importance of early recognition, comprehensive evaluation, and appropriate corticosteroid therapy. It also raises awareness of the potential for i-HES to present with life-threatening complications, underscoring the need for multidisciplinary management.

# data[].attributes.attachment_link.title
When I say … neurodiversity paradigm - PubMed

# data[].attributes.headline
Iatrogenic Type A Aortic Dissection Following Percutaneous Coronary Intervention

# data[].attributes.subject
Iatrogenic Type A Aortic Dissection Following Percutaneous Coronary Intervention

# data[].attributes.body
Percutaneous Coronary Intervention

# data[].attributes.headline
Carbon footprinting and sustainability impact assessment in urological surgical practice - A systematic review

# data[].attributes.subject
Carbon footprinting and sustainability impact assessment in urological surgical practice - A systematic review

# data[].attributes.attachment_link.readable_text
The .gov means it's official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

doi: 10.1177/00369330241280206.

Affiliations

1 Department Of Urology, Cardiff, and Vale University Health Board, Cardiff, UK.

2 Department of Urology, Dartford, and Gravesham NHS Trust, Dartford, UK.

3 Department of Urology, Royal Glamorgan Hospital, Llantrisant, Rhondda Cynon Taff, UK.

4 Pro Vice Chancellor Research and Innovation, University of South Wales, Pontypridd, Wales, UK.

5 School of Medicine, Centre for Medical Engineering and Technology, University of Dundee, Dundee, UK.

doi: 10.1177/00369330241280206.

Affiliations

1 Department Of Urology, Cardiff, and Vale University Health Board, Cardiff, UK.

2 Department of Urology, Dartford, and Gravesham NHS Trust, Dartford, UK.

3 Department of Urology, Royal Glamorgan Hospital, Llantrisant, Rhondda Cynon Taff, UK.

4 Pro Vice Chancellor Research and Innovation, University of South Wales, Pontypridd, Wales, UK.

5 School of Medicine, Centre for Medical Engineering and Technology, University of Dundee, Dundee, UK.

Abstract

Objectives: To systematically synthesize existing reported literature calculating the carbon footprint (CFP) of urological surgical practice and identify opportunities for improving the environmental impact of urology surgical practice.

Methods: A systematic review was performed following PRISMA guidelines. The Cochrane, Embase, Ovid MEDLINE, and PubMed were searched between 1971 and 2023, with inclusion and exclusion criteria. The outcome measures were mapped across the included studies including assessment of risk of bias.

Results: A total of 345 studies with titles were identified from an initial search, however only 5 were included. Three studies compared singleuse with reusable cystoscopes concluded that single-use cystoscopes are non-inferior to reusable cystoscopes environmentally due to the carbon footprint associated with decontamination and repackaging. Similarly, in a single study, the CFP of single-use and reusable ureteroscopes is comparable. Lastly, a single study concluded that robotics-assisted surgery in prostate cancer may be a better option than other approaches in terms of environmental sustainability.

Conclusions: In conclusion, although minimally invasive (including robotic approaches) and endoscopic surgeries offer significant opportunities to improve healthcare we do need to consider the environmental impact. However, there is a paucity of good-quality literature to guide urological surgical practice to reduce the CFP and improve sustainability.

Keywords: Carbon footprinting; sustainability; urological surgery.

PubMed Disclaimer

Conflict of interest statement

Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Similar articles

Carbon Footprint in Flexible Ureteroscopy: A Comparative Study on the Environmental Impact of Reusable and Single-Use Ureteroscopes.

Davis NF, McGrath S, Quinlan M, Jack G, Lawrentschuk N, Bolton DM. Davis NF, et al. J Endourol. 2018 Mar;32(3):214-217. doi: 10.1089/end.2018.0001. Epub 2018 Feb 21. J Endourol. 2018. PMID: 29373918

The Carbon Footprint of Surgical Operations: A Systematic Review.

Rizan C, Steinbach I, Nicholson R, Lillywhite R, Reed M, Bhutta MF. Rizan C, et al. Ann Surg. 2020 Dec;272(6):986-995. doi: 10.1097/SLA.0000000000003951. Ann Surg. 2020. PMID: 32516230

Perspectives on technology: to use or to reuse, that is the endoscopic question-a systematic review of single-use endoscopes.

Anderson S, Patterson K, Skolarikos A, Somani B, Bolton DM, Davis NF. Anderson S, et al. BJU Int. 2024 Jan;133(1):14-24. doi: 10.1111/bju.16206. Epub 2023 Nov 8. BJU Int. 2024. PMID: 37838621 Review.

Uncovering the Evidence for Sustainability in Urology: A Scoping Review.

Abdulrasheed H, Adenipekun A, Elsayed W, Mohsin MS, Madarshahian D, Almedej H, Osman B. Abdulrasheed H, et al. Urol Res Pract. 2024 Oct 21;50(3):160-166. doi: 10.5152/tud.2024.24093. Urol Res Pract. 2024. PMID: 39498946 Free PMC article. Review.

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Carbon footprinting and sustainability impact assessment in urological surgical practice - A systematic review - PubMed

# data[].attributes.attachment_link.description
In conclusion, although minimally invasive (including robotic approaches) and endoscopic surgeries offer significant opportunities to improve healthcare we do need to consider the environmental impact. However, there is a paucity of good-quality literature to guide urological surgical practice to re ...

# data[].attributes.headline
Gas Embolism Complicating Endoscopic Retrograde Cholangiopancreaticography: Case Report of a Complex Condition

# data[].attributes.subject
Gas Embolism Complicating Endoscopic Retrograde Cholangiopancreaticography: Case Report of a Complex Condition

# data[].attributes.attachment_link.title
Gas Embolism Complicating Endoscopic Retrograde Cholangiopancreaticography: Case Report of a Complex Condition

# data[].attributes.attachment_link.description
This case report explores the complex clinical trajectory of a 72-year-old female with a history of hypertension, iron-deficiency anaemia, and vertigo, who underwent an endoscopic retrograde cholangiopancreaticography (ERCP) procedure for common bile duct (CBD) stone removal. After an uneventful laparoscopic cholecystectomy, she continued to experience abdominal pain and icterus.

# data[].attributes.headline
Using disease-modifying treatments in multiple sclerosis: Association of British Neurologists (ABN) 2024 guidance

# data[].attributes.subject
Using disease-modifying treatments in multiple sclerosis: Association of British Neurologists (ABN) 2024 guidance

# data[].attributes.attachment_link.title
Using disease-modifying treatments in multiple sclerosis: Association of British Neurologists (ABN) 2024 guidance

# data[].attributes.attachment_link.description
The Association of British Neurologists last published guidelines on disease-modifying treatment (DMT) in multiple sclerosis (MS) in 2015. Since then, additional DMTs have been licensed and approved for prescribing within the National Health Service for relapsing-remitting MS, early primary progressive MS and active secondary progressive MS. This updated guidance provides a consensus-based approach to using DMTs. We provide recommendations for eligibility, starting, monitoring, switching and stopping of DMTs; pregnancy; equitable access to DMT; autologous haemopoietic stem-cell transplantation; and use of generics. We highlight best practice where it exists and discuss future priorities. No data are available.

# data[].attributes.headline
A case of SLE presenting with acute haemorrhagic longitudinally extensive transverse myelitis

# data[].attributes.subject
A case of SLE presenting with acute haemorrhagic longitudinally extensive transverse myelitis

# data[].attributes.attachment_link.provider_name
Journal of Neurology, Neurosurgery & Psychiatry

# data[].attributes.attachment_link.authors[].name
Zieda Anete, Lichtblau Nicole, Doshi Anisha, Kumar GuruDarent Valley Hospital

# data[].attributes.attachment_link.title
A case of SLE presenting with acute haemorrhagic longitudinally extensive transverse myelitis

# data[].attributes.attachment_link.description
A 54-year-old Ghanaian woman with a history of chronic back pain and sciatica presented with acute severe lower radicular pain followed by flaccid areflexic paraplegia, T9 sensory level and urinary retention. Weakness reached nadir within 3 hours of pain onset. Magnetic resonance imaging demonstrated complete cross sectional spinal cord oedema from T9 to the conus, with small foci of intramedullary haemorrhage. There was lumbosacral nerve root enhancement. Laboratory investigations revealed strongly positive ANA, Anti-Ro, and Anti- Smith antibodies in keeping with a new diagnosis of systemic lupus erythematosus (SLE). Cerebrospinal fluid showed raised protein and mild predominantly neutrophilic pleocytosis. Further assessment revealed long standing arthralgia of the feet with no signs of active inflammation on examination. There was no other organ involvement from SLE, and no other cause of LETM was identified. Transverse myelitis is a rare (0.5% to 1%) complication of SLE. Acute haemorrhagic LETM is exceedingly more uncommon, reported in only a handful of cases. Unlike typical inflammatory myelitis, it has a hyperacute onset more evocative of a vascular event and a medically refractory course. This unique case alerts neurologists to a rare presentation and also highlights the importance of detailed radiological and laboratory evaluation of such cases.

# data[].attributes.headline
CSF neurofilament light chain profiling and quantitation in neurological diseases

# data[].attributes.subject
CSF neurofilament light chain profiling and quantitation in neurological diseases

# data[].attributes.attachment_link.readable_text
Abstract

Introduction

Neurofilament light chain (NfL) is a structural protein found within large fibre myelinated axons of the human central and peripheral nervous system and is an established fluid biomarker of neuronal injury. It is released into the CSF and blood of healthy individuals, but concentrations are elevated in a range of neurodegenerative and neuroinflammatory diseases. NfL is also significantly increased in non-primary neurological diseases such as hypoxic brain injury and COVID-19. Levels change dynamically in response to acute neuronal injury in traumatic brain injury and multiple sclerosis relapses. In chronic neurodegenerative diseases, levels correlate with rates of brain atrophy and with clinical progression making it an attractive biomarker of neurodegeneration. It is now widely used for clinical diagnostic purposes (e.g. to help identify neuronal damage) and on a research basis for measuring the clinical response to disease-modifying therapies. It is frequently deployed as an outcome measure in clinical trials across a range of diseases, including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis.

NfL concentration in biofluids is currently measured using sandwich immunoassays with antibodies directed against the rod domain of the protein, for example using single-molecule array (Simoa) or enzyme-linked lectin assay (Ella). There are several limitations to these immunoassay platforms: scientific, logistic and economic. Firstly, antibody approaches are less reliable for absolute quantitation because they may miss protein oligomerization, post-translational modification, truncation and are liable to epitope masking by auto-antibodies and/or the presence of hetero-aggregates in biofluids. This is because the epitope to which the antibody binds may not be 'visible' to the antibody if it is not accessible. Secondly, the antibody is produced by commercial entities, which limits its characterization and adaptability. Finally, the antibody and assay kits are costly, which may restrict the uptake of NfL into widespread clinical practice especially as alternative tests for NfL are unavailable.

NfL has previously been characterized in CSF, identifying three main truncated species. One particular peptide that corresponds to the rod Coil 2B domain of the protein is elevated in Alzheimer's disease and is more likely to be relevant as a biomarker. It is not yet clear whether this peptide has similar relevance across the other neurological diseases. We aimed to profile NfL across a range of neurological diseases and then develop a rapid translational targeted mass spectrometry (MS) assay, using antibodies against tryptic peptides for more reliable quantitation of this particular rod domain of NfL. We aimed to compare this against the Simoa immunoassay and with an alternative independent targeted MS assay. The intended outcome was to generate a cost-effective diagnostic and reference tool that can be used across the full spectrum of neurological diseases.

Materials and methods

Participant recruitment and clinical demographics

Dementia

We prospectively recruited individuals with suspected neurodegenerative diseases from the specialist cognitive disorders clinics at the National Hospital for Neurology and Neurosurgery (NHNN), Queen Square and Darent Valley Hospital in Kent. Individuals provided consent to donate additional CSF for research prior to undergoing diagnostic lumbar puncture. Consensus criteria were used to classify individuals as probable Alzheimer's disease, behavioural variant frontotemporal dementia, dementia with Lewy bodies, corticobasal syndrome and semantic dementia. All individuals gave informed written consent (ethical permit: 12/LO/1504).

Huntington's disease

Individuals were recruited from the Huntington's disease multidisciplinary clinic at NHNN to the HD-CSF study. Expanded CAG repeat in HTT was genetically confirmed, and participants consented to research lumbar puncture. Ethical approval was provided by the London Camberwell St Giles Ethics Committee (ref: 186932).

Multiple sclerosis

Individuals were recruited from the multiple sclerosis service at the Royal London Hospital to the MS-SMART study. All individuals fulfilled clinical criteria for secondary progressive multiple sclerosis and gave consent to a research lumbar puncture at University College London (UCL). Ethical approval was provided by the Scotland A Research Ethics Committee (REC: 13/SS/0007).

Healthy controls

Controls were spouses or relatives of individuals attending the specialist cognitive disorder clinic at NHNN or who expressed an interest in research through Join Dementia Research ( www.joindementiaresearch.nihr.ac.uk). They did not have cognitive concerns and scored >27 on Mini-Mental State Examination, but CSF neurodegenerative biomarker profiles are not available. They were known not to be at risk of a genetic neurodegenerative disease. All individuals provided informed written consent. Ethical approval was given by the Hampstead Ethics Committee (ref: 19/LO/0913).

Sample collection

All CSF was collected by lumbar puncture according to local clinical standard operating procedures, in polypropylene containers between 09:00 and 15:00 and handled according to standardized predefined standard operating procedures as previously described. All CSF samples were stored at −80°C until analysis.

Simoa

CSF analysis was performed using the NF-L advantage kit with NfL concentrations measured on a Simoa HDx analyser (Quanterix). Samples were diluted 100×, and the assay performed as per the manufacturer's protocol. All samples were measured within one experiment and in singlicate with the analyst blinded to clinical status. Internal quality controls (QCs) were monitored to assess the intra-assay and inter-assay coefficients of variation (CV), which were determined to be 5.1-10.5 and 7.8%, respectively.

IP-MS for profiling of NfL (Washington University in St Louis)

Protein-level immunoprecipitation and sample preparation

As previously described, antibodies targeting Coil 1A/1B (HJ30.13), rod domain Coil 2B (HJ30.4) and tail subdomain (HJ30.11) of NfL were coupled to M270 Epoxy Dynabeads (Invitrogen) and mixed in a 1:1:1 ratio and suspended in 1× phosphate-buffered saline (PBS) to a final concentration of 15 mg/mL coupled beads. CSF samples (350 µL aliquots) were thawed and mixed with 0.5 ng of isotopically labelled internal standard ('ISTD', recombinant, ubiquitously labelled 15N-NfL, Promise Proteomics) and spiked with 25 µL of a master mix containing detergent (0.5% IGEPAL CA630), chaotropic reagent (5 mM guanidine) and 1× protease inhibitors (Roche cOmplete Protease Inhibitor Cocktail). CSF-ISTD mixes were transferred to a 96-well plate, at which point 30 µL antibody slurry was added to each sample well. Immunoprecipitation (IP) was carried out on a Kingfisher Flex Station (Thermo Scientific), which mixed CSF and antibody slurry for 90 min prior to three sequential washes of the NfL-coupled beads [25 mM triethylammonium bicarbonate (TEABC), 1 mL]. NfL-coupled beads were suspended in 100 µL TEABC (25 mM) for on-bead reduction and alkylation with dithiothreitol (50 mM DTT in 25 mM TEABC, 49 μg spike/sample, 1 h, 1000 rpm, room temperature (RT)] followed by iodoacetamide (IAA, 100 mM in 25 mM TEABC, 50 min, RT, light protected). Trypsin-Lys-C mix (Mass Spec Grade, Promega, in 25 mM TEABC) was then spiked into each sample (400 ng per sample) and incubated for 16 h at 37°C. Resultant tryptic peptides of NfL were isolated and cleaned up via solid-phase extraction (SPE; C-18 TopTip, Glygen). Stationary phase was wetted with 60% acetonitrile (ACN) and 0.1% formic acid (FA; 150 μL) and re-equilibrated with 0.1% FA (three additions of 150 μL). NfL peptides were loaded to TopTip via centrifugation (1109 x g, 2 min) and washed by adding 0.1% FA (three additions of 150 μL) to TopTip and centrifugation (1109 x g, 2 min). Peptides were eluted by adding 60% ACN and 0.1% FA (two additions of 50 μL) to TopTip and centrifugation (1109 x g, 1 min). Cleaned peptide extracts were concentrated by evaporation of eluent in vacuo and reconstituted in 25 μL 0.1% FA. Reconstituted samples were centrifuged (21 000 × g, 4°C, 15 min), and 21 μL was transferred for analysis via nano-liquid chromatography (LC)-tandem MS (MS/MS).

LC-MS/MS

Samples were injected (4.5 µL aliquot) by an M-Class nano-Acquity LC (Waters Corporation) fitted with High Strength Silica (HSS) C18 T3 analytical column (75 µm × 100 µm, 1.8 µm particle diameter). Samples were loaded on column via direct inject at 0.7 µL/min, with mobile phase composition of 99.5% A (0.1% FA) and 0.5% B (ACN, 0.1% FA) from t = 0 to 7.5 min. NfL peptides were separated at 0.4 µL/min with the following gradient: t = 7.6 min, %A: 99.5, %B: 0.5; t = 7.7 min, %A: 94, %B: 6; t = 24 min, %A: 66, %B: 34; t = 25 min, %A: 5, %B: 95; t = 26.99 min, %A: 5, %B: 95; and t = 27 min, %A: 99.5, %B: 0.5. NfL peptides were analysed in positive ion mode, spray voltage was 2.2 kV, and ion transfer tube temperature was 275°C. Parallel reaction monitoring was employed for characteristic transitions of endogenous and isotopically labelled (U-15N) NfL peptides (see Supplementary Table 1). All samples were measured with the analyst blinded to clinical status. NfL concentrations were calculated based on ratio to ISTD and reported in picograms per millilitre based on the volume of CSF used for IP.

Quantitative IP-MS/MS for NfL in CSF (University College London)

Tryptic digestion and peptide-level IP of NfL

For each sample, 450 μL of CSF was thawed and spiked with 1 ng of heavy labelled recombinant NfL (Promise Proteomics) prior to protein precipitation by addition of three sample volumes of ice-cold acetone and incubation at −20°C for 16 h. Precipitated protein was pelleted by centrifugation at 14 000 × g for 15 min at 4°C. The protein pellet was allowed to air-dry before re-solubilizing in 40 μL digest buffer (8 M urea, 200 mM Tris HCl, pH 8) for at least 30 min. Reduction and alkylation were performed with dithioerythritol (90 μg/sample) at RT with shaking at 1500 rpm for 1 h, followed by incubation with IAA (216 μg/sample) in the dark and at RT with shaking at 1500 rpm for 50 min. Samples were diluted with high-performance LC-grade ultrapure water prior to addition of MS-grade Trypsin-Lys-C to a final concentration of 2 µg/mL, and samples were digested for 16 hours at 37˚C. Post-digestion, and immediately prior to IP, all samples were spiked with 5 μL 6 mM tosyl-L-lysine chloromethyl ketone hydrochloride to inhibit Trypsin-Lys-C activity.

To provide enrichment of NfL, custom rabbit polyclonal antibodies were generated against the NfL 316-323 peptide (TLEIEACR) from the Coil 2B rod domain (Eurogentec, Belgium). Purified IgG antibodies were coupled to M270 Epoxy Dynabeads™ following the manufacturer's instructions of the Dynabeads™ Antibody coupling kit (Invitrogen). Coupled beads were resuspended in 1× PBS at 10 9 beads/mL. Fifty microlitres of antibody-coupled beads were added to each sample digest and incubated with rotation for 1.5 h at RT (20°C). The NfL-coupled beads were washed three times in 0.5 mM CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propane s ulfonate) in PBS before eluting in 50 μL 1% FA (in 0.5 mM CHAPS) with shaking at 1000 rpm for 6 min. Eluates containing the enriched NfL peptide were transferred to a 96-well sample collection plate fitted at the bottom with a magnet (SISCAPA Assay Technologies) ready for ultra-performance LC (UPLC)-MS/MS analysis.

UPLC-MS/MS

Analysis of NfL was performed on an Acquity™ I-Class PLUS UPLC coupled to a Xevo™ TQ-XS triple quadrupole mass spectrometer operated in positive electrospray ionization (ESI+) mode (Waters Corporation). Samples (15 μL) were injected onto an Acquity Premier peptide ethylene bridged hybrid (BEH) C18 analytical column (300 Å, 1.7 μm, 2.1 × 50 mm) held at 50°C. Initial mobile phase composition was set to 97% A (0.1% FA) and 3% B (ACN, 0.1% FA) at 0.2 mL/min. Chromatographic separation was performed over the following 16-min gradient: initial conditions were held until 0.2 min after which B was linearly increased to 35% by 11 min. To wash the column, B was increased to 100% over a 1-min linear gradient and held for 1.8 min at an increased flow rate of 0.6 mL/min before returning the system to initial conditions and re-equilibrating the column for 2.2 min. Mass spectrometer settings were as follows: 300°C desolvation temperature, 600 L/h desolvation gas flow, 2.5 kV capillary voltage, 150 L/h cone gas and 0.15 mL/min collision gas.

Samples were injected in a randomized order, with high and low QC samples analysed every 20 injections to monitor system performance. All samples were measured with the analyst blinded to clinical status.

All data were acquired by scheduled multiple reaction monitoring (MRM), with one quantifier and one qualifier ion monitored for each transition (see Supplementary Table 1). Raw acquisition data were imported and processed in Skyline (version 22.2, MacCoss Lab, University of Washington). Integrated peak areas and peak area ratios were exported into Microsoft Excel. NfL concentrations in picograms per millilitre were calculated based on an eight-point calibration curve as previously described.

Statistical analysis

Statistical analysis was performed in IBM Statistical Package for the Social Sciences (SPSS) Statistics (version 26) and R (version 4.2.2). Normality of the data was assessed visually by Q-Q plots and numerically by the Shapiro-Wilk or Kolmogorov-Smirnov tests where appropriate. Due to cohort ( n = 85) and disease group ( n = 6-19) size, the Spearman ranked correlation was used to assess the relationship between analytical methods for the overall cohort and within clinical diagnostic groups. To identify significant differences in NfL 316-323 (TLEIEACR) concentrations between clinical groups, non-parametric Mann-Whitney U-tests were performed.

To assess agreement between quantitative methods, IP-MS/MS (UCL) and Simoa, Bland-Altman testing was performed. The calculated differences between methods were assessed for normality, and data found to reject the null hypothesis were log transformed prior to the Bland-Altman analysis.

To evaluate and compare method performance, confusion matrix analysis was performed based on current age-related clinical cut-off values for normal CSF NfL concentrations. Actual class positive or negative assignment was based on clinical diagnosis of study participants at time of sampling as those with a neurodegenerative disease or as a healthy control, respectively. Predictive class positive or negative assignment was based on current age-related clinical cut-off concentrations for normal CSF NfL as specified in Yilmaz et al.

Results

Profiles of NfL in CSF across neurodegenerative and neuroinflammatory disease groups

To map the relative amounts of protein fragments (proteoforms) of NfL in CSF, protein-level IP-MS analysis was performed at Washington University in St Louis (WashU) with the analyst blinded to clinical status. For all clinical groups, a total of 13 NfL peptides were detected across the following structural domains: Coil 1A ( n = 3), Coil 1B ( n = 5), Coil 2B ( n = 3), C-terminal tail subdomain A ( n = 1) and tail subdomain B ( n = 1). The resulting CSF NfL profiles for healthy controls and the studied neurodegenerative and neuroinflammatory diseases are shown in Fig. 1, with the greatest detection for the neighbouring Coil 2B peptides NfL 324-331 (GMNEALEK) and NfL 316-323 (TLEIEACR) observed in all clinical groups. Some notable but subtle differences were observed at the N- and C-terminus peptides ( Fig. 1). NfL 324-331 and NfL 530-540 relative profiles by disease are shown in Supplementary Fig. 1 to determine potential qualitative differences in NfL proteolysis by pathology.

Comparison of NfL targeted MS methods to Simoa

The study cohort demographics and NfL measures across analytical assays by clinical group are summarized below in Table 1, with NfL peptide-level IP-MS/MS (UCL) and NfL protein-level IP-MS (WashU) determined by detection of the NfL 316-323 peptide (TLEIEACR).

Relative differences in mean NfL concentration across groups remained the same for all assays, with lowest-highest mean NfL concentrations observed in healthy controls, multiple sclerosis, dementia with Lewy bodies, Alzheimer's disease, semantic dementia, corticobasal syndrome, behavioural variant frontotemporal dementia and Huntington's disease ( Supplementary Fig. 2).

From all the NfL peptides measured during CSF profiling, NfL 316-323 peptide concentrations quantified by IP-MS/MS (UCL) and IP-MS (WashU) methods were found to correlate most strongly with Simoa measures, r = 0.90 ( P < 0.001) and r = 0.89 ( P < 0.001), respectively ( Fig. 2A and B). NfL 316-323 concentrations measured by the different targeted MS approaches across the study centres were also found to strongly correlate, r = 0.86 ( P < 0.001) ( Fig. 2C). Correlations between IP-MS (WashU) and Simoa for all detected NfL peptides are provided in Table 2.

To better determine the agreement between Simoa and the IP-MS/MS (UCL) method, Bland-Altman analysis was performed on log-transformed NfL concentrations ( Supplementary Fig. 3E), with limits of agreement (LoA) defined as the mean difference ± 1.96 × the standard deviation of the differences (s; Fig. 3). Visual assessment of the Bland-Altman plot suggests good agreement between IP-MS/MS (UCL) and Simoa methods. NfL concentrations measured by IP-MS/MS (UCL) were on average 59% higher than those measured by Simoa. Further comparison of all methods showed good agreement between the IP-MS/MS (UCL) and IP-MS (WashU) methods ( Supplementary Fig. 3C and D) and the IP-MS (WashU) method with Simoa ( Supplementary Fig. 3A and B).

Clinical group differences determined by Simoa are replicated by quantitative NfL316-323 IP-MS/MS (UCL)

To further assess agreement between quantitative methods, differences in NfL concentrations across clinical diagnosis groups were evaluated for IP-MS/MS (UCL) and Simoa measures ( Fig. 4). The same significant differences in NfL concentrations measured by Simoa ( Fig. 4A) and IP-MS/MS ( Fig. 4B) were observed between healthy controls and all neurodegenerative diseases, except for the multiple sclerosis group. The most significant difference in NfL concentration between healthy controls and disease was observed for the Huntington's disease group ( P < 0.0005; n = 10) for both IP-MS/MS and Simoa methods.

Spearman ranked correlation was used to assess the relationship between analytical methods within clinical diagnostic groups. We found that the correlation strength of Simoa and IP-MS/MS (UCL) methods varied by disease group ( Supplementary Fig. 4). Very strong correlations were seen in behavioural variant frontotemporal dementia ( r = 0.94, P < 2.2e −16), multiple sclerosis ( r = 0.85, P = 0.004), dementia with Lewy bodies ( r = 0.81, P = 3e −5), corticobasal syndrome ( r = 0.8, P = 0.3) and Alzheimer's disease ( r = 0.79, P = 7e −04). Strong correlations were seen in Huntington's disease ( r = 0.64, P = 0.05) and controls ( P = 0.56, P = 0.1). The weakest correlation was seen in semantic dementia ( r = 0.37, P = 0.1; slope = 0.23).

Finally, we evaluated the clinical sensitivity, specificity and positive and negative predictive values of the IP-MS/MS (UCL) assay compared to Simoa. This analysis determined the IP-MS/MS (UCL) assay to provide equivalent positive and negative predictive values as Simoa, but greater sensitivity, accuracy and precision ( Supplementary Fig. 5).

Discussion

We have characterized NfL in CSF across a range of neurodegenerative and neuroinflammatory diseases and show that the most abundant NfL peptides identifiable by MS were from Coil 2B of the protein (amino acids 281-396). Having confirmed this, we have developed a targeted MRM method (IP-MS/MS) to quantitate NfL in CSF. Our results are highly correlated with the current 'gold standard' clinically accredited Simoa immunoassay that is used in clinical research to quantitate NfL in CSF and plasma to support diagnosis and monitor disease progression.

As disease-modifying therapies are now widely used in multiple sclerosis, have recently been licenced in Alzheimer's disease, with more FDA approvals likely and are in trial in other neurodegenerative diseases, it is critically important that we have access to biomarkers that support diagnosis and can be used to monitor target engagement. We show that this novel multiplexable assay can reliably and inexpensively quantitate NfL across a broad spectrum of neurodegenerative and neuroinflammatory diseases and has similar clinical diagnostic utility.

We used a large cohort of well-characterized participants from a single specialist centre. These findings were replicated between two independent research institutions, using autonomously developed methods, in academic labs in the UK and USA. One used peptide-level IP and the other used protein-level IP, both delivering similar results. We show that the targeted IP-MS/MS method has potential for translation into a clinical assay on a MS platform that is widely available in routine clinical laboratories. Although the upfront cost of a MS is high, the test itself costs around 12 USD, making it up to 10-fold cheaper than Simoa to run and could be multiplexed with other MS assays. It could also be used to value assign reference materials in further standardization projects.

Based on previous work, we suspected that existing immunoassays bind and quantitate the rod domain of the NfL protein. We set out to establish whether the relevant abundance of this NfL species was consistent across diseases. Using in-house antibodies that bind to different regions of the NfL protein, we were able to obtain comprehensive antibody pull-down in human CSF. We show that the most abundant NfL peptides identifiable by MS were from peptides corresponding to Coil 2B of the protein (amino acids 281-396). Importantly, this region is consistently increased across neurodegenerative and neuroinflammatory diseases and controls, showing that we are likely to be measuring the same NfL species across very different diseases, at unselected stages of disease.

Although the relative concentrations of NfL were consistent between the two assays (with some exceptions, discussed below), we noted with interest a ∼2-fold increase in mean CSF NfL 316-323 concentration measured by MS compared to Simoa ( Supplementary Fig. 2), which may reflect the detection of NfL forms that are missed by Simoa. We already know that different truncations are found in CSF, and that these truncations are dimerized, making them difficult to detect by sandwich immunoassays. More specifically, it may be that most NfL species in CSF are dimers with truncated N- and C-termini; such a dimer would be quantified as one monomer using a sandwich immunoassay and two monomers using MS-based assays, potentially explaining our results.

There are few studies that directly compare protein and peptide antibody approaches for the same protein, but it has been suggested that peptide antibodies are more sensitive and specific, but with antibody efficiency being dependent on the structure of the protein or peptide in question. It is noteworthy that both approaches for purifying NfL, using either peptide or protein-level IP, delivered comparable results. This implies that NfL can, in principle, be effectively captured by either approach.

We observed some subtle disease-specific differences in correlations. The weakest correlation and notably different correlation slope between assays were observed in semantic dementia, a language-led variant of frontotemporal dementia with a strong clinicopathological correlation with TDP-43 type C pathology. This raises the possibility that the CSF pool of NfL in semantic dementia could represent different NfL truncations or different sub-populations of truncations.

We also observed some differences in peptide fold change stratification by disease state ( Fig. 1I and J). Generally, fold change ranking and stratification were consistent by disease state from Coil 1 to Coil 2 peptides (including immunoassay analogues NfL 316-323 and NfL 324-331). Mean fold change ranking by disease state was identical to a larger ELISA-based meta-analysis. Stratification and disease state fold change rank changed for C-terminal tail subdomain B peptide (NfL 530-540), where semantic dementia, corticobasal syndrome, Huntington's disease, and behavioural variant frontotemporal dementia show highest fold change (ranked third, fourth, first and second, respectively, by NfL 316-323 fold change stratification). This could imply variability in proteolysis of the tail subdomain relative to processing of Coil 2 of NfL and warrants further investigation.

A major strength of this study is that we developed a targeted method for NfL in one academic laboratory and then validated it using an independent method on a different mass spectrometer in a different institution. We used the same cohort of participants from CSF aliquots collected and handled identically. We were able to show a high level of correlation of results between centres, methods and equipment. This demonstrates that IP targeted MS is an extremely sensitive, specific and reproducible method for quantitating NfL, with potential for simple translation into validated clinical laboratories-for example, triple quadrupole platforms are found in many clinical laboratories in the UK, making it potentially translatable into clinical practice.

This study is not free from limitations. Our clinical cohorts are not demographically balanced; however, this reflects the rarity of selected conditions and the different ages at which these diseases commonly present. Methodologically, the use of different methods to report NfL concentrations between the IP-MS and IP-MS/MS assays limits the extent to which the two can be quantitatively compared.

In summary, we describe a novel assay to quantitate NfL, a widely used fluid biomarker that tracks disease activity and neurodegeneration. Our assay requires an antibody for tryptic peptide pull-down, but is less dependent on epitope visibility and other potential analytical challenges of current immunoassays such as the documented presence of auto-antibodies against neurofilaments due to their release into CSF during neurodegeneration and the masking of the epitopes of Uman antibodies used in immunoassays for NfL. Specifically, peptide-based MS assays overcome such issues due to the sample preparation pipeline prior to analysis, which utilizes trypsin to digest proteins. This makes it inherently more suitable for absolute protein quantitation as the peptides detected result from tryptic cleavage of all forms of NfL. The IP-MS/MS (UCL) method can be run rapidly in 16 min on a triple quadrupole mass spectrometer, such as those currently used in clinical practice and at a lower cost of ∼£10 (∼12 USD) per sample compared to ∼£80/sample by immunoassay. This assay could also be multiplexed with other targeted MRMs to allow quantitation of several proteins in tandem at low cost and on a high-throughput basis.

Supplementary material

Supplementary material is available at Brain Communications online.

Acknowledgements

The authors would like to thank all the study participants and those who care for them, for their time and contribution to this research. We are grateful to Prof. Simon Eaton (UCL) for his statistical expertise and to The NfL Consortium (AbbVie, Biogen, Bristol Myers Squibb and Hoffman de la Roche).

Funding

This research was supported by funding for C.A.L., J.B.C. and R.W.P. C.A.L. was supported by research funding from The Neurofilament Light Consortium and Medical Research Council. R.W.P. is supported by an Alzheimer's Association clinician scientist fellowship (AACSF-20-685780), an Alzheimer's Association Part the Cloud grant (AACSF-20-685780), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre and UK Dementia Research Institute. T.A.G. is supported by an Alzheimer's Association Research Fellowship (23AARFD-1029918). E.J.W. is supported by CHDI Foundation. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement no. 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer's Drug Discovery Foundation (#201809-2016862), the Alzheimer's Disease Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 860197 (MIRIADE), the European Union Joint Programme-Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre and the UK Dementia Research Institute (UKDRI-1003). L.M.B. is supported by the Medical Research Council (MR/W026686/1).

Competing interests

H.Z. has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). R.J.B. and R.W.P. lead The Neurofilament Light Consortium, an industry academic collaboration that is supported by AbbVie, Bristol Myers Squibb, Biogen and Roche. R.W.P. has received honoraria from GE Healthcare for educational talks, which is used to support academic work. R.J.B. has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb and Novartis. Washington University and R.J.B. have equity ownership interest in C2N Diagnostics and receive income based on technology (neurofilament light chain assays and materials) licenced by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientiﬁc advisory board. R.J.B. serves on the Roche Gantenerumab Steering Committee as an unpaid member. J.C. has received support from the Health Technology Assessment (HTA) Programme (National Institute for Health Research, NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in multiple sclerosis funded by the Multiple Sclerosis Society of Canada. A local principal investigator for commercial trials was funded by Ionis, Novartis and Roche and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. The MS-SMART trial was funded by the Efficacy and Mechanism Evaluation programme as project number 11/30/11. MS-SMART is an investigator-led project sponsored by the University College London. This independent research is awarded by and funded by the Medical Research Council, the UK MS Society and the National MS Society and is managed by the National Institute for Health Research on behalf of the Medical Research Council-National Institute for Health partnership. Additional support came from the University of Edinburgh, the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London and the National Institute for Health Research Leeds Clinical Research Facility (Dental Translational and Clinical Research Unit). Riluzole was provided without charge by Sanofi-Genzyme who was not involved in either the trial design, running of the trial or analysis. F.D.A. received speaker honoraria from Neurology Academy, Janssen, Merck, Novartis and Sanofi; is on the advisory board for Novartis and Coloplast; has received congress fees from Janssen, Merck, Novartis and Roche; and is a regional coordinator for the Oratorio Hand Trial (Hoffmann-La Roche). The rest of the authors declared no conflicting interests.

Data availability

The data sets generated during the current study are available from the corresponding author upon reasonable request.

References

Author notes

# data[].attributes.attachment_link.title
CSF neurofilament light chain profiling and quantitation in neurological diseases

# data[].attributes.attachment_link.description
Leckey et al. report a new mass spectrometry-based method to capture and quantify neurofilament light (NfL) from CSF. The assay targets a specific tryptic

# data[].attributes.headline
International Alliance of Urolithiasis (IAU) consensus on miniaturized percutaneous nephrolithotomy

# data[].attributes.subject
International Alliance of Urolithiasis (IAU) consensus on miniaturized percutaneous nephrolithotomy

# data[].attributes.attachment_link.title
International Alliance of Urolithiasis (IAU) consensus on miniaturized percutaneous nephrolithotomy - Military Medical Research

# data[].attributes.attachment_link.description
Over the past three decades, there has been increasing interest in miniaturized percutaneous nephrolithotomy (mPCNL) techniques featuring smaller tracts as they offer potential solutions to mitigate complications associated with standard PCNL (sPCNL). However, despite this growing acceptance and recognition of its benefits, unresolved controversies and acknowledged limitations continue to impede widespread adoption due to a lack of consensus on optimal perioperative management strategies and procedural tips and tricks. In response to these challenges, an international panel comprising experts from the International Alliance of Urolithiasis (IAU) took on the task of compiling an expert consensus document on mPCNL procedures aimed at providing urologists with a comprehensive clinical framework for practice. This endeavor involved conducting a systematic literature review to identify research gaps (RGs), which formed the foundation for developing a structured questionnaire survey. Subsequently, a two-round modified Delphi survey was implemented, culminating in a group meeting to generate final evidence-based comments. All 64 experts completed the second-round survey, resulting in a response rate of 100.0%. Fifty-eight key questions were raised focusing on mPCNLs within 4 main domains, including general information (13 questions), preoperative work-up (13 questions), procedural tips and tricks (19 questions), and postoperative evaluation and follow-up (13 questions). Additionally, 9 questions evaluated the experts’ experience with PCNLs. Consensus was reached on 30 questions after the second-round survey, while professional statements for the remaining 28 key questions were provided after discussion in an online panel meeting. mPCNL, characterized by a tract smaller than 18 Fr and an innovative lithotripsy technique, has firmly established itself as a viable and effective approach for managing upper urinary tract stones in both adults and pediatrics. It offers several advantages over sPCNL including reduced bleeding, fewer requirements for nephrostomy tubes, decreased pain, and shorter hospital stays. The series of detailed techniques presented here serve as a comprehensive guide for urologists, aiming to improve their procedural understanding and optimize patient outcomes.

# data[].attributes.headline
Case Series of Abdominal Actinomycosis: An Old Diagnostic Conundrum

# data[].attributes.subject
Case Series of Abdominal Actinomycosis: An Old Diagnostic Conundrum

# data[].attributes.attachment_link.title
Case Series of Abdominal Actinomycosis: An Old Diagnostic Conundrum

# data[].attributes.attachment_link.description
Abdominal actinomycosis is a rare disease caused by the Actinomyces bacteria. We report a case series of two similar cases with a mismatch between the initial differential diagnosis, the radiological findings, the surgical findings, and the actual histological result. The first case is a 25-year-old woman with a month’s history of right-sided abdominal pain. The diagnostic workup including computed tomography (CT) showed possible acute appendicitis, in addition to ascending colon looking abnormal with inflammatory changes and adjacent peritoneal nodules. A diagnostic laparoscopy revealed a normal-looking appendix and a hard mass involving the ascending colon potentially of inflammatory or malignant origin. A laparoscopic right hemicolectomy was performed. Surprisingly, the histology concluded actinomycosis. The second case is a 38-year-old woman with a six-week history of lower abdominal pain and right iliac fossa (RIF) swelling. The diagnostic workup including a CT scan showed a complex mass suggesting complicated appendicitis, pelvic inflammatory disease, or neoplastic process. Furthermore, magnetic resonance imaging (MRI) of the pelvis showed complex bilateral cystic lesions in both iliac fossas with an abscess formation within the subcutaneous fat overlying the lower pelvis. The patient underwent an ultrasound (US)-guided drainage of the subcutaneous pelvic collection and a diagnostic laparoscopy that showed an inflamed mass with dense adhesions to the anterior abdominal wall. Intraoperative biopsies were taken to confirm the diagnosis, which ultimately confirmed severe pelvic actinomycosis. Both patients were discharged home and received extended antibiotic treatment according to microbiology guidelines with good outcomes. Both cases are interesting because there was a mismatch between the initial differential diagnosis, the radiological findings, the intraoperative findings, and the final histology. Reported cases in the literature highlight the diagnostic challenges of abdominal actinomycosis, as it often presents with atypical symptoms and imaging findings sometimes mimic malignancy leading to surgical intervention.

# data[].attributes.headline
Laparoscopic renal denervation: A treatment option for management of refractory loin pain

# data[].attributes.subject
Laparoscopic renal denervation: A treatment option for management of refractory loin pain

# data[].attributes.headline
Risk Factors Associated With Negative Appendicectomy Rates: A Retrospective Cohort Study

# data[].attributes.subject
Risk Factors Associated With Negative Appendicectomy Rates: A Retrospective Cohort Study

# data[].attributes.attachment_link.title
Risk Factors Associated With Negative Appendicectomy Rates: A Retrospective Cohort Study

# data[].attributes.attachment_link.description
Background: Acute appendicitis (AA) is the most common emergency general surgical condition worldwide. Diagnosis is challenging and incorporates clinical, biochemical and radiological investigations. Our aim was to provide data from routine practice investigating widely utilised diagnostic methods from a single centre within the United Kingdom.

# data[].attributes.headline
Description and Cross-Sectional Analyses of 25,880 Adults and Children in the UK National Registry of Rare Kidney Diseases Cohort

# data[].attributes.subject
Description and Cross-Sectional Analyses of 25,880 Adults and Children in the UK National Registry of Rare Kidney Diseases Cohort

# data[].attributes.headline
Cystoscopic retrograde study using gadolinium as a contrast medium in a patient with iodinated contrast agent allergy

# data[].attributes.subject
Cystoscopic retrograde study using gadolinium as a contrast medium in a patient with iodinated contrast agent allergy

# data[].attributes.headline
Resolution of multiorgan sarcoid-like reaction after treatment of renal cell carcinoma

# data[].attributes.subject
Resolution of multiorgan sarcoid-like reaction after treatment of renal cell carcinoma

# data[].attributes.attachment_link.readable_text
Resolution of multiorgan sarcoid-like reaction after treatment of renal cell carcinoma

Abstract

Sarcoid -like reactions (SLRs) can occur in several malignancies adjacent to primary tumour location or the draining lymph nodes. The presence of peritumoural and intratumoural SLR in patients suffering from renal cell carcinoma (RCC) has been reported in few instances. However, the association of RCC with SLR in spleen, liver and other organs in the absence of systemic sarcoidosis is very rare.

We present an unusual case of a gentleman in his 30s, who presented with a lesion in the left kidney along with non-specific lesions (likely granulomatous) in liver, spleen and lungs. Partial Nnephrectomy specimen confirmed conventional/clear cell RCC. The histopathology revealed an extensive epithelioid granulomatous reaction affecting both peritumoural and intratumoural areas. Follow-up images demonstrated an almost complete resolution of lesions in the spleen, liver and lungs. Our case supports the hypothesis that non-caseating granulomas of SLR could be a manifestation of an immunologically mediated antitumour response.

Renal intervention

Cancer intervention

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center's RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Read the full text or download the PDF:

# data[].attributes.attachment_link.title
Resolution of multiorgan sarcoid-like reaction after treatment of renal cell carcinoma

# data[].attributes.attachment_link.description
Sarcoid -like reactions (SLRs) can occur in several malignancies adjacent to primary tumour location or the draining lymph nodes. The presence of peritumoural and intratumoural SLR in patients suffering from renal cell carcinoma (RCC) has been reported in few instances.

# data[].attributes.headline
Patients' Preferences for Cytoreductive Treatments in Newly Diagnosed Metastatic Prostate Cancer: The IP5-MATTER Study

# data[].attributes.subject
Patients' Preferences for Cytoreductive Treatments in Newly Diagnosed Metastatic Prostate Cancer: The IP5-MATTER Study

# data[].attributes.headline
Intracardiac diffuse large B-cell lymphoma: an unexpected diagnosis

# data[].attributes.subject
Intracardiac diffuse large B-cell lymphoma: an unexpected diagnosis

# data[].attributes.attachment_link.readable_text
Abstract

Intracardiac lymphomas are exceedingly rare accounting for only 1% of all primary cardiac tumours. Historically, due to their insidious development and non-specific clinical presentation, the diagnosis has been challenging with most cases being confirmed on post-mortem examination. Our case report details the experience of a previously fit and active woman in her 60s who presented with gradual onset exertional dyspnoea. Through a series of multimodal imaging tools (including echocardiogram, cardiac MRI, CT and positron emission tomography-CT) and biopsy, we confirmed the diagnosis of intracardiac diffuse large B-cell lymphoma. Our patient was managed with chemotherapy and went on to demonstrate excellent radiological response with near-complete resolution of the intracardiac mass. Subjectively, our patient reported significant improvement in exercise tolerance within weeks of commencing treatment.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center's RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Read the full text or download the PDF:

# data[].attributes.attachment_link.title
Intracardiac diffuse large B-cell lymphoma: an unexpected diagnosis

# data[].attributes.attachment_link.description
Intracardiac lymphomas are exceedingly rare accounting for only 1% of all primary cardiac tumours. Historically, due to their insidious development and non-specific clinical presentation, the diagnosis has been challenging with most cases being confirmed on post-mortem examination. Our case report details the experience of a previously fit and active woman in her 60s who presented with gradual onset exertional dyspnoea. Through a series of multimodal imaging tools (including echocardiogram, cardiac MRI, CT and positron emission tomography-CT) and biopsy, we confirmed the diagnosis of intracardiac diffuse large B-cell lymphoma. Our patient was managed with chemotherapy and went on to demonstrate excellent radiological response with near-complete resolution of the intracardiac mass. Subjectively, our patient reported significant improvement in exercise tolerance within weeks of commencing treatment.

# data[].attributes.headline
Global 30-Day Morbidity and Mortality of Primary Bariatric Surgery Combined with Another Procedure: The BLEND Study - Amira Said - June 2024

# data[].attributes.subject
Global 30-Day Morbidity and Mortality of Primary Bariatric Surgery Combined with Another Procedure: The BLEND Study - Amira Said - June 2024

# data[].attributes.attachment_link.readable_text
Abstract

Background

No robust data are available on the safety of primary bariatric and metabolic surgery (BMS) alone compared to primary BMS combined with other procedures.

Objectives

The objective of this study is to collect a 30-day mortality and morbidity of primary BMS combined with cholecystectomy, ventral hernia repair, or hiatal hernia repair.

Setting

This is as an international, multicenter, prospective, and observational audit of patients undergoing primary BMS combined with one or more additional procedures.

Methods

The audit took place from January 1 to June 30, 2022. A descriptive analysis was conducted. A propensity score matching analysis compared the BLEND study patients with those from the GENEVA cohort to obtain objective evaluation between combined procedures and primary BMS alone.

Results

A total of 75 centers submitted data on 1036 patients. Sleeve gastrectomy was the most commonly primary BMS ( N = 653, 63%), and hiatal hernia repair was the most commonly concomitant procedure ( N  = 447, 43.1%). RYGB accounted for the highest percentage (20.6%) of a 30-day morbidity, followed by SG (10.5%). More than one combined procedures had the highest morbidities among all combinations (17.1%). Out of overall 134 complications, 129 (96.2%) were Clavien-Dindo I-III, and 4 were CD V. Patients who underwent a primary bariatric surgery combined with another procedure had a pronounced increase in a 30-day complication rate compared with patients who underwent only BMS (12.7% vs. 7.1%).

Conclusion

Combining BMS with another procedure increases the risk of complications, but most are minor and require no further treatment. Combined procedures with primary BMS is a viable option to consider in selected patients following multi-disciplinary discussion.

Graphical Abstract

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Article Open access

References

Marzouk AMSM, Ali HOE. Laparoscopic ventral hernia repair combined with sleeve gastrectomy in morbidly obese patients: early outcomes. Surg J (N Y). 2019;05(3):e87-91. https://doi.org/10.1055/s-0039-1694979.

Article Google Scholar

von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344-9. https://doi.org/10.1016/j.jclinepi.2007.11.008.

Article Google Scholar

IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp

R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2019. https://www.R-project.org/.

Ho D, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw. 2011;42:1-28. https://doi.org/10.18637/jss.v042.i08.

Article Google Scholar

ACS National Surgical Quality Improvement Program. ACS. Accessed December 5, 2023. https://www.facs.org/quality-programs/data-and-registries/acs-nsqip/

Malaussena Z, Mhaskar R, Richmond N, et al. Hernia repair in the bariatric patient: a systematic review and meta-analysis. Surg Obes Relat Dis. Published online October 14, 2023:S1550-7289(23)00749-9. https://doi.org/10.1016/j.soard.2023.10.005

Download references

Author information

Authors and Affiliations

Department of Surgery, Duke University, Durham, NC, USA

Alessandro Martinino

University Hospitals of Derby & Burton NHS Foundation Trust, Derby, UK

Kushan D. L. Nanayakkara & Brij Madhok

Northern Clinical School, The University of Sydney, Camperdown, Australia

Geoffrey Yuet Mun Wong

Department of Surgery, Barts Health NHS Trust, Royal London Hospital, London, UK

Mohamed Abouelazayem

Internal Medicine Department, Advocate Illinois Masonic Medical Center, Chicago, IL, USA

Juan Pablo Scarano Pereira

ABVIMS & Dr.RML Hospital, New Delhi, India

Ishaan Wazir

Ysbyty Gwynedd Hospital, Bangor, Wales

Vignesh Balasubaramaniam

Department of Surgery, Darent Valley Hospital, Dartford, UK

Amira Said

Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal

Cláudia Marques

Badr Hospital - Helwan University, Cairo, Egypt

Amr Abdelbaeth, Ayman Kamal, Ahmed Mohamed Ali, Karim Mostafa Mohamed & Omnya Osama

Al-Basheer Hospital, Amman, Jordan

Khayry Al-Shami, Almu'atasim Khamees & Khaled Ahmad Sawaftah

Alfaisal University, Riyadh, Saudi Arabia

Muna Albashari

Gharyan Central Hospital, Gharyan, Libya

Akram Alkaseek

Prince Sattam Bin Abdulaziz University, Riyadh, Saudi Arabia

Mohammad Abdullah Almayouf

Aleppo Private Hospital, Aleppo, Syria

Mohammad Aloulou

King Saud University, Riyadh, Saudi Arabia

Awadh Robaan Alqahtan

Luton and Dunstable University Hospital, Luton, UK

Alan Askari & HMinali R. Perera

General Surgery Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Meena Faiez Assad Attia, Ahmed K. Awad & Amr Elgazar

Pamukkale University, Denizli, Turkey

Muhammed Rasid Aykota

Cantacuzino Clinical Hospital, Bucharest, Romania

Nicolae Bacalbasa

Christus Muguerza Hospital Sur, Monterrey, Mexico

Francisco J. Barrera-Rodriguez

Department of Bariatric and Metabolic Surgery, San Carlo of Nancy Hospital and University of Rome Tor Vergata, Rome, Italy

Domenico Benavoli, Michela Campanelli & Paolo Gentileschi

Dr. Sulaiman Alhabib Hospital, Riyadh, Saudi Arabia

Srikar Billa

IRCCS Humanitas Research Hospital, Milan, Italy

Vincenzo Borrelli, Giuseppe M. Marinari, Giovanni Piscitelli & Manuela Trotta

Çam&Sakura City Hospital, Istanbul, Turkey

İsmail Çalıkoğlu

Center of Excellence for the Study and Treatment of Obesity and Diabetes, Valladolid, Spain

Miguel A. Carbajo & David Ramírez

King Saud Medical City, Riyadh, Saudi Arabia

Sharfuddin Chowdhury

Faculty of Medicine and Surgery, University of Verona, Verona, Italy

Luca Cristin

International School Reduced Scar Laparoscopy, Humanitas Gavazzeni University Hospital, Bergamo, Italy

Giovanni Dapri

The First Affiliated Hospital of Jinan University, Guangzhou, China

Zhiyong Dong, Cunchuan Wang, Zhuoqi Wei & Wah Yang

Najjar Hospital, Beirut, Lebanon

Mohamad Hayssam Elfawal & Diyaaldeen Mohammed

Faculty of Medicine, University of Tripoli, Tripoli, Libya

Muhammed Elhadi

Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland, UK

Yitka Graham

Holy Family Hospital, Nazareth, Israel

Bassel Haj & Nasser Sakran

The Azrieli Faculty of Medicine, Bar-Ilan University, ZefatRamat Gan, Israel

Bassel Haj

Highland Hospital, University of Rochester, Rochester, NY, USA

Joseph Andrew Johnson, Anna Kamocka, William Edward O'Malley, Aaron Sabbota, Nasser Sakran & Kaci Schiavone

Al-Azhar University, Cairo, Egypt

Abd-Elfattah Morsi Kalmoush

Department of Surgery, Sant'Eugenio Hospital, Viale Dell'Umanesimo 10, Rome, Italia

Giorgio Lisi

Hospital Regional de Alta Especialidad del Bajio, León, Mexico

Edgard Efren Lozada Hernandez

Azienda Ospedaliero Universitaria Policlinico, Bari, Italy

Gennaro Martines

Bagcilar Training and Research Hospital, Istanbul, Turkey

Serhat Meric & Merve Tokocin

University of Oklahoma, Oklahoma City, USA

Fernando Mier

General University Hospital of Patras, Patras, Greece

Francesk Mulita & Georgios -Ioannis Verras

Advanced Biomedical Sciences Department, Federico II University, Naples, Italy

Mario Musella

San Marco Hospital GSD, Zingonia, Italy

Stefano Olmi & Matteo Uccelli

Azerbaijan Medical University, Baku, Azerbaijan

Taryel Omarov

Hopital Bichât, Paris, France

Tigran Poghosyan

Inova Fairoaks Hospital, Bariatric Center of Excellence, Fairfax, USA

Masoud Rezvani

Hospital Lusiadas Amadora, Amadora, Portugal

Rui Ribeiro

Nişantaşı University, Istanbul, Turkey

Ozan Şen

Evaggelismos Hospital, Athen, Greece

Maria Sotiropoulou

University of Foggia, Foggia, Italy

Nicola Tartaglia

Türkçapar Bariatrics, Istanbul, Turkey

Ahmet Gökhan Türkçapar

Hospital General Tlahuac, Mexico City, Mexico

Cesar Vargas & Carlos Zerrweck

Department of Surgery & Cancer, Imperial College London, London, UK

Eloise Owen

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK

Georgios V. Gkoutos & Victor Roth Cardoso

University Hospital Birmingham NHS Foundation Trust, West Midlands, UK

Rishi Singhal

South Tyneside and Sunderland NHS Foundation Trust, University of Sunderland, Sunderland, UK

Kamal Mahawar

Consortia

BLEND Study Collaborative Group

Corresponding author

Correspondence to Alessandro Martinino.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

KeyPoints

* Primary bariatric surgery combined with another procedure had a pronounced increase in 30-day complication rate.

* RYGB accounted for the highest percentage (20.6%) of 30-day morbidity, followed by SG (10.5%).

* More than one combined procedures had the highest morbidities among combined procedures (17.1%).

* Combined procedures with primary BMS is a viable option to consider in selected patients.

Supplementary Information

Below is the link to the electronic supplementary material.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Reprints and permissions

About this article

Cite this article

Martinino, A., Nanayakkara, K.D.L., Madhok, B. et al. Global 30-Day Morbidity and Mortality of Primary Bariatric Surgery Combined with Another Procedure: The BLEND Study. OBES SURG (2024). https://doi.org/10.1007/s11695-024-07296-0
Download citation

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

# data[].attributes.attachment_link.title
Global 30-Day Morbidity and Mortality of Primary Bariatric Surgery Combined with Another Procedure: The BLEND Study - Obesity Surgery

# data[].attributes.attachment_link.description
Background No robust data are available on the safety of primary bariatric and metabolic surgery (BMS) alone compared to primary BMS combined with other procedures. Objectives The objective of this study is to collect a 30-day mortality and morbidity of primary BMS combined with cholecystectomy, ventral hernia repair, or hiatal hernia repair.

# data[].attributes.headline
The development of the Egyptian 24-h movement guidelines for adults aged 50 years and older: an integration of sleep, sedentary behavior, and physical activity by the Egyptian Academy of Bone and Muscle Health

# data[].attributes.subject
The development of the Egyptian 24-h movement guidelines for adults aged 50 years and older: an integration of sleep, sedentary behavior, and physical activity by the Egyptian Academy of Bone and Muscle Health

# data[].attributes.attachment_link.readable_text
The development of the Egyptian 24-h movement guidelines for adults aged 50 years and older: an integration of sleep, sedentary behavior, and physical activity by the Egyptian Academy of Bone and Muscle Health

Abstract

Background

With the vision of healthy aging, the Egyptian Academy of Bone and Muscle Health followed an established guideline development process to create the Egyptian 24-h movement clinical guideline for adults aged 50 years and older adults. This guideline highlights the significance of movement behaviors across the whole 24-h day. Online databases (PubMed, Embase, and Cochrane Library) were searched for relevant peer-reviewed studies that met the a priori inclusion criteria.

Results

A total of 53 studies met the inclusion criteria. Leveraging evidence from the review of the literature led to the development of 27 statements answering the 5 key questions. Results revealed a major change in the previous basic understandings as it shifts away from focussing on a sole movement behavior to the combination of all the movement behaviors. Based on this, the final guideline was developed providing evidence-based recommendations for a "Healthy 24-Hour Day", comprising a mix of light-intensity and moderate-to-vigorous-intensity physical activity, sleep, and sedentary behavior.

Conclusion

The developed guidelines are meant to help in the decision-making process and are intended for use by adults and older both nationally and internationally; also, for endorsement by the policy-makers. Dissemination and implementation efforts would impact positively on both health professionals and researchers and would also be useful to interested members of the public sector.

Similar content being viewed by others

Article Open access

Article Open access

Article Open access

Background

Lack of physical activity has been linked to poor health and the development of various chronic illnesses with consequent potential disability in later life [ 1]. Despite these findings, it has been reported that nearly a quarter of people aged 50 years and older do less than 30 min of physical activity a week [ 2]. Musculoskeletal-wise, physical inactivity has a negative impact on both bone and muscle strength, reaction time, as well as endurance and posture. Concerning body organs, low level of physical activity is a well-known predisposing factor for several comorbidities including obesity, type II diabetes mellitus, hyperlipidemia, hypertension, coronary artery disease, stroke, and cancer particularly colon and breast cancer leading to premature death or disability [ 3]. At the supernational level, the World Health Organization (WHO) had estimated a yearly rate of two million premature deaths due to physical inactivity [ 4]. Although most of this data are from younger populations, other studies reported that this problem applies to older populations as well [ 2].

In the next Egyptian demographic transition, the number of elderly persons aged 60 + is expected to be more than twice as high between 2020 and 2050 from 8.4 million (8% of the total population) to 22 million (14%) [ 5]. In concordance with the industrial countries, a lack of physical activity has also been reported amongst Egyptian older adults. Earlier data revealed that less than 10% of the Egyptian population practice regular exercises, of them, the most inactive population were those over the age of 60 years old [ 6, 7]. The WHO report about physical activity in Egypt revealed that the prevalence of physical inactivity in Egyptian females over 70 years old was 55% whereas in men of the same age group was 35% [ 8]. Ageing is an evitable stage of life; therefore, it is important to have guidelines for physical activity which so far are not available in Egypt. With the vision of healthy aging, this work was carried out aiming to develop the Egyptian 24-h movement guidelines for adults aged 50 years and older with consideration of a balanced approach to sleep, sedentary behavior, and physical activity. These guidelines emphasize the significance of movement behaviors across the whole 24-h day.

Methodology

Study design

The framework used to develop the guidelines is consistent with the "Clinical, Evidence-based, Guidelines" (CEG) initiative protocol [ 9]. The methodology was designed to minimize bias, maximize transparency, and ensure high quality of the systematic reviews. The evidence-based component of the manuscript accommodated the preferred reporting items for systematic reviews and meta-analysis guidelines for reporting systematic reviews [ 10]. The project was an initiative led by the Egyptian Academy of Bone and Muscle Health.

Ethical aspects

This study was performed in accordance with the Helsinki Declaration. This was a multistep process that followed the "Clinical, Evidence-based, Guidelines" (CEG) initiative protocol, ethical approval code: 34842/8/21, ethical board Tanta University.

Core team

The core team provided an overview of the guideline development process, responsibilities, and timelines. The core team also drafted a set of research questions for each of the three behaviors: sleep, sedentary, and physical activity, as well as the integration of all these behaviors. The core team reached an agreement on the target Population, Intervention, Comparator and Outcomes (PICO) [ 11] (Table 1).

Literature review team

The evidence reviews were conducted by 2 experienced researchers and an expert in methodology. This depended on the identified research questions. The team addressed the gaps and generated the info for every behavior [ 12]. The articles search was carried out for the period from January 2000 till January 2024. The search keywords were identified based on different combinations of the PICO elements. Literature searches were carried out on 18th December 2023 for PubMed and Cochrane Library databases, and on 29th December 2023 for Embase. Duplicate screening of literature search results was carried out electronically. Further studies of relevance to the review were identified by an update of the review of the literature and from the lists of references of studies retrieved in the former initial database search. Recommendations regarding each section were provided by each of the experts in charge of the review of the literature, based on the evidence, when this was available, or on their own experience. The workgroup used the Oxford Centre for Evidence-based Medicine (OCEBM) system [ 13] to determine the level of evidence for each section.

Inclusion criteria

To be included in the current review, studies were required to meet the following criteria: (1) the study was published in an English-language, refereed journal with full-text availability; (2) the study contained original research (clinical guidelines, systematic reviews, randomized controlled trials (RCTs), uncontrolled trials, observational studies including cohort, case-control and cross-sectional studies); (3) the study included one or more assessment of each 24-h movement behavior, that is, physical activity, sedentary behavior and sleep; (4) to have a clearly described methodology including the PICO elements of the reviewed question.

Exclusion criteria

(1) Editorials, commentaries, conference abstracts, and non-evidence-based narrative/personal reviews were excluded; 2. Studies or clinical guidelines that referred only to admitted or hospitalized populations; 3. Studies or clinical guidelines that included populations other than adults or older adults.

Results

Review of the literature

The database systematic literature search yielded a total of 4987 relevant potential publications. Figure 1 shows the flowchart summarising the study selection process. After removing duplicates, 3813 records remained. After screening the titles and abstracts, 99 potentially relevant citations were obtained for full-text review. Of those, after completing the reading 51 studies met the inclusion criteria. Two additional citations relevant to this work were identified following an up-to-date search and those retrieved from the bibliography of the included articles. Therefore, a total of 53 studies published met the eligibility criteria and consequently were included in this work. These included nine clinical guidelines: WHO [ 14] (World Health Organization, 2010), USA [ 15] (Department of Health and Human Services, 2018), Canada [ 16] (Canadian Society for Exercise Physiology, 2011), Germany [ 17], United Kingdom-UK [ 18] (Department of Health, Physical Activity, Health Improvement and Protection, 2011), Australia [ 19], the Netherlands [ 20], New Zealand (Ministry of Health, 2013) [ 21] and India [ 22].

Flow chart for the literature review and study selection process

Targeted population and guidelines development process

The targeted population included adults aged 50 years and older. The Egyptian Academy of Bone and Muscle Health was the organizing body. The professionals involved were experts in rehabilitation medicine, physical activity and health promotion, epidemiology, guidelines development, psychology as well as fall prevention. Consensus was achieved following multiple online meetings followed by online comprehensive feedback.

Results of the systematic review

The exercise prescription

This guideline provides evidence-based public health physical activity programs constructed in a systematic and individualized style in terms of frequency, intensity, time, type, volume, and progression that offer significant health benefits and mitigate health risks. This has been identified as the FITT-VP formula or principle. The FITT is a good approach to monitor the individual person's exercise program and progression. The parameters of the exercise prescription are shown in Table 2.

Baseline assessment and goal setting

The initial step to implement changes in the subject's physical activity is best predicted by evaluating the person's baseline activities and readiness to change. This should be carried out using an evidence-informed model with the goal of identifying: (1) the current level of exercise, (2) the presence or absence of asymptomatic/symptomatic known disease, and (3) desired intensity of exercise. Subsequently, the healthcare professional should educate the individual about the benefits of physical activity, changing some of the current behaviors, and motivate him/her with relevant personal goals, such as improving physical function or strength, balance, preventing falls, management of weight, improving chronic disease management, and preventing falls. Consequently, the individual should be able to agree with the healthcare professional on an initial set of achievable goals. Table 3 shows the developed Arabic Sedentary, Activity, Sleep Assessment (SASA) questionnaire, and associated explanatory figures for the assessment and monitoring of the exercise level of the individual subject (Supplement 1 shows the English copy of the SASA questionnaire).

Statements

Guided by the key questions, the systematic review was carried out to identify the effects of the 4 behaviors on the identified health outcomes. These are summarized in Table 4.

The Egyptian 24-h movement guidelines

Considering the overall health benefits, adults aged 50 years and older should be physically active every day, ensure sufficient sleep, and minimize sedentary behavior. Greater health benefits can be achieved by replacing sedentary behavior with extra physical activity and trading light physical activity for more moderate to vigorous physical activity, whilst continuing to have adequate sleep.

Overarching principles

All persons 50 years and above should keep moving/physically active as much and as frequently as possible. They should practice physical exercises on a regular basis at least 5 days a week.

Exercise programs should be customized to the individual's needs. No common exercise program can fit all.

Individual's medical and physical status are considerable factors in choosing the parameters of the adopted exercise program.

The heavier the exercise level, the greater the benefit. However, light-moderate physical activity is better than nothing.

Benefits of physical activity included a reduced risk of falling and the potential to develop a fracture; also reduced risk of several chronic health conditions, provides longer healthy life span, improved quality of life, and reduced overall mortality rate.

Sedentary behavior in the elderly is the biggest opponent of healthy aging.

Whenever appropriate, daily physical activity is advised.

Baseline assessments for functional ability, quality of life, sarcopenia, and falls risk are important and should be carried out for every older adult.

The physical activity programs are dynamic and progressive in nature, including exercises with a progressive intensity focusing on daily mobility routine with a flexible frequency.

Gradual increase in physical activity is the safest method for minimizing the risk of injury. The optimum approach is to start with moderate-intensity activities, with a progressive increase first in terms of activity duration, then in frequency, and finally in intensity. This would lead to increased benefits with a low incidence of side effects.

Physically inactive people but otherwise healthy and asymptomatic may start with light- to moderate-intensity exercise. In the absence of symptoms, they should progress gradually as advised by the exercise prescription guidelines.

Progression of physical activity over time is not only important for more health benefits but also for motivation and adherence.

Active older adults may engage in physical activities beyond the identified thresholds.

Consulting an experienced healthcare professional/practitioner is advisable before increasing the physical load is recommended for healthy older adults.

Multicomponent physical activities integrating many types of exercises (strengthening, endurance, and balance exercises) are advised.

Injuries and adverse effects during all forms of physical activity are negligible, however appropriate safety practices must be ensured.

Structured and group-based intervention/rehabilitation is advised for improving motivation, reducing cost, understaffing, and improving long-term adherence.

The guidelines and physical activities advised should be promoted at several levels individual, family, community, caregivers, technology, and policymakers.

No current recommendations support the use of personal devices such as wearables

Guidelines

To achieve a healthy 24-h, adults aged 50 years or older should:

General elderly population

1.
Physical activity

1.1 Aerobic training:

Thirty to 60 min a day of moderate-intensity aerobic activity at least 5 days/week; or

Fifteen to 30 min a day of high-intensity aerobic activity at least 5 days/week; or

an equivalent mix of moderate- and high-intensity aerobic workouts all around the week.

1.2 Resistance training:

Non-consecutive 2 to 3 days a week of resistance training should be recommended.

Each exercise should include 2-3 sets of resistance exercises working on multi-joint exercises per major muscle group and of intensity equal to 70-85% of 1 repetition maximum (1RM).

Performing the muscle strengthening exercises in the positions and forms of real-life daily activity movements is prescribed as functional strengthening exercises. This type of exercise is recommended as well as regular strengthening exercises.

1.3 Balance training:

2.
Sedentary behavior:

All adults including older adults are advised to decrease their sedentary time and push their bodies to move as frequently as possible; therefore, the individual should:

3.
Sleep:

4.
Integrated behavior:

All adults and older adults are advised to practice regular frequent multicomponent physical training exercise that involves a combination of aerobic, strengthening, and balance exercises in different levels of intensity. This is besides decreasing the inactive time and ensuring good sleep quality.

Elderly people with special conditions

1.
People with chronic conditions

Among older adults, chronic comorbidities and illnesses such as cancer, obesity, diabetes, cardiovascular, hyperlipidemia, and arthritis are the leading causes of death and/or disability among older adults [ 35]. There is no direct evidence of specific sedentary behavior for these subpopulations. Hence, the evidence for sedentary behavior recommendations for general populations remains applicable to them [ 14]. On the other hand, special precautions should be considered when offering an exercise prescription for those patients with chronic conditions. Table 5 shows the suggested exercise prescription modifications and special considerations and physical activity recommendations for patients with specific medical conditions.

2.
Patients at high risk of fragility fracture

Strict caution should be practiced when prescribing moderate (e.g., running, racquet sports, skipping) or high (e.g., drop or high vertical jumps) impact exercise for these patients.

Safety or efficacy is questionable in individuals with a history of fractured vertebrae or Major osteoporotic fracture FRAX score of 15% calculated by the Egyptian FRAX.

The most dangerous movements especially for those with vertebral fracture are those that entail flexion and twisting of the spine or rapid, repetitive, sustained, weighted, or end range of motion

3.
Frail adults/older adults

Multicomponent exercise program including progressive resistance training works well for frailty fighting.

Before prescribing the exercise dose, measuring aerobic fitness by cardiopulmonary exercise testing is recommended to determine exercise tolerance.

Progression or regression of exercise intensity is dependent on the person's tolerance and general condition is recommended according to the person's tolerance and health condition.

Resistance training has better results if accompanied by the intake of the proper amount of protein.

Specific structured exercise programs such as modified tai chi or certain types of yoga could prevent injury from falls.

Supervised, group-based exercising protocols are advised as they may enhance motivation and adherence

Homed-based and even bedside exercises are possible options to promote physical activity in very frail old adults.

Table 6 shows a summary, with examples of the Egyptian "Healthy 24-Hour" movement guideline.

Discussion

Preceded only by tobacco use, hypertension, and high blood glucose levels, physical inactivity was categorized as the fourth leading risk factor for noncommunicable diseases [ 36, 37], triggering about 41 million deaths annually (correspondent to 74% of all deaths globally) [ 38]. New research studies recommend that the structure of movement behaviors within a 24-h period may have a strong effect on health across the lifespan. Consistent with this paradigm of integrated movement behavior, the WHO as well as several countries across the world have developed "24-h movement guidelines" for different age groups. The purpose of this work was to develop "the Egyptian 24-h movement guidelines" for adults 50 years and older. This document is proposed for use by policymakers, health professionals, researchers, and interested individuals. Figure 2 shows the logo of the proposed national campaign. This 24-h movement guideline is relevant to all Egyptians aged 50 years or older, irrespective of gender, socio-economic status, or cultural background. The guideline development process adhered to the "Clinical, Evidence-based, Guideline" framework used to develop previous national guidelines in Egypt [ 9].

The logo of the proposed national campaign in Egypt: Movement is a blessing "الحركه بركه" composed of 4 s (strong, step, sit, and sleep)

The principal concept of the developed 24-h movement guideline is that the structure of all movement behaviors throughout the day is strongly correlated to the individual's health, and delivers exclusive, evidence-based opportunities to participate in movement behavior integrations that meet the individual's requirements and personal preferences. This comes in agreement with the previously published 24-h guidelines published by the WHO and 8 other health authorities worldwide [ 14, 15, 17, 18, 19, 20, 21, 22]. This paradigm represents a major change in the previous basic understandings, as it shifts away from focussing on a sole movement behavior to the combination of all the movement behaviors. In turn, this endorses the growing body of evidence advocating that the mix of movement behaviors over a 24-h day impacts a wide range of health outcomes [ 39, 40, 41, 42].

The disengagement from any form of physical activity is not only prevalent in Egypt. In fact, it is an international challenge. Whilst 35% of older adult men and 55% of women have been reported as physically inactive, more than 40% of the adult European population do not engage in any form of physical activity, and only 8% regularly exercise [ 43]. Sedentary behavior and physical inactivity are directly linked to increased prevalence of cardiovascular disease [ 44], obesity, diabetes [ 45], and autoimmune rheumatic diseases [ 46]. WHO data [ 8] indicate that 86% of deaths in Egypt are due to non-communicable diseases (NCDs) mortality, with cardiovascular disease followed by cancer being the main causes on top of the list. This highlights the importance of having a national 24-h movement guideline in Egypt, particularly, increasing levels of physical activity have been reported as a catalyst in the reduction of the above consequences.

In concordance with the earlier published guidelines [ 5, 29], the developed Egyptian 24-h movement guideline, revealed similar physical activity components for both adults and older adult age groups. Demographic data from Egypt reveal that life expectancy at birth for men is 68.5 years whereas for women it is 73.2 years. Results of a recent study in Egypt revealed that patients aged 50 years and older are at higher risk of falling and sustaining a fragility fracture [ 47]. This was the reason for including Egyptian adults aged 50 years and older in this guideline. However, this guideline may not be appropriate for adults aged 50 years or older living with a disability or a medical condition; these individuals should seek advice from their treating health professional for guidance. The guidelines are meant to help in the decision-making process but do not clarify all uncertainties of patient care. Although adopting this guideline can be challenging at times; progressing towards any of the targets identified in this guideline will result in some health benefits.

These guidelines stated that enhancing physical activities among adults and older adults should be promoted at different levels. This can be at the individual level, based on instinct-individual motivation; or community-based (families, friends, caregivers, policy-makers), or health professionals (individually or in small groups in generic or tailored exercise regimen) to technology (devices that assess activity, e-health or m-health solutions, mixed reality platform for increasing motivation). A logo (Fig. 2) has been developed by the Egyptian Academy of Bone and Muscle Health to spread the word and enhance the involvement of Egyptian adults and older adults at a national level. Evidence-based strategies could enhance adherence and monitoring could facilitate success.

In conclusion, there is a large body of evidence for the benefits of physical activities for healthy aging, and this is expressed in the development of several guidelines for different health conditions that stress the importance of incorporating physical activities for adults and older adults. This is endorsed by the fact that promoting physical activity, particularly in older adults could be more beneficial as health gains could come faster than in other age groups. physical inactivity results in limitations in body functioning and mobility and reduces the opportunity for independent living in later life. Physical activity in both adults and older adults, regardless of chronic disease, was reported to be associated with delayed physical disability and the maintenance of independent living. The developed Egyptian 24-h movement guideline endorses the recommendations for physical activity, sedentary behavior, and sleep which should be combined into a single public health domain that incorporates movement across the full 24-h day. A national campaign should be launched under the title "Moving more make your life matter".

Availability of data and materials

Available upon reasonable request.

Abbreviations

BMD:

Bone mineral density

FRAX:

Fracture Risk Assessment

NCDs:

Non-communicable diseases

PICO:

Population, Intervention, Comparator and Outcomes

RCT:

Randomized controlled trials

WHO:

World Health Organization

References

Warburton DE, Nicol C, Bredin SS (2006) Health benefits of physical activity: the evidence. Can Med Assoc J 174:801-809. https://doi.org/10.1503/cmaj.051351

Article Google Scholar

Luo L, Cao Y, Hu Y, Wen S, Tang K, Ding L, Song N (2022) The associations between meeting 24-Hour Movement Guidelines (24-HMG) and self-rated physical and mental health in older adults-cross sectional evidence from China. Int J Environ Res Public Health 19(20):13407. https://doi.org/10.3390/ijerph192013407

The rights and wellbeing of older persons in Egypt. https://arabstates.unfpa.org/sites/default/files/pub-pdf/country_profile_-_egypt_27-10-2021_0.pdf Accessed on 7 Mar 2024

El Miedany Y, Mahran S, Elwakil W (2023) One musculoskeletal health: towards optimizing musculoskeletal health in Egypt-how to be a bone and muscle builder by the Egyptian Academy of Bone Health and Metabolic Bone Diseases. Egypt Rheumatol Rehabil 50:33. https://doi.org/10.1186/s43166-023-00199-5

Article Google Scholar

Abdelkawy K, Elbarbry F, El-Masry SM, Zakaria AY, Rodríguez-Pérez C, El-Khodary NM (2023) Changes in dietary habits during Covid-19 lockdown in Egypt: the Egyptian COVIDiet study. BMC Public Health 23(1):956. https://doi.org/10.1186/s12889-023-15777-7

WHO report on physical activity profile in Egypt (2022) https://cdn.who.int/media/docs/default-source/country-profiles/physical-activity/physical-activity-egy-2022-country-profile.pdf?sfvrsn=50db9547_5&download=true. Accessed on 7 Mar 2024

El Miedany Y, Abu-Zaid MH, El Gaafary M et al (2022) Egyptian guidelines for the treatment of Rheumatoid Arthritis - 2022 update. Egypt Rheumatol Rehabil 49:56. https://doi.org/10.1186/s43166-022-00153-x

Article Google Scholar

Schardt C, Adams MB, Owens T, Keitz S, Fontelo P (2007) Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak 2007(7):16

Article Google Scholar

OCEBM Levels of Evidence Working Group (2011) The Oxford levels of evidence 2. Oxford Centre for Evidence-Based Medicine, Oxford, UK

Google Scholar

Physical Activity (2018) Guidelines for Americans, 2nd edition. U.S. Department of Health and Human Services. Physical Activity Guidelines for Americans, 2nd edition. Washington, DC: U.S. Department of Health and Human Services; https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf. Accessed 30 April 2024

Canadian Society for Exercise Physiology (2011) Canadian Physical Activity Guidelines and Canadian Sedentary Behaviour Guidelines. http://www.csep.ca/en/guidelines/read-the-guidelines

Rütten A & Pfeifer K (2016) National Recommendations for Physical Activity and Physical Activity Promotion FAU University Press. https://opus4.kobv.de/opus4-fau/home

Department of Health, Physical Activity, Health Improvement and Protection Start Active, Stay Active:A report on physical activity from the four home countries'Chief Medical Officers. London: Department of Health, Physical Activity, Health Improvement and Protection; 2011. https://www.sportengland.org/media/2928/dh_128210.pdf

Brown WJ, Moorhead GE, Marshall AL (2005) Choose Health:Be Active:a physical activity guide for older Australians. Commonwealth of Australia and the Repatriation Commission, Canberra

Google Scholar

Weggemans RM, Backx FJG, Borghouts L, Chinapaw M, Hopman MTE, Koster A et al (2018) Committee Dutch Physical Activity Guidelines 2017. The 2017 Dutch Physical Activity Guidelines. Int J BehavNutr Phys Act 15(1):58

Article Google Scholar

Ministry of Health Guidelines on Physical Activity for Older People (aged 65 years and over) Wellington: Ministry of Health; 2013. https://www.health.govt.nz/publication/guidelines-physical-activity-older-people-aged-65-years-and-over.

Misra A, Nigam P, Hills AP, Chadha DS, Sharma V, Deepak KK et al (2012) Physical Activity Consensus Group. Consensus physical activity guidelines for Asian Indians. Diabetes TechnolTher 14(1):83-98

Article Google Scholar

El-Kotob, R., Ponzano, M., Chaput, J.-P., Janssen, I., Kho, M.E., Poitras, V.J., et al. (2020) Resistance training and health in adults: an overview of systematic reviews. Appl. Physiol. Nutr. Metab. 45(10 Suppl. 2): this issue. https://doi.org/10.1139/apnm-2020-0245

Ross R, Chaput JP, Giangregorio LM, Janssen I, Saunders TJ, Kho ME, Poitras VJ, Tomasone JR, El-Kotob R, McLaughlin EC, Duggan M, Carrier J, Carson V, Chastin SF, Latimer-Cheung AE, Chulak-Bozzer T, Faulkner G, Flood SM, Gazendam MK, Healy GN, Katzmarzyk PT, Kennedy W, Lane KN, Lorbergs A, Maclaren K, Marr S, Powell KE, Rhodes RE, Ross-White A, Welsh F, Willumsen J, Tremblay MS (2020) Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older: an integration of physical activity, sedentary behaviour, and sleep. Appl Physiol Nutr Metab 45(10 (Suppl. 2):S57-S102. https://doi.org/10.1139/apnm-2020-0467

Sherrington C, Fairhall NJ, Wallbank GK, Tiedemann A, Michaleff ZA, Howard K et al (2019) New Cochrane review assesses the benefits and harms of exercise for preventing fall s in older people living in the community. Saudi Med J 40(2):204-205

Google Scholar

2018 Physical Activity Guidelines Advisory Committee (2018) 2018 Physical Activity Guidelines Advisory Committee Scientific Report, Washington, DC, USA. https://health.gov/sites/default/files/2019-09/PAG_Advisory_Committee_Report.pdf Accessed on 8 Mar 2024

Chaput JP, Dutil C, Featherstone R, Ross R, Giangregorio LM, Saunders TJ et al. (2020) Sleep duration and health in adults: an overview of systematic reviews. Appl. Physiol. Nutr. Metab 45(10 Suppl. 2). https://doi.org/10.1139/apnm-2020-0034

Janssen I, Clarke AE, Carson V, Chaput JP, Giangregorio LM, Kho ME, et al. (2020) A systematic review of compositional data analysis studies examining associations between sleep, sedentary behaviour, and physical activity with health outcomes in adults. Appl. Physiol. Nutr. Metab 45(10 Suppl. 2): https://doi.org/10.1139/apnm-2020-0160

Kochanek KD, Murphy SL, Xu J, Arias E (2014) Mortality in the United States, 2013. NCHS Data Brief 178:1-8

Google Scholar

WHO. Global status report on noncommunicable diseases (2014) World Health Organization. https://www.who.int/publications/i/item/9789241564854. Accessed 9 Mar 2024

World Health Organization (‎2009)‎ Global health risks : mortality and burden of disease attributable to selected major risks. World Health Organization. https://iris.who.int/handle/10665/44203. Accessed 9 March 2024

WHO. Physical activity. https://www.who.int/news-room/fact-sheets/detail/physical-activity Accessed on 9 Mar 2024

McGregor DE, Carson V, Palarea-Albaladejo J, Dall PM, Tremblay MS, Chastin SFM (2018) Compositional analysis of the associations between 24-h movement behaviours and health indicators among adults and older adults from the Canadian health measure survey. Int J Environ Res Publ Health 15(8):1779

Article Google Scholar

Nikitas C, Kikidis D, Bibas A, Pavlou M, Zachou Z, Bamiou DE (2022) Recommendations for physical activity in the elderly population: a scoping review of guidelines. J Frailty Sarcopenia Falls 7(1):18-28. https://doi.org/10.22540/JFSF-07-018

(2014) European Commmision Eurobarometer on Sport and Physical Activity. Brussels. http://europa.eu/rapid/press-release_MEMO-14-207_el.htm

Download references

Funding

All authors declare that they did not receive any kind of funding.

Author information

Authors and Affiliations

Canterbury Christ Church University, Canterbury, England, UK

Yasser El Miedany

Darent Valley Hospital, Kent, England

Mathias Toth

Institute of Medical Science, Canterbury Christ Church University, Canterbury, UK

Susan Plummer

Community and Public Health, Ain Shams University, Cairo, Egypt

Maha El Gaafary

Physical Medicine, Rheumatology and Rehabilitation, Assiut University, Assiut, Egypt

Safaa Mahran

Lecturer Physical Medicine, Rheumatology and Rehabilitation, Alexandria University, Alexandria University, Alexandria, Egypt

Walaa Elwakil

H. senior Clinical Lecturer, King's college, London, United Kingdom

Mathias Toth

Contributions

All the authors contributed to the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yasser El Miedany.

Ethics declarations

Ethics approval and consent to participate

The Clinical, Evidence-based, Guidelines (CEG) initiative protocol was approved by the local ethical committee. Ethical approval code: 34842/8/21, ethical board Tanta University.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

Prof. Safaa Mahran and Yasser El Miedany are from the editorial board of the journal. All other authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Supplement 1. Self-reported sedentary, physical activity and sleep quality assessment questionnaire for the evaluation and monitoring of the exercise level of the individual person.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Reprints and permissions

About this article

Cite this article

El Miedany, Y., Toth, M., Plummer, S. et al. The development of the Egyptian 24-h movement guidelines for adults aged 50 years and older: an integration of sleep, sedentary behavior, and physical activity by the Egyptian Academy of Bone and Muscle Health. Egypt Rheumatol Rehabil 51, 31 (2024). https://doi.org/10.1186/s43166-024-00259-4
Download citation

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

# data[].attributes.attachment_link.title
The development of the Egyptian 24-h movement guidelines for adults aged 50 years and older: an integration of sleep, sedentary behavior, and physical activity by the Egyptian Academy of Bone and Muscle Health - Egyptian Rheumatology and Rehabilitation

# data[].attributes.attachment_link.description
Background With the vision of healthy aging, the Egyptian Academy of Bone and Muscle Health followed an established guideline development process to create the Egyptian 24-h movement clinical guideline for adults aged 50 years and older adults. This guideline highlights the significance of movement behaviors across the whole 24-h day.

# data[].attributes.headline
Prostatic stents: a narrative review of current evidence

# data[].attributes.subject
Prostatic stents: a narrative review of current evidence

# data[].attributes.headline
Prevalence of Prehypertension, Hypertension, and its Determinants Among Young Adults in Enugu State, Nigeria.

# data[].attributes.subject
Prevalence of Prehypertension, Hypertension, and its Determinants Among Young Adults in Enugu State, Nigeria.

# data[].attributes.attachment_link.readable_text
Main Article Content

Obinna C Nwoke

Department of Pharmacology and Therapeutics, Faculty of Medical Sciences, College of Medicine, University of Nigeria, Nsukka, Nigeria

Department of Pharmacology and Therapeutics, Faculty of Medical Sciences, College of Medicine, University of Nigeria, Nsukka, Nigeria.

Acute Medicine Department, Darent Valley Hospital, Dartford, United Kingdom

Ndubuisi Hospital and Maternity, Achara Road, Nsukka, Enugu State, Nigeria

Department od Medical Laboratory Sciences, Faculty of Health Sciences and Technology, College of Medicine, University of Nigeria, Nsukka, Nigeria.

Department of Pharmacology and Therapeutics, Faculty of Medical Sciences, College of Medicine, University of Nigeria, Nsukka, Nigeria

Keywords

Prehypertension, Hypertension, Medical Students, Risk Factors, Blood Pressure

Abstract

Background: Emerging epidemiological data suggest that Hypertension (HTN) has become a significant public health challenge in sub-Saharan Africa. HTN in young adults is a problem lacking relevant attention because it is still erroneously considered a disease of the old. This study aimed to determine the prevalence of hypertension and its associated risk factors in undergraduate medical students at the University of Nigeria, Enugu Campus, Enugu State, Nigeria.
Methodology: This was a cross-sectional study conducted between March and April 2021. This study recruited 279 consenting medical students (136 males and 143 females) aged 18-35 years. They were administered with a structured questionnaire. Data on sociodemographic information and risk factors for hypertension were collected. Blood pressure, waist circumference, weight, height, and body mass index were measured using standard methods. All data collected were carried out following the Institutional ethical guidelines and that of the Helsinki as revised in 2000. Data were analyzed using IBM Statistical Package for Social Sciences version 25, and statistical tools employed include descriptive statistics and Chi tests. Results were recorded as mean standard deviation, and statistical significance was taken at p<0.05. Results: This present study has shown a prevalence rate of 19.93% for hypertension. Isolated diastolic hypertension constituted a greater burden with a prevalence of 13.65% than systolic Hypertension (0.74%) and systolic-diastolic Hypertension 5.4%. The prevalence of prehypertension was 48.7%, with a higher incidence observed in females (25.8%), individuals aged 21-25 years (26.4), and those with normal BMI (35.1%). A significant association was observed between the stage of hypertension and gender (p = 0.005), and age category (p = 0.037). Of the examined cohort, 7.75% were underweight, 16.5% overweight, and 2.2% obese. Notably, systolic, and diastolic blood pressure, weight, as well as waist circumference showed significant (p = 0.01, p = 0.007, p =0.01 and p<0.0001 respectively) increases concomitant with advancing age.
Conclusion: There is an increased prevalence of prehypertension and hypertension among young adults. This calls for a comprehensive national screening, public enlightenment, and targeted prevention programs that foster healthy lifestyle behaviours, physical activity, and healthy eating among students

Abstract 1 | PDF Downloads 0

References

1. Chijioke C, Anakwue R, Okolo T, Ekwe E, Eze C, Agunyenwa C, Nwosu N, amah C, Nwadike K, Chijioke U. Awareness, treatment, and control of hypertension in primary health care and secondary referral medical outpatient clinic settings at Enugu, Southeast Nigeria. Inter. J. Hypertens.2016: 1-5. http://dx.doi.org/10.1155/2016/5628453.
2. Nwaneli CU, Omejua EG. Clinical presentation and aetiology of hypertension in young adults in Nnewi South East Nigeria. AFRIMEDIC Journal 2010:1(1):24-6.
3. Choi J, Oh C, Shim SJS, Kim HS and Kim M. Reduction in prevalence of hypertension and blood heavy metals among curry-consumed Korean. TJEM.2018: 244:219-29.
4. Pawliczak F, Bielecka-Dabrowa A, Maciejewski M, Banach M. Treating mild hypertension in young adults: is pharmacotherapy necessary? Exp Opi on Pharmaco.2020: 21(10):1115-8.
5. Xu J, White AJ, Niehoff NM, O'Brien M, Sandler DP. Airborne metals exposure and risk of hypertension in the Sister Study. Environ Res. 2020:119: 110144
6. Odili AN, Chori BS, Danladi B, Nwakile PC, Okoye IC, Abdullah U, et al. Prevalence, Awareness, Treatment and Control of Hypertension in Nigeria: Data from a Nationwide Survey 2017. Glob. Heart; 2020;15(1):47.
7. Banigbe BF, Itanyi IU, Ofili EO, Ogidi AG, Patel D, Ezeanolue EE. High prevalence of undiagnosed hypertension among men in North Central Nigera: Results from the Healthy beginning Initiative. PLoS One 2020;15 (11): e0242870. 1-15.
8. Oguanobi NI, Ejim ECE, Onwubere BJB, Ike SOS, Anisiuba BBC, Ikeh VVO, et al. Pattern of cardiovascular disease amongst medical admissions in a regional teaching hospital in Southeastern Nigeria. Nigerian Journal of Cardiology. 2013;10:77-80. https://doi.org/10.4103/0189-7969.127005.
9. Okubadejo NU, Ozoh OB, Ojo OO, Akinkugbe AO, Odeniyi IA, Adegoke O, Bello BT, Agabi OP (2019). Prevalence of hypertension and blood pressure profile amongst urban-dwelling adults in Nigeria: a comparative analysis based on recent guideline recommendations. Clin Hypertens 2019;25:7. https://doi.org/10.1186/s40885-019-0112-
10. Umegbolu EI, Ogamba JO. Primary hypertension in young adults (18-40 years) in Enugu State, Southeast Nigeria: a cross-sectional study. IJCMPH 2016; 3(10):2825-31.
11. Hinton TC, Adams ZH, Baker RP, Hope KA, Paton JFR, Hart EC, Nightingale AK. Investigation and treatment of high blood pressure in young people. Too much medicine or appropriate risk reduction? Hypertension. 2020; 75:16-22.
12. Ujunwa AF, Ikefuna NA, Nwokocha RCA, Chinawa MJ. Hypertentsion and prehypertension among adolescents in secondary schools in Enugu, South East Nigeria. Ital. J Pediatr.2013; 39(70):1-6.
13. Ezeudu CE, Chukwuka JO, Ebenebe JC, Igwe WC, Egbuonu I. Hypertension and prehypertension among adolescents attending secondary schools in urban area of South- East, Nigeria. PAMJ. 2018;31(145): 1-9.
14. Ugochukwu EF, Onubogu CU, Ofora VC, Okeke KN, Uju CM. Blood pressure profiles and determinants of hypertension among public secondary school students in Nnewi, Southeast Nigeria. EJMED. 2020;2(3): 1-7.
15. Jones SWE, Esack I, Mangena P, Rayner LB. Hypertension in adolescents and young adults referred to a tertiary hypertension clinic in cape Town, South Africa. Medicine.2020; 99(48): 1-5.
16. Liu X, Xiang Z, Shi X, Schenck H, Yi X, Ni R, Liu C. The risk factors of high blood pressure among youg adults in the Tujia-Nationality settlement of China. Biomed. Res. Int. 2017: 1-6.
17. Dahiru T, Aliyu A, Kene TS. Statistics in medical research: Misuse of sampling and sample size determination. Ann. Afri. Med.. 2006; 5(3):158-61.
18. Onwubere BJC, Ejim EC, Okafor CI, Emehel A, Mbah AU, Onyia U, Mendis S. Pattern of blood pressure indices among the residents of a rural community in South East Nigeria. Int. J. Hypertens 2011:ID 621074. 1-6. Doi:10.4061/2011/621074.
19. Donato KA. Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch. Intern. Med. 1998; 158:1855-67.
20. Chobanian AV, Bakris GL, Black H.R, Cushman WC, Green LA, Izzo J.L, et al . The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA .2003; 289:2560-72.
21. Peters JL, Fabian MP, Levy JI. Epidemiologically-informed cumulative risk hypertension models simulating the impact of changes in metal, organochlorine, and non-chemical exposures in an environmental justice community. Environ Res. 2019;176:108544.
22. Adeloye D, Owolabi EO, Ojji DB, Auta A, Dewan MT, Olanrewaju TO, et al. Prevalence, awareness, treatment, and control of hypertension in Nigeria in 1995 and 2020: A systematic analysis of current evidence. J Clin Hypertens (Greenwich). 2021 May;23(5):963-977.
23. Ondimu DO, Kikuvi GM, Otieno WN. Risk factors for hypertension among young adults (18-35) years attending in Tenwek mission hospital, Bomet County, Kenya in 2018. PAMJ.2019; 33:210 doi:10.11604/pamj.2019.33.210.18407.
24. De Venecia T, Lu M, Figueredo VM. Hypertension in young adults. Postgrad Med. 2016;128(2):201-7.
25. Chattopadhyay A, Taraphdar P, KumarSahu B, Maulik S, Ghosh R, Sinha A, Biswas M. A study on prevalence of Hypertension and its related risk factors among undergraduate medical students in Kolkata. IOSR-JDMS.2014;13: 01-07.
26. Abd-Elaziz KM, Dewedar SA, Sabbour S, El Gafaary MM, Marzouk DM, Aboul Fotouh A, Allam MF. Screening for hypertension among adults: community outreach in Cairo, Egypt. J Public Health (Oxf). 2014;37(4), 701-6.
27. AlWabel AH, Almufadhi MA, Alayed FM, Aloraini A.Y, Alobaysi HM, Alawi RM. Assessment of hypertension and its associated risk factors among medical students in Qassi University. Saudi J. Kidney Dis Transplant 29:1100-8.
28. Isezuo SA, Sabir AA, Ohwovorilole AE, Fasanmade OA. Prevalence, associated factors and relationship between prehypertension and hypertension: a study of two ethnic African populations in Northern Nigeria 2011. J Hum Hypertens. 25: 224-230.
29. Tadesse T, Alemu H. Hypertension and associated factors among university students in Gondar, Ethiopia: a cross-sectional study. BMC Public Health 14, 937 (2014). https://doi.org/10.1186/1471-2458-14-937
30. Al-Majed H, Sadek A: Pre-hypertension and hypertension in college students in Kuwait: a neglected issue. J Family Community Med. 2012, 19: 105-10.4103/2230-8229.98296.
31. Hajer A-S, Jalila El A, Pierre T, Habiba B, Sabrina E, Francis D, Noureddine A, Bernard M. Blood pressure and associated factors in a North African adolescent population. A national cross-sectional study in Tunisia. BMC Public Health. 2012, 12: 98-10.1186/1471-2458-12-98.
32. Van der Sande MA, Milligan PJ, Nyan OA, Rowley JT, Banya WA, Ceesay SM, Dolmans WM, Thien T, McAdam KP, Walraven GE: Blood pressure patterns and cardiovascular risk factors in rural and urban Gambian communities. J Hum Hypertens. 2000, 14: 489-496. 10.1038/sj.jhh.1001050.
33. Awoke A, Awoke T, Alemu S, Megabiaw B: Prevalence and associated factors of hypertension among adults in Gondar. Northwest Ethiopia: a community-based cross-sectional study. BMC Cardiovasc Disord. 2012, 12: 113-10.1186/1471-2261-12-113.
34. World Health Organisation (2013). A global brief on hypertension, Geneva: WHO Press.2013.

Article Details

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

This is an open-access journal and articles are distributed under the terms of the Creative Commons Attribution Non-Commercial Share-Alike License 4.0. This licence allows users to download and share, remix, tweak and build upon the article for non-commercial purposes, so long as the original authorship is acknowledged and the new creations are licensed under identical terms.

# data[].attributes.attachment_link.description
Background: Emerging epidemiological data suggest that Hypertension (HTN) has become a significant public health challenge in sub-Saharan Africa. HTN in young adults is a problem lacking relevant attention because it is still erroneously considered a disease of the old.

# data[].attributes.headline
Meaningful patient engagement in inflammatory arthritis: development of the Patient Motivation Questionnaire

# data[].attributes.subject
Meaningful patient engagement in inflammatory arthritis: development of the Patient Motivation Questionnaire

# data[].attributes.attachment_link.readable_text
Abstract

The objective of this study is to develop a questionnaire for evaluating the patient's "motivation" and assess the psychometric properties of that measure in patients with chronic inflammatory arthritis. Using Rasch analysis and questions item pool, content analysis, and semi-structured group discussion, the questionnaire was developed including 10-item scale (0-10 on VAS scale). Construct validity was assessed by correlating the questionnaire score to parameters of disease activity (DAS-28, ASDAS, and DAPSA scores), functional disability, quality of life, patient self-helplessness measure, as well as the patients' compliance to therapy. Reliability and comprehensibility and sensitivity to change were also assessed. The questionnaire was assessed in 432 RA, 415 psoriatic arthritis patients, and 232 ankylosing spondylitis patients. Dimensionality analysis revealed a 1-factor solution, explaining 98% of the total variance. It showed acceptable validity as it correlated significantly with disease activity measures: DAS-28: r = −0.85, ASDAS: r = −0.86, and DAPSA: r = −0.89. It also correlated significantly with functional disability score: r = −0.91, QoL: r = −0.90, as well as patient self-helplessness: r = −0.88. The questionnaire was reliable (Cronbach's alpha 0.958) and had no misfitting items. In addition, it was comprehensible (9.4) and sensitive to change ( p < 0.01). The patient motivation score showed significant ( p < 0.01) variation with the medication compliance. The measure is a patient-reported tool that is valid, reliable, comprehensible, and unidimensional scale that reflects the patients' motivation and engagement. The measure has good psychometric properties indicating that it can be used at the individual patient level to tailor management and monitor changes.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Article Open access

Article Open access

References

Ruta DA, Garratt AM, Russell IT (1999) Patient centered assessment of quality of life for patients with four common conditions. Qual Health Care 8:22-29

Article CAS PubMed PubMed Central Google Scholar

Garratt AM, Ruta DA (1999) The Patient Generated Index. In: Joyce CRB, O'Boyle CA, McGee HM (eds). Individual quality of life: Approaches to conceptualisation and assessment. Amsterdam Harwood Academic Publishers;105-18

Ahn, Y. H., Yi, C. H., Ham, O. K., & Kim, B. J (2014) Psychometric properties of the Korean version of the "Patient Activation Measure 13"(PAM13-K) in patients with osteoarthritis. Eval Health Prof: 0163278714540915

Barello, S., & Graffigna, G (2014) Engaging patients to recover life projectuality: an Italian cross disease framework. Qual Life Res; doi: 1-10. 10.1007/s11136-014-0846-x

Download references

Acknowledgements

We express thanks to all participants, our colleagues, research assistants, and nurses for their cooperation and help to bring this research to its final conclusions. Special thanks to Ms. Deborah Palmer, advanced nurse practitioner, North Middlesex University Hospital, London for her contribution in the work.

Author information

Authors and Affiliations

Rheumatology and Rehabilitation, Ain Shams University, Cairo, Egypt

Y. El Miedany, Sally Youssef & Nadia El Aroussy

Darent Valley Hospital, Dartford, Kent, England, DA2 8DA, UK

Y. El Miedany

Public Health and Community Department, Ain Shams University, Cairo, Egypt

Maha El Gaafary

Contributions

All authors had a substantial contribution to the conception and design of the study, drafting/revising of the article and final approval of the version to be published.

Corresponding author

Correspondence to Y. El Miedany.

Ethics declarations

Local ethical and methodological protocols for approval of the study were followed. All patients who participated in the study signed an informed consent according to the Declaration of Helsinki (at the General Assembly in October 2008).

Disclosures

None.

Ethics approval

The study was approved by the Ain Shams University Research Ethics Board.

Electronic supplementary material

About this article

Cite this article

El Miedany, Y., El Gaafary, M., Youssef, S. et al. Meaningful patient engagement in inflammatory arthritis: development of the Patient Motivation Questionnaire. Clin Rheumatol 43, 1793-1801 (2024). https://doi.org/10.1007/s10067-017-3605-x
Download citation

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

# data[].attributes.attachment_link.title
Meaningful patient engagement in inflammatory arthritis: development of the Patient Motivation Questionnaire - Clinical Rheumatology

# data[].attributes.attachment_link.description
The objective of this study is to develop a questionnaire for evaluating the patient's "motivation" and assess the psychometric properties of that measure in patients with chronic inflammatory arthritis. Using Rasch analysis and questions item pool, content analysis, and semi-structured group discussion, the questionnaire was developed including 10-item scale (0-10 on VAS scale).

# data[].attributes.headline
Innovations, interventions and insights in clinical child psychology and psychiatry

# data[].attributes.subject
Innovations, interventions and insights in clinical child psychology and psychiatry

# data[].attributes.headline
A low-grade somatotroph adenoma presenting as a giant pituitary macro-adenoma

# data[].attributes.subject
A low-grade somatotroph adenoma presenting as a giant pituitary macro-adenoma

# data[].attributes.attachment_link.readable_text
A 31-year-old lady was referred to the outpatient endocrine clinic for subfertility, intermittent galactorrhoea and amenorrhoea since birth of her son 5 year ago. However, she denied visual disturbances and headache. She was struggling to lose weight but she had no clinical features suggestive of corticosteroid or growth hormone excess apart from an increase in her UK shoe size from 5.5 to 6.5 and family members noted her hands were slightly bigger. She was on an antidepressant, Sertraline, which was withheld for two weeks, so that a repeat pituitary profile can be carried out. It showed hypogonadotropic hypogonadism. The results were as follows: FSH 1.2 IU/l (2.5-10.2), LH <0.2 IU/l (1.9-12.5); oestradiol <55 pmol/l (55 - 422), Prolactin 1200 mIU/l (70 - 566) and IGF11 45 mol/l (10.2 to 40.7). But the Cortisol level, TSH and ACTH were within acceptable range. MRI pituitary demonstrated a pituitary/suprasellar mass with a 45mm craniocaudally dimension, which was displacing the optic chiasm superiorly and compressing on it. Formal visual field testing showed bilateral superior temporal quadrantanopia. She underwent Trans-sphenoidal surgery and was initiated on hydrocortisone replacement post-operatively. There was evidence of residual tumour in postoperative MRI scan and histology showed eosinophilic excess with intranuclear inclusions and immunohistochemistry demonstrated PIT 1 lineage pituitary adenoma, variably intense positivity for TSH predominantly, second most frequent was GH with Ki 67 3 %. Post-surgery, the Pituitary multidisciplinary team meeting (MDT), diagnosis was clinically silent and low-grade somatotroph adenoma biochemically. There was subjective improvement in the vision post operatively with normal VF confrontation and normal prolactin 289 mIU/l but persistently raised IGF153.9 mol/l. MDT noted that good debulking surgery but there was still a residual suprasellar part of tumour. Somatostatin analogue (SSA) therapy was recommended and re-do surgery for residual tumour if SSA therapy failed to achieve the therapeutic goal. The plan is to repeat MRI Pituitary and assess pituitary function with insulin tolerance test in 3 months. Learning points: This case highlights the somatotroph adenoma is presenting with a silent pituitary mass for decades and that diagnosis can be delayed until the clinical or biochemical manifestation of acromegaly. We picked up the diagnosis early by chance simply because she was investigated for subfertility. Surgical debulking surgery is main stay of treatment in somatotroph adenoma as it can lower GH levels and improve the cure rate with subsequent SSAs.

# data[].attributes.attachment_link.description
A 31-year-old lady was referred to the outpatient endocrine clinic for subfertility, intermittent galactorrhoea and amenorrhoea since birth of her son 5 year ago. However, she denied visual disturbances and headache.

# data[].attributes.headline
Streams, rivers and data lakes: an introduction to understanding modern electronic healthcare records

# data[].attributes.subject
Streams, rivers and data lakes: an introduction to understanding modern electronic healthcare records

# data[].attributes.attachment_link.description
About ScienceDirect
Shopping cart
Contact and
supportTerms and
conditionsPrivacy policy

# data[].attributes.headline
Medicine Trainees attending clinics – easier said than done!

# data[].attributes.subject
Medicine Trainees attending clinics – easier said than done!

# data[].attributes.attachment_link.description
About ScienceDirect
Shopping cart
Contact and
supportTerms and
conditionsPrivacy policy

# data[].attributes.headline
Strengthening the trainee voice at the Medical Local Faculty Group

# data[].attributes.subject
Strengthening the trainee voice at the Medical Local Faculty Group

# data[].attributes.attachment_link.description
About ScienceDirect
Shopping cart
Contact and
supportTerms and
conditionsPrivacy policy

# data[].attributes.headline
Skills not roles: the key to better training and better patient care

# data[].attributes.subject
Skills not roles: the key to better training and better patient care

# data[].attributes.headline
Identifying barriers to engaging older adults with primary care sexual health services

# data[].attributes.subject
Identifying barriers to engaging older adults with primary care sexual health services

# data[].attributes.attachment_link.readable_text
Helen Chilmaid Staff nurse, Darent Valley Hospital, Dartford, Kent, England

Despite the prevalent cultural stereotype that people's sexual activity declines or ceases as they grow older, adults in the UK remain sexually active throughout later life. This review of the literature investigates the factors influencing older adults' engagement with primary care sexual health services and makes recommendations about potential interventions.

Primary Health Care. doi: 10.7748/phc.2019.e1532

Peer review

This article has been subject to external double-blind review and has been checked for plagiarism using automated software

Correspondence

h.chilmaid@gmail.com

Conflict of interest

None declared

Chilmaid H (2019) Identifying barriers to engaging older adults with primary care sexual health services. Primary Health Care. doi: 10.7748/phc.2019.e1532

Published online: 11 September 2019

Want to read more?

or

3-month trial offer for £5.25/month

Subscribe today and save 50% on your first three months

RCNi Plus users have full access to the following benefits:

Unlimited access to all 10 RCNi Journals

RCNi Learning featuring over 175 modules to easily earn CPD time

NMC-compliant RCNi Revalidation Portfolio to stay on track with your progress

Personalised newsletters tailored to your interests

A customisable dashboard with over 200 topics

Subscribe
Alternatively, you can purchase access to this article for the next seven days. Buy now

Are you a student? Our student subscription has content especially for you.
Find out more

# data[].attributes.attachment_link.title
Identifying barriers to engaging older adults with primary care sexual health services

# data[].attributes.attachment_link.description
Identifying barriers to engaging older adults with primary care sexual health services

# data[].attributes.headline
Psychological effects of choosing active surveillance on men with prostate cancer

# data[].attributes.subject
Psychological effects of choosing active surveillance on men with prostate cancer

# data[].attributes.attachment_link.readable_text
Nicola Lancaster Uro-oncology clinical nurse specialist, Darent Valley Hospital, Dartford and Gravesham NHS Trust, Dartford, Kent, England

Greater awareness about prostate cancer has led to an increase in early detection of organ-confined prostate cancers and, as a result, some men are diagnosed with a cancer that may not affect their mortality. These men may be given treatment options including surgery, radiotherapy or active surveillance.

Surgery and radiotherapy can have side effects, such as urinary incontinence and erectile dysfunction, that may affect quality of life. Active surveillance enables urology and oncology teams to monitor the cancer and delay radical treatment until it is necessary, thereby maintaining a good quality of life. However, some men may feel anxious about the idea of not treating a cancer and opt instead for treatment.

This article examines the psychological effects of choosing active surveillance and discusses how nurses can support patients throughout the decision-making process and follow up.

Cancer Nursing Practice. doi: 10.7748/cnp.2019.e1575

Peer review

This article has been subject to external double-blind peer review and has been checked for plagiarism using automated software

Correspondence

n.lancaster@nhs.net

Conflict of interest

None declared

Lancaster N (2019) Psychological effects of choosing active surveillance on men with prostate cancer. Cancer Nursing Practice. doi: 10.7748/cnp.2019.e1575

Published online: 01 April 2019

Want to read more?

or

# data[].attributes.attachment_link.title
Psychological effects of choosing active surveillance on men with prostate cancer

# data[].attributes.attachment_link.description
Psychological effects of choosing active surveillance on men with prostate cancer

# data[].attributes.headline
Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

# data[].attributes.subject
Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

# data[].attributes.attachment_link.readable_text
Abstract

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Similar content being viewed by others

Keith Sacco, Riccardo Castagnoli, ... Luigi D. Notarangelo

Michael Maes, Walton Luiz Del Tedesco Junior, ... Andréa Name Colado Simão

Sizhen Su, Yimiao Zhao, ... Lin Lu

Main

One in ten severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections results in post-acute sequelae of coronavirus disease 2019 (PASC) or long coronavirus disease (COVID), which affects 65 million people worldwide1. Long COVID (LC) remains common, even after mild acute infection with recent variants2, and it is likely LC will continue to cause substantial long-term ill health, requiring targeted management based on an understanding of how disease phenotypes relate to underlying mechanisms. Persistent inflammation has been reported in adults with LC1,3, but studies have been limited in size, timing of samples or breadth of immune mediators measured, leading to inconsistent or absent associations with symptoms. Markers of oxidative stress, metabolic disturbance, vasculoproliferative processes and IFN-, NF-κB- or monocyte-related inflammation have been suggested3,4,5,6.

The PHOSP-COVID study, a multicenter United Kingdom study of patients previously hospitalized with COVID-19, has reported inflammatory profiles in 626 adults with health impairment after COVID-19, identified through clustering. Elevated IL-6 and markers of mucosal inflammation were observed in those with severe impairment compared with individuals with milder impairment7. However, LC is a heterogeneous condition that may be a distinct form of health impairment after COVID-19, and it remains unclear whether there are inflammatory changes specific to LC symptom subtypes. Determining whether activated inflammatory pathways underlie all cases of LC or if mechanisms differ according to clinical presentation is essential for developing effective therapies and has been highlighted as a top research priority by patients and clinicians8.

In this Letter, in a prospective multicenter study, we measured 368 plasma proteins in 657 adults previously hospitalized for COVID-19 (Fig. 1a and Table 1). Individuals in our cohort experienced a range of acute COVID-19 severities based on World Health Organization (WHO) progression scores9; WHO 3-4 (no oxygen support, n = 133 and median age of 55 years), WHO 5-6 (oxygen support, n = 353 and median age of 59 years) and WHO 7-9 (critical care, n = 171 and median age of 57 years). Participants were hospitalized for COVID-19 ≥3 months before sample collection (median 6.1 months, interquartile range (IQR) 5.1-6.8 months and range 3.0-8.3 months) and confirmed clinically ( n = 36/657) or by PCR ( n = 621/657). Symptom data indicated 233/657 (35%) felt fully recovered at 6 months (hereafter 'recovered') and the remaining 424 (65%) reported symptoms consistent with the WHO definition for LC (symptoms ≥3 months post infection10). Given the diversity of LC presentations, patients were grouped according to symptom type (Fig. 1b). Groups were defined using symptoms and health deficits that have been commonly reported in the literature1 ( Methods). A multivariate penalized logistic regression model (PLR) was used to explore associations of clinical covariates and immune mediators at 6 months between recovered patients ( n = 233) and each LC group (cardiorespiratory symptoms, cardioresp, n = 398, Fig. 1c; fatigue, n = 384, Fig. 1d; affective symptoms, anxiety/depression, n = 202, Fig. 1e; gastrointestinal symptoms, GI, n = 132, Fig. 1f; and cognitive impairment, cognitive, n = 61, Fig. 1g). Women ( n = 239) were more likely to experience CardioResp (odds ratio (OR 1.14), Fatigue (OR 1.22), GI (OR 1.13) and Cognitive (OR 1.03) outcomes (Fig. 1c,d,f,g). Repeated cross-validation was used to optimize and assess model performance ( Methods and Extended Data Fig. 1). Pre-existing conditions, such as chronic lung disease, neurological disease and cardiovascular disease (Supplementary Table 1), were associated with all LC groups (Fig. 1c-g). Age, C-reactive protein (CRP) and acute disease severity were not associated with any LC group (Table 1).

a, Distribution of time from COVID-19 hospitalization at sample collection. All samples were cross-sectional. The vertical red line indicates the 3 month cutoff used to define our final cohort and samples collected before 3 months were excluded. b, An UpSet plot describing pooled LC groups. The horizontal colored bars represent the number of patients in each symptom group: cardiorespiratory (Cardio_Resp), fatigue, cognitive, GI and anxiety/depression (Anx_Dep). Vertical black bars represent the number of patients in each symptom combination group. To prevent patient identification, where less than five patients belong to a combination group, this has been represented as '<5'. The recovered group ( n = 233) were used as controls. c- g, Forest plots of Olink protein concentrations (NPX) associated with Cardio_Resp ( n = 365) ( c), fatigue (n = 314) ( d), Anx_Dep ( n = 202) ( e), GI ( n = 124) ( f) and cognitive ( n = 60) ( g). Neuro_Psych, neuropsychiatric. The error bars represent the median accuracy of the model. h, i, Distribution of Olink values (NPX) for IL-1R2 ( h) and MATN2, neurofascin and sCD58 ( i) measured between symptomatic and recovered individuals in recovered ( n = 233), Cardio_Resp ( n = 365), fatigue ( n = 314) and Anx_Dep ( n = 202) groups ( h) and MATN2 in GI ( n = 124), neurofascin in cognitive ( n = 60) and sCD58 in Cardio_Resp and recovered groups ( i). The box plot center line represents the median, the boundaries represent IQR and the whisker length represents 1.5× IQR. The median values were compared between groups using two-sided Wilcoxon signed-rank test, * P < 0.05, ** P < 0.01, *** P < 0.001 and **** P  < 0.0001.

Table 1 Cohort demographics

To study the association of peripheral inflammation with symptoms, we analyzed cross-sectional data collected approximately 6 months after hospitalizations. We measured 368 immune mediators from plasma collected contemporaneously with symptom data. Mediators suggestive of myeloid inflammation were associated with all symptoms (Fig. 1c-h). Elevated IL-1R2, an IL-1 receptor expressed by monocytes and macrophages modulating inflammation11 and MATN2, an extracellular matrix protein that modulates tissue inflammation through recruitment of innate immune cells12, were associated with cardioresp (IL-1R2 OR 1.14, Fig. 1c,h), fatigue (IL-1R2 OR 1.45, Fig. 1d,h), anxiety/depression (IL-1R2 OR 1.34. Fig. 1e,h) and GI (MATN2 OR 1.08, Fig. 1f). IL-3RA, an IL-3 receptor, was associated with cardioresp (OR 1.07, Fig. 1c), fatigue (OR 1.21, Fig. 1d), anxiety/depression (OR 1.12, Fig. 1e) and GI (OR 1.06, Fig. 1f) groups, while CSF3, a cytokine promoting neutrophilic inflammation13, was elevated in cardioresp (OR 1.06, Fig. 1c), fatigue (OR 1.12, Fig. 1d) and GI (OR 1.08, Fig. 1f).

Elevated COLEC12, which initiates inflammation in tissues by activating the alternative complement pathway14, associated with cardioresp (OR 1.09, Fig. 1c), fatigue (OR 1.19, Fig. 1d) and anxiety/depression (OR 1.11, Fig. 1e), but not with GI (Fig. 1f) and only weakly with cognitive (OR 1.02, Fig. 1g). C1QA, a degradation product released by complement activation15 was associated with GI (OR 1.08, Fig. 1f) and cognitive (OR 1.03, Fig. 1g). C1QA, which is known to mediate dementia-related neuroinflammation16, had the third strongest association with cognitive (Fig. 1g). These observations indicated that myeloid inflammation and complement activation were associated with LC.

Increased expression of DPP10 and SCG3 was observed in the GI group compared with recovered (DPP10 OR 1.07 and SCG3 OR 1.08, Fig. 1f). DPP10 is a membrane protein that modulates tissue inflammation, and increased DPP10 expression is associated with inflammatory bowel disease17,18, suggesting that GI symptoms may result from enteric inflammation. Elevated SCG3, a multifunctional protein that has been associated with irritable bowel syndrome19, suggested that noninflammatory disturbance of the brain-gut axis or dysbiosis, may occur in the GI group. The cognitive group was associated with elevated CTSO (OR 1.04), NFASC (OR 1.03) and SPON-1 (OR 1.02, Fig. 1g,i). NFASC and SPON-1 regulate neural growth20,21, while CTSO is a cysteine proteinase supporting tissue turnover22. The increased expression of these three proteins as well as C1QA and DPP10 in the cognitive group (Fig. 1g) suggested neuroinflammation and alterations in nerve tissue repair, possibly resulting in neurodegeneration. Together, our findings indicated that complement activation and myeloid inflammation were common to all LC groups, but subtle differences were observed in the GI and cognitive groups, which may have mechanistic importance. Acutely elevated fibrinogen during hospitalization has been reported to be predictive of LC cognitive deficits23. We found elevated fibrinogen in LC relative to recovered (Extended Data Fig. 2a; P = 0.0077), although this was not significant when restricted to the cognitive group ( P = 0.074), supporting our observation of complement pathway activation in LC and in keeping with reports that complement dysregulation and thrombosis drive severe COVID-19 (ref. 24).

Elevated sCD58 was associated with lower odds of all LC symptoms and was most pronounced in cardioresp (OR 0.85, Fig. 1c,i), fatigue (OR 0.80, Fig. 1d) and anxiety/depression (OR 0.83, Fig. 1e). IL-2 was negatively associated with the cardioresp (Fig. 1c, OR 0.87), fatigue (Fig. 1d, OR 0.80), anxiety/depression (Fig. 1e, OR 0.84) and cognitive (Fig. 1g, OR 0.96) groups. Both IL-2 and sCD58 have immunoregulatory functions25,26. Specifically, sCD58 suppresses IL-1- or IL-6-dependent interactions between CD2+ monocytes and CD58+ T or natural killer cells26. The association of sCD58 with recovered suggests a central role of dysregulated myeloid inflammation in LC. Elevated markers of tissue repair, IDS and DNER27,28, were also associated with recovered relative to all LC groups (Fig. 1c-g). Taken together, our data suggest that suppression of myeloid inflammation and enhanced tissue repair were associated with recovered, supporting the use of immunomodulatory agents in therapeutic trials29 (Supplementary Table 2).

We next sought to validate the experimental and analytical approaches used. Although Olink has been validated against other immunoassay platforms, showing superior sensitivity and specificity30,31, we confirmed the performance of Olink against chemiluminescent immunoassays within our cohort. We performed chemiluminescent immunoassays on plasma from a subgroup of 58 participants (recovered n = 13 and LC n = 45). There were good correlations between results from Olink (normalized protein expression (NPX)) and chemiluminescent immunoassays (pg ml −1) for CSF3, IL-1R2, IL-3RA, TNF and TFF2 (Extended Data Fig. 3). Most samples did not have concentrations of IL-2 detectable using a mesoscale discovery chemiluminescent assay, limiting this analysis to 14 samples (recovered n = 4, LC n = 10, R = 0.55 and P = 0.053, Extended Data Fig. 3). We next repeated our analysis using alternative definitions of LC. The Centers for Disease Control and Prevention and National Institute for Health and Care Excellence definitions for LC include symptoms occurring 1 month post infection32,33. Using the 1 month post-infection definition included 62 additional participants to our analysis (recovered n = 21, 3 females and median age 61 years and LC n = 41, 15 females and median age 60 years, Extended Data Fig. 2c) and found that inflammatory associations with each LC group were consistent with our analysis based on the WHO definition (Extended Data Fig. 2d-h). Finally, to validate the analytical approach (PLR) we examined the distribution of data, prioritizing proteins that were most strongly associated with each LC/recovered group (IL-1R2, MATN2, NFASC and sCD58). Each protein was significantly elevated in the LC group compared with recovered (Fig. 1h,i and Extended Data Fig. 4), consistent with the PLR. Alternative regression approaches (unadjusted regression models and partial least squares, PLS) reported results consistent with the original analysis of protein associations and LC outcome in the WHO-defined cohort (Fig. 1c-g, Supplementary Table 3 and Extended Data Figs. 5 and 6). The standard errors of PLS estimates were wide (Extended Data Fig. 6), consistent with previous demonstrations that PLR is the optimal method to analyze high-dimensional data where variables may have combined effects34. As inflammatory proteins are often colinear, working in-tandem to mediate effects, we prioritized PLR results to draw conclusions.

To explore the relationship between inflammatory mediators associated with different LC symptoms, we performed a network analysis of Olink mediators highlighted by PLR within each LC group. COLEC12 and markers of endothelial and mucosal inflammation (MATN2, PCDH1, ROBO1, ISM1, ANGPTL2, TGF-α and TFF2) were highly correlated within the cardioresp, fatigue and anxiety/depression groups (Fig. 2 and Extended Data Fig. 7). Elevated PCDH1, an adhesion protein modulating airway inflammation35, was highly correlated with other inflammatory proteins associated with the cardioresp group (Fig. 2), suggesting that systemic inflammation may arise from the lung in these individuals. This was supported by increased expression of IL-3RA, which regulates innate immune responses in the lung through interactions with circulating IL-3 (ref. 36), in fatigue (Figs. 1d and 2), which correlated with markers of tissue inflammation, including PCDH1 (Fig. 2). MATN2 and ISM1, mucosal proteins that enhance inflammation37,38, were highly correlated in the GI group (Fig. 2), highlighting the role of tissue-specific inflammation in different LC groups. SCG3 correlated less closely with mediators in the GI group (Fig. 2), suggesting that the brain-gut axis may contribute separately to some GI symptoms. SPON-1, which regulates neural growth21, was the most highly correlated mediator in the cognitive group (Fig. 2 and Extended Data Fig. 7), highlighting that processes within nerve tissue may underlie this group. These observations suggested that inflammation might arise from mucosal tissues and that additional mechanisms may contribute to pathophysiology underlying the GI and cognitive groups.

Network analysis of Olink mediators associated with cardioresp ( n = 365), fatigue ( n = 314), anxiety/depression ( n = 202), GI ( n = 124) and cognitive groups ( n = 60). Each node corresponds to a protein mediator identified by PLR. The edges (blue lines) were weighted according to the size of Spearman's rank correlation coefficient between proteins. All edges represent positive and significant correlations ( P  < 0.05) after FDR adjustment.

Women were more likely to experience LC (Table 1), as found in previous studies1. As estrogen can influence immunological responses39, we investigated whether hormonal differences between men and women with LC in our cohort explained this trend. We grouped men and women with LC symptoms into two age groups (those younger than 50 years and those 50 years and older, using age as a proxy for menopause status in women) and compared mediator levels between men and women in each age group, prioritizing those identified by PLR to be higher in LC compared with recovered. As we aimed to understand whether women with LC had stronger inflammatory responses than men with LC, we did not assess differences in men and women in the recovered group. IL-1R2 and MATN2 were significantly higher in women ≥50 years than men ≥50 years in the cardioresp group (Fig. 3a, IL-1R2 and MATN2) and the fatigue group (Fig. 3b). In the GI group, CSF3 was higher in women ≥50 years compared with men ≥50 years (Fig. 3c), indicating that the inflammatory markers observed in women were not likely to be estrogen-dependent. Women have been reported to have stronger innate immune responses to infection and to be at greater risk of autoimmunity39, possibly explaining why some women in the ≥50 years group had higher inflammatory proteins than men the same group. Proteins associated with the anxiety/depression (IL-1R2 P = 0.11 and MATN2 P = 0.61, Extended Data Fig. 8a) and cognitive groups (CTSO P = 0.64 and NFASC P = 0.41, Extended Data Fig. 8b) were not different between men and women in either age group, consistent with the absent/weak association between sex and these outcomes identified by PLR (Fig. 1e,g). Though our findings suggested that nonhormonal differences in inflammatory responses may explain why some women are more likely to have LC, they require confirmation in adequately powered studies.

a- c, Olink-measured plasma protein levels (NPX) of IL-1R2 and MATN2 ( a and b) and CSF3 ( c) between LC men and LC women divided by age (<50 or ≥50 years) in the cardiorespiratory group (<50 years n = 8 and ≥50 years n = 270) ( a), fatigue group (<50 years n = 81 and ≥50 years n = 227) ( b) and GI group (<50 years n = 34 and ≥50 years n = 82) ( c). the median values were compared between men and women using two-sided Wilcoxon signed-rank test, * P < 0.05, ** P < 0.01, *** P < 0.001 and **** P  < 0.0001. The box plot center line represents the median, the boundaries represent IQR and the whisker length represents 1.5× IQR.

To test whether local respiratory tract inflammation persisted after COVID-19, we compared nasosorption samples from 89 participants (recovered, n = 31; LC, n = 33; and healthy SARS-CoV-2 naive controls, n = 25, Supplementary Tables 4 and 5). Several inflammatory markers were elevated in the upper respiratory tract post COVID (including IL-1α, CXCL10, CXCL11, TNF, VEGF and TFF2) when compared with naive controls, but similar between recovered and LC (Fig. 4a). In the cardioresp group ( n = 29), inflammatory mediators elevated in plasma (for example, IL-6, APO-2, TGF-α and TFF2) were not elevated in the upper respiratory tract (Extended Data Fig. 9a) and there was no correlation between plasma and nasal mediator levels (Extended Data Fig. 9b). This exploratory analysis suggested upper respiratory tract inflammation post COVID was not specifically associated with cardiorespiratory symptoms.

a, Nasal cytokines measured by immunoassay in post-COVID participants ( n = 64) compared with healthy SARS-CoV-2 naive controls ( n = 25), and between the the cardioresp group ( n = 29) and the recovered group ( n = 31). The red values indicate significantly increased cytokine levels after FDR adjustment ( P < 0.05) using two-tailed Wilcoxon signed-rank test. b, SARS-CoV-2 N antigen measured in sputum by electrochemiluminescence from recovered ( n = 17) and pooled LC ( n = 23) groups, compared with BALF from SARS-CoV-2 naive controls ( n = 9). The horizontal dashed line indicates the lower limit of detection of the assay. c, Plasma S- and N-specific IgG responses measured by electrochemiluminescence in the LC ( n = 35) and recovered ( n = 19) groups. The median values were compared using two-sided Wilcoxon signed-rank tests, NS P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001 and **** P  < 0.0001. The box plot center lines represent the median, the boundaries represent IQR and the whisker length represents 1.5× IQR.

To explore whether SARS-CoV-2 persistence might explain the inflammatory profiles observed in the cardioresp group, we measured SARS-CoV-2 nucleocapsid (N) antigen in sputum from 40 participants (recovered n = 17 and LC n = 23) collected approximately 6 months post hospitalization (Supplementary Table 6). All samples were compared with prepandemic bronchoalveolar lavage fluid ( n = 9, Supplementary Table 4). Only four samples (recovered n = 2 and LC n = 2) had N antigen above the assay's lower limit of detection, and there was no difference in N antigen concentrations between LC and recovered (Fig. 4b, P = 0.78). These observations did not exclude viral persistence, which might require tissues samples for detection40,41. On the basis of the hypothesis that persistent viral antigen might prevent a decline in antibody levels over time, we examined the titers of SARS-CoV-2-specific antibodies in unvaccinated individuals (recovered n = 19 and LC n = 35). SARS-CoV-2 N-specific ( P = 0.023) and spike (S)-specific ( P = 0.0040) immunoglobulin G (IgG) levels were elevated in LC compared with recovered (Fig. 4c).

Overall, we identified myeloid inflammation and complement activation in the cardioresp, fatigue, anxiety/depression, cognitive and GI groups 6 months after hospitalization (Extended Data Fig. 10). Our findings build on results of smaller studies5,6,42 and are consistent with a genome-wide association study that identified an independent association between LC and FOXP4, which modulates neutrophilic inflammation and immune cell function43,44. In addition, we identified tissue-specific inflammatory elements, indicating that myeloid disturbance in different tissues may result in distinct symptoms. Multiple mechanisms for LC have been suggested, including autoimmunity, thrombosis, vascular dysfunction, SARS-CoV-2 persistence and latent virus reactivation1. All these processes involve myeloid inflammation and complement activation45. Complement activation in LC has been suggested in a proteomic study in 97 mostly nonhospitalized COVID-19 cases42 and a study of 48 LC patients, of which one-third experienced severe acute disease46. As components of the complement system are known to have a short half-life47, ongoing complement activation suggests active inflammation rather than past tissue damage from acute infection.

Despite the heterogeneity of LC and the likelihood of coexisting or multiple etiologies, our work suggests some common pathways that might be targeted therapeutically and supports the rationale for several drugs currently under trial. Our finding of increased sCD58 levels (associated with suppression of monocyte-lymphocyte interactions26) in the recovered group, strengthens our conclusion that myeloid inflammation is central to the biology of LC and that trials of steroids, IL-1 antagonists, JAK inhibitors, naltrexone and colchicine are justified. Although anticoagulants such as apixaban might prevent thrombosis downstream of complement dysregulation, they can also increase the risk of serious bleeding when given after COVID-19 hospitalization48. Thus, clinical trials, already underway, need to carefully assess the risks and benefits of anticoagulants (Supplementary Table 2).

Our finding of elevated S- and N-specific IgG in LC could suggest viral persistence, as found in other studies6,42,49. Our network analysis indicated that inflammatory proteins in the cardioresp group interacted strongly with ISM1 and ROBO1, which are expressed during respiratory tract infection and regulate lung inflammation50,51. Although we were unable to find SARS-CoV-2 antigen in sputum from our LC cases, we did not test for viral persistence in GI tract and lung tissue40,41 or in plasma52. Evidence of SARS-CoV-2 persistence would justify trials of antiviral drugs (singly or in combination) in LC. It is also possible that autoimmune processes could result in an innate inflammatory profile in LC. Autoreactive B cells have been identified in LC patients with higher SARS-CoV-2-specific antibody titers in a study of mostly mild acute COVID cases (59% WHO 2-3)42, a different population from our study of hospitalized cases.

Our observations of distinct protein profiles in GI and cognitive groups support previous reports on distinct associations between Epstein-Barr virus reactivation and neurological symptoms, or autoantibodies and GI symptoms relative to other forms of LC49,53. We did not assess autoantibody induction but found evidence of brain-gut axis disturbance (SCG3) in the GI group, which occurs in many autoimmune diseases54. We found signatures suggestive of neuroinflammation (C1QA) in the cognitive group, consistent with findings of brain abnormalities on magnetic resonance imaging after COVID-19 hospitalization55, as well as findings of microglial activation in mice after COVID-19 (ref. 56). Proinflammatory signatures dominated in the cardioresp, fatigue and anxiety/depression groups and were consistent with those seen in non-COVID depression, suggesting shared mechanisms57. The association between markers of myeloid inflammation, including IL-3RA, and symptoms was greatest for fatigue. Whilst membrane-bound IL-3RA facilitates IL-3 signaling upstream of myelopoesis36 its soluble form (measured in plasma) can bind IL-3 and can act as a decoy receptor, preventing monocyte maturation and enhancing immunopathology58. Monocytes from individuals with post-COVID fatigue are reported to have abnormal expression profiles (including reduced CXCR2), suggestive of altered maturation and migration5,59. Lung-specific inflammation was suggested by the association between PCDH1 (an airway epithelial adhesion molecule35) and cardioresp symptoms.

Our observations do not align with all published observations on LC. One proteomic study of 55 LC cases after generally mild (WHO 2-3) acute disease found that TNF and IFN signatures were elevated in LC3. Vasculoproliferative processes and metabolic disturbance have been reported in LC4,60, but these studies used uninfected healthy individuals for comparison and cannot distinguish between LC-specific phenomena and residual post-COVID inflammation. A study of 63 adults (LC, n = 50 and recovered, n = 13) reported no association between immune cell activation and LC 3 months after infection61, though myeloid inflammation was not directly measured, and 3 months post infection may be too early to detect subtle differences between LC and recovered cases due to residual acute inflammation.

Our study has limitations. We designed the study to identify inflammatory markers identifying pathways underlying LC subgroups rather than diagnostic biomarkers. The ORs we report are small, but associations were consistent across alternative methods of analysis and when using different LC definitions. Small effect sizes can be expected when using PLR, which shrinks correlated mediator coefficients to reflect combined effects and prevent colinear inflation62, and could also result from measurement of plasma mediators that may underestimate tissue inflammation. Although our LC cohort is large compared with most other published studies, some of our subgroups are small (only 60 cases were designated cognitive). Though the performance of the cognitive PLR model was adequate, our findings should be validated in larger studies. It should be noted that our cohort of hospitalized cases may not represent all types of LC, especially those occurring after mild infection. We looked for an effect of acute disease severity within our study and did not find it, and are reassured that the inflammatory profiles we observed were consistent with those seen in smaller studies including nonhospitalized cases42,46. Studies of posthospital LC may be confounded by 'posthospital syndrome', which encompasses general and nonspecific effects of hospitalization (particularly intensive care)63.

In conclusion, we found markers of myeloid inflammation and complement activation in our large prospective posthospital cohort of patients with LC, in addition to distinct inflammatory patterns in patients with cognitive impairment or gastrointestinal symptoms. These findings show the need to consider subphenotypes in managing patients with LC and support the use of antiviral or immunomodulatory agents in controlled therapeutic trials.

Methods

Study design and ethics

After hospitalization for COVID-19, adults who had no comorbidity resulting in a prognosis of less than 6 months were recruited to the PHOSP-COVID study ( n = 719). Patients hospitalized between February 2020 and January 2021 were recruited. Both sexes were recruited and gender was self-reported (female, n = 257 and male, n  = 462). Written informed consent was obtained from all patients. Ethical approvals for the PHOSP-COVID study were given by Leeds West Research Ethics Committee (20/YH/0225).

Symptom data and samples were prospectively collected from individuals approximately 6 months (IQR 5.1-6.8 months and range 3.0-8.3 months) post hospitalization (Fig. 1a), via the PHOSP-COVID multicenter United Kingdom study64. Data relating to patient demographics and acute admission were collected via the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization Clinical Characterisation Protocol United Kingdom (ISARIC4C study; IRAS260007/IRAS126600) (ref. 65). Adults hospitalized during the SARS-CoV-2 pandemic were systematically recruited into ISARIC4C. Written informed consent was obtained from all patients. Ethical approval was given by the South Central-Oxford C Research Ethics Committee in England (reference 13:/SC/0149), Scotland A Research Ethics Committee (20/SS/0028) and WHO Ethics Review Committee (RPC571 and RPC572l, 25 April 2013).

Data were collected to account for variables affecting symptom outcome, via hospital records and self-reporting. Acute disease severity was classified according to the WHO clinical progression score: WHO class 3-4: no oxygen therapy; class 5: oxygen therapy; class 6: noninvasive ventilation or high-flow nasal oxygen; and class 7-9: managed in critical care9. Clinical data were used to place patients into six categories: 'recovered', 'GI', 'cardiorespiratory', 'fatigue', 'cognitive impairment' and 'anxiety/depression' (Supplementary Table 7). Patient-reported symptoms and validated clinical scores were used when feasible, including Medical Research Council (MRC) breathlessness score, dyspnea-12 score, Functional Assessment of Chronic Illness Therapy (FACIT) score, Patient Health Questionnaire (PHQ)-9 and Generalized Anxiety Disorder (GAD)-7. Cognitive impairment was defined as a Montreal Cognitive Assessment score <26. GI symptoms were defined as answering 'Yes' to the presence of at least two of the listed symptoms. 'Recovered' was defined by self-reporting. Patients were placed in multiple groups if they experienced a combination of symptoms.

Matched nasal fluid and sputum samples were prospectively collected from a subgroup of convalescent patients approximately 6 months after hospitalization via the PHOSP-COVID study. Nasal and bronchoalveolar lavage fluid (BALF) collected from healthy volunteers before the COVID-19 pandemic were used as controls (Supplementary Table 4). Written consent was obtained for all individuals and ethical approvals were given by London-Harrow Research Ethics Committee (13/LO/1899) for the collection of nasal samples and the Health Research Authority London-Fulham Research Ethics Committee (IRAS project ID 154109; references 14/LO/1023, 10/H0711/94 and 11/LO/1826) for BALF samples.

Procedures

Ethylenediaminetetraacetic acid plasma was collected from whole blood taken by venepuncture and frozen at −80 °C as previously described7,66. Nasal fluid was collected using a NasosorptionTM FX·I device (Hunt Developments), which uses a synthetic absorptive matrix to collect concentrated nasal fluid. Samples were eluted and stored as previously described67. Sputum samples were collected via passive expectoration and frozen at −80 °C without the addition of buffers. Sputum samples from convalescent individuals were compared with BALF from healthy SARS-CoV-2-naive controls, collected before the pandemic. BALF samples were used to act as a comparison for lower respiratory tract samples since passively expectorated sputum from healthy SARS-CoV-2-naive individuals was not available. BALF samples were obtained by instillation and recovery of up to 240 ml of normal saline via a fiberoptic bronchoscope. BALF was filtered through 100 µM strainers into sterile 50 ml Falcon tubes, then centrifuged for 10 min at 400  g at 4 °C. The resulting supernatant was transferred into sterile 50 ml Falcon tubes and frozen at −80 °C until use. The full methods for BALF collection and processing have been described previously68,69.

Immunoassays

To determine inflammatory signatures that associated with symptom outcomes, plasma samples were analyzed on an Olink Explore 384 Inflammation panel70. Supplementary Table 8 (Appendix 1) lists all the analytes measured. To ensure the validity of results, samples were run in a single batch with the use of negative controls, plate controls in triplicate and repeated measurement of patient samples between plates in duplicate. Samples were randomized between plates according to site and sample collection date. Randomization between plates was blind to LC/recovered outcome. Data were first normalized to an internal extension control that was included in each sample well. Plates were standardized by normalizing to interplate controls, run in triplicate on each plate. Each plate contained a minimum of four patient samples, which were duplicates on another plate; these duplicate pairs allowed any plate to be linked to any other through the duplicates. Data were then intensity normalized across all cohort samples. Finally, Olink results underwent quality control processing and samples or analytes that did not reach quality control standards were excluded. Final normalized relative protein quantities were reported as log 2 NPX values.

To further validate our findings, we performed conventional electrochemiluminescence (ECL) assays and enzyme-linked immunosorbent assay for Olink mediators that were associated with symptom outcome ( Supplementary Methods). Contemporaneously collected plasma samples were available from 58 individuals. Like most omics platforms, Olink measures relative quantities, so perfect agreement with conventional assays that measure absolute concentrations is not expected.

Sputum samples were thawed before analysis and sputum plugs were extracted with the addition of 0.1% dithiothreitol creating a one in two sample dilution, as previously described71. SARS-CoV-2 S and N proteins were measured by ECL S-plex assay at a fixed dilution of one in two (Mesoscale Diagnostics), as per the manufacturers protocol72. Control BALF samples were thawed and measured on the same plate, neat. The S-plex assay is highly sensitive in detecting viral antigen in respiratory tract samples73.

Nasal cytokines were measured by ECL (mesoscale discovery) and Luminex bead multiplex assays (Biotechne). The full methods and list of analytes are detailed in Supplementary Methods.

Statistics and reproducibility

Clinical data was collected via the PHOSP REDCap database, to which access is available under reasonable request as per the data sharing statement in the manuscript. All analyses were performed within the Outbreak Data Analysis Platform (ODAP). All data and code can be accessed using information in the 'Data sharing' and 'Code sharing' statements at the end of the manuscript. No statistical method was used to predetermine sample size. Data distribution was assumed to be normal but this was not formally tested. Olink assays and immunoassays were randomized and investigators were blinded to outcomes.

To determine protein signatures that associated with each symptom outcome, a ridge PLR was used. PLR shrinks coefficients to account for combined effects within high-dimensional data, preventing false discovery while managing multicollinearity34. Thus, PLR was chosen a priori as the most appropriate model to assess associations between a large number of explanatory variables (that may work together to mediate effects) and symptom outcome34,62,70,74. In keeping with our aim to perform an unbiased exploration of inflammatory process, the model alpha was set to zero, facilitating regularization without complete penalization of any mediator. This enabled review of all possible mediators that might associate with LC62.

A 50 repeats tenfold nested cross-validation was used to select the optimal lambda for each model and assess its accuracy (Extended Data Fig. 1). The performance of the cognitive impairment model was influenced by the imbalance in size of the symptom group ( n = 60) relative to recovered ( n = 250). The model was weighted to account for this imbalance resulting in a sensitivity of 0.98, indicating its validity. We have expanded on the model performance and validation approaches in Supplementary Information.

Age, sex, acute disease severity and preexisting comorbidities were included as covariates in the PLR analysis (Supplementary Tables 1 and 3). Covariates were selected a priori using features reported to influence the risk of LC and inflammatory responses1,39,64,75. Ethnicity was not included since it has been shown not to predict symptom outcome in this cohort64. Individuals with missing data were excluded from the regression analysis. Each symptom group was compared with the 'recovered' group. The model coefficients of each covariate were converted into ORs for each outcome and visualized in a forest plot, after removing variables associated with regularized OR between 0.98 and 1.02 or in cases where most variables fell outside of this range, using mediators associated with the highest decile of coefficients either side of this range. This enabled exclusion of mediators with effect sizes that were unlikely to have clinical or mechanistic importance since the ridge PLR shrinks and orders coefficients according to their relative importance rather than making estimates with standard error. Thus, confidence intervals cannot be appropriately derived from PLR, and forest plot error bars were calculated using the median accuracy of the model generated by the nested cross-validation. To verify observations made through PLR analysis, we also performed an unadjusted PLR, an unadjusted logistic regression and a PLS analysis. Univariate analyses using Wilcoxon signed-rank test was also performed (Supplementary Table 8, Appendix 1). Analyses were performed in R version 4.2.0 using 'data.table v1.14.2', 'EnvStats v2.7.0' 'tidyverse v1.3.2', 'lme4 v1.1-32', 'caret v6.0-93', 'glmnet v4.1-6', 'mdatools v0.14.0', 'ggpubbr v0.4.0' and 'ggplot2 v3.3.6' packages.

To further investigate the relationship between proteins elevated in each symptom group, we performed a correlation network analysis using Spearman's rank correlation coefficient and false discovery rate (FDR) thresholding. The mediators visualized in the PLR forest plots, which were associated with cardiorespiratory symptoms, fatigue, anxiety/depression GI symptoms and cognitive impairment were used, respectively. Analyses were performed in R version 4.2.0 using 'bootnet v1.5.6 ' and 'qgraph v1.9.8 ' packages.

To determine whether differences in protein levels between men and women related to hormonal differences, we divided each symptom group into premenopausal and postmenopausal groups using an age cutoff of 50 years old. Differences between sexes in each group were determined using the Wilcoxon signed-rank test. To understand whether antigen persistence contributed to inflammation in adults with LC, the median viral antigen concentration from sputum/BALF samples and cytokine concentrations from nasal samples were compared using the Wilcoxon signed-rank test. All tests were two-tailed and statistical significance was defined as a P value < 0.05 after adjustment for FDR ( q-value of 0.05). Analyses were performed in R version 4.2.0 using 'bootnet v1.5.6' and 'qgraph v1.9.8' packages.

Extended Data Fig. 10 was made using Biorender, accessed at www.biorender.com.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

References

Klein, J. et al. Distinguishing features of Long COVID identified through immune profiling. Nature https://doi.org/10.1038/s41586-023-06651-y (2023).

Woo, W.-M. et al. The C. elegans F-spondin family protein SPON-1 maintains cell adhesion in neural and non-neural tissues. Development 135, 2747-2756 (2008).

Taquet, M. et al. Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization. Nat. Med. https://doi.org/10.1038/s41591-023-02525-y (2023).

Firinguetti, L., Kibria, G. & Araya, R. Study of partial least squares and ridge regression methods. Commun. Stat. Simul. Comput 46, 6631-6644 (2017).

Article Google Scholar

Rivera-Torruco, G. et al. Isthmin 1 identifies a subset of lung hematopoietic stem cells and it is associated with systemic inflammation. J. Immunol. 202, 118.18 (2019).

Article Google Scholar

Raman, B. et al. Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study. Lancet Respir. Med 11, 1003-1019 (2023).

Article Google Scholar

Download references

Acknowledgements

This research used data assets made available by ODAP as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref. MC_PC_20058). This work is supported by the following grants: the PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research (NIHR; grant references MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the MRC (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference C18616/A25153). Other grants that have supported this work include the UK Coronavirus Immunology Consortium (funder reference 1257927), the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit in Respiratory Infections at Imperial College London and NIHR Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, (NIHR award 200907), Wellcome Trust and Department for International Development (215091/Z/18/Z), Health Data Research UK (grant code 2021.0155), MRC (grant code MC_UU_12014/12) and NIHR Clinical Research Network for providing infrastructure support for this research. We also acknowledge the support of the MRC EMINENT Network (MR/R502121/1), which is cofunded by GSK, the Comprehensive Local Research Networks, the MRC HIC-Vac network (MR/R005982/1) and the RSV Consortium in Europe Horizon 2020 Framework Grant 116019. F.L. is supported by an MRC clinical training fellowship (award MR/W000970/1). C.E. is funded by NIHR (grant P91258-4). L.-P.H. is supported by Oxford NIHR Biomedical Research Centre. A.A.R.T. is supported by a British Heart Foundation (BHF) Intermediate Clinical Fellowship (FS/18/13/33281). S.L.R.-J. receives support from UK Research and Innovation (UKRI), Global Challenges Research Fund (GCRF), Rosetrees Trust, British HIV association (BHIVA), European & Developing Countries Clinical Trials Partnership (EDCTP) and Globvac. J.D.C. has grants from AstraZeneca, Boehringer Ingelheim, GSK, Gilead Sciences, Grifols, Novartis and Insmed. R.A.E. holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). A. Horsley is currently supported by UK Research and Innovation, NIHR and NIHR Manchester BRC. B.R. receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. D.G.W. is supported by an NIHR Advanced Fellowship. A. Ho has received support from MRC and for the Coronavirus Immunology Consortium (MR/V028448/1). L.T. is supported by the US Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085 and the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections (NIHR200907) at the University of Liverpool in partnership with UK Health Security Agency (UK-HSA), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. L.V.W. has received support from UKRI, GSK/Asthma and Lung UK and NIHR for this study. M.G.S. has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool. J.K.B. is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1 and MC_PC_20029). The funders were not involved in the study design, interpretation of data or writing of this manuscript. The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care (DHSC), the Department for International Development (DID), NIHR, MRC, the Wellcome Trust, UK-HSA, the National Health Service or the Department of Health. P.J.M.O. is supported by a NIHR Senior Investigator Award (award 201385). We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the PHOSP-COVID study at all of the 65 NHS trusts/health boards and 25 research institutions across the United Kingdom, as well as those who contributed to setting up and delivering the ISARIC4C study at 305 NHS trusts/health boards. We also thank all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland and Public Health England. We thank K. Holmes at the NIHR Office for Clinical Research Infrastructure for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well the NIHR Office for Clinical Research Infrastructure for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer's Research UK, Asthma and Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and Long Covid Support. We also thank G. Khandaker and D. C. Newcomb who provided valuable feedback on this work. Extended Data Fig. 10 was created using Biorender.

Author information

Author notes

These authors contributed equally: Felicity Liew, Claudia Efstathiou, Ryan S. Thwaites, Peter J. M. Openshaw.

Authors and Affiliations

National Heart and Lung Institute, Imperial College London, London, UK

Felicity Liew, Claudia Efstathiou, Sara Fontanella, Dawid Swieboda, Jasmin K. Sidhu, Stephanie Ascough, Onn Min Kon, Luke S. Howard, Jennifer K. Quint, Christopher Chiu, Ryan S. Thwaites, Peter J. M. Openshaw, Jake Dunning & Peter J. M. Openshaw

Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK

Matthew Richardson, Ruth Saunders, Olivia C. Leavy, Omer Elneima, Hamish J. C. McAuley, Amisha Singapuri, Marco Sereno, Victoria C. Harris, Neil J. Greening, Rachael A. Evans, Louise V. Wain, Christopher Brightling & Ananga Singapuri

NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

Shona C. Moore, Daniel G. Wootton, Malcolm G. Semple, Lance Turtle, William A. Paxton & Georgios Pollakis

The Imperial Clinical Respiratory Research Unit, Imperial College NHS Trust, London, UK

Noura Mohamed

Cardiovascular Research Team, Imperial College Healthcare NHS Trust, London, UK

Jose Nunag & Clara King

Department of Population Health Sciences, University of Leicester, Leicester, UK

Olivia C. Leavy, Louise V. Wain & Beatriz Guillen-Guio

NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK

Aarti Shikotra

Centre for Exercise and Rehabilitation Science, NIHR Leicester Biomedical Research Centre-Respiratory, University of Leicester, Leicester, UK

Linzy Houchen-Wolloff

Usher Institute, University of Edinburgh, Edinburgh, UK

Nazir I. Lone, Luke Daines, Annemarie B. Docherty, Nazir I. Lone, Matthew Thorpe, Annemarie B. Docherty, Thomas M. Drake, Cameron J. Fairfield, Ewen M. Harrison, Stephen R. Knight, Kenneth A. Mclean, Derek Murphy, Lisa Norman, Riinu Pius & Catherine A. Shaw

Centre for Medical Informatics, The Usher Institute, University of Edinburgh, Edinburgh, UK

Matthew Thorpe, Annemarie B. Docherty, Ewen M. Harrison, J. Kenneth Baillie, Sarah L. Rowland-Jones, A. A. Roger Thompson & Thushan de Silva

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

A. A. Roger Thompson, Sarah L. Rowland-Jones, Thushan I. de Silva & James D. Chalmers

University of Dundee, Ninewells Hospital and Medical School, Dundee, UK

James D. Chalmers & Ling-Pei Ho

MRC Human Immunology Unit, University of Oxford, Oxford, UK

Ling-Pei Ho & Alexander Horsley

Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Alexander Horsley & Betty Raman

Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Betty Raman & Krisnah Poinasamy

Asthma + Lung UK, London, UK

Krisnah Poinasamy & Michael Marks

Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK

Michael Marks

Hospital for Tropical Diseases, University College London Hospital, London, UK

Michael Marks

Division of Infection and Immunity, University College London, London, UK

Michael Marks & Mahdad Noursadeghi

MRC Centre for Virus Research, School of Infection and Immunity, University of Glasgow, Glasgow, UK

Antonia Ho & William Greenhalf

Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

William Greenhalf & J. Kenneth Baillie

The Roslin Institute, University of Edinburgh, Edinburgh, UK

J. Kenneth Baillie, J. Kenneth Baillie, Sara Clohisey, Fiona Griffiths, Ross Hendry, Andrew Law & Wilna Oosthuyzen

Pandemic Science Hub, University of Edinburgh, Edinburgh, UK

J. Kenneth Baillie

The Pandemic Institute, University of Liverpool, Liverpool, UK

Malcolm G. Semple & Lance Turtle

University of Manchester, Manchester, UK

Kathryn Abel, Perdita Barran, H. Chinoy, Bill Deakin, M. Harvie, C. A. Miller, Stefan Stanel & Drupad Trivedi

Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK

Kathryn Abel & J. Kenneth Baillie

North Bristol NHS Trust and University of Bristol, Bristol, UK

H. Adamali, David Arnold, Shaney Barratt, A. Dipper, Sarah Dunn, Nick Maskell, Anna Morley, Leigh Morrison, Louise Stadon, Samuel Waterson & H. Welch

University of Edinburgh, Manchester, UK

Davies Adeloye, D. E. Newby, Riinu Pius, Igor Rudan, Manu Shankar-Hari, Catherine Sudlow, Sarah Walmsley & Bang Zheng

King's College Hospital NHS Foundation Trust and King's College London, London, UK

Oluwaseun Adeyemi, Rita Adrego, Hosanna Assefa-Kebede, Jonathon Breeze, S. Byrne, Pearl Dulawan, Amy Hoare, Caroline Jolley, Abigail Knighton, M. Malim, Sheetal Patale, Ida Peralta, Natassia Powell, Albert Ramos, K. Shevket, Fabio Speranza & Amelie Te

Guy's and St Thomas' NHS Foundation Trust, London, UK

Laura Aguilar Jimenez, Gill Arbane, Sarah Betts, Karen Bisnauthsing, A. Dewar, Nicholas Hart, G. Kaltsakas, Helen Kerslake, Murphy Magtoto, Philip Marino, L. M. Martinez, Marlies Ostermann, Jennifer Rossdale & Teresa Solano

Royal Free London NHS Foundation Trust, London, UK

Shanaz Ahmad, Simon Brill, John Hurst, Hannah Jarvis, C. Laing, Lai Lim, S. Mandal, Darwin Matila, Olaoluwa Olaosebikan & Claire Singh

University Hospital Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK

N. Ahmad Haider, Catherine Atkin, Rhiannon Baggott, Michelle Bates, A. Botkai, Anna Casey, B. Cooper, Joanne Dasgin, Camilla Dawson, Katharine Draxlbauer, N. Gautam, J. Hazeldine, T. Hiwot, Sophie Holden, Karen Isaacs, T. Jackson, Vicky Kamwa, D. Lewis, Janet Lord, S. Madathil, C. McGee, K. Mcgee, Aoife Neal, Alex Newton-Cox, Joseph Nyaboko, Dhruv Parekh, Z. Peterkin, H. Qureshi, Liz Ratcliffe, Elizabeth Sapey, J. Short, Tracy Soulsby, J. Stockley, Zehra Suleiman, Tamika Thompson, Maximina Ventura, Sinead Walder, Carly Welch, Daisy Wilson, S. Yasmin & Kay Por Yip

Stroke Association, London, UK

Rubina Ahmed & Richard Francis

University College London Hospital and University College London, London, UK

Nyarko Ahwireng, Dongchun Bang, Donna Basire, Jeremy Brown, Rachel Chambers, A. Checkley, R. Evans, M. Heightman, T. Hillman, Joseph Jacob, Roman Jastrub, M. Lipman, S. Logan, D. Lomas, Marta Merida Morillas, Hannah Plant, Joanna Porter, K. Roy & E. Wall

Oxford University Hospitals NHS Foundation Trust and University of Oxford, Oxford, UK

Mark Ainsworth, Asma Alamoudi, Angela Bloss, Penny Carter, M. Cassar, Jin Chen, Florence Conneh, T. Dong, Ranuromanana Evans, V. Ferreira, Emily Fraser, John Geddes, F. Gleeson, Paul Harrison, May Havinden-Williams, P. Jezzard, Ivan Koychev, Prathiba Kurupati, H. McShane, Clare Megson, Stefan Neubauer, Debby Nicoll, C. Nikolaidou, G. Ogg, Edmund Pacpaco, M. Pavlides, Yanchun Peng, Nayia Petousi, John Pimm, Najib Rahman, M. J. Rowland, Kathryn Saunders, Michael Sharpe, Nick Talbot, E. M. Tunnicliffe & C. Xie

St George's University Hospitals NHS Foundation Trust, London, UK

Mariam Ali, Raminder Aul, A. Dunleavy, D. Forton, Mark Mencias, N. Msimanga, T. Samakomva, Sulman Siddique, Vera Tavoukjian & J. Teixeira

University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK

M. Aljaroof, Natalie Armstrong, H. Arnold, Hnin Aung, Majda Bakali, M. Bakau, E. Baldry, Molly Baldwin, Charlotte Bourne, Michelle Bourne, Nigel Brunskill, P. Cairns, Liesel Carr, Amanda Charalambou, C. Christie, Melanie Davies, Enya Daynes, Sarah Diver, Rachael Dowling, Sarah Edwards, C. Edwardson, H. Evans, J. Finch, Sarah Glover, Nicola Goodman, Bibek Gooptu, Kate Hadley, Pranab Haldar, Beverley Hargadon, W. Ibrahim, L. Ingram, Kamlesh Khunti, A. Lea, D. Lee, Gerry McCann, P. McCourt, Teresa Mcnally, George Mills, Will Monteiro, Manish Pareek, S. Parker, Anne Prickett, I. N. Qureshi, A. Rowland, Richard Russell, Salman Siddiqui, Sally Singh, J. Skeemer, M. Soares, E. Stringer, T. Thornton, Martin Tobin, T. J. C. Ward, F. Woodhead, Tom Yates & A. J. Yousuf

University of Exeter, Exeter, UK

Louise Allan, Clive Ballard & Andrew McGovern

University of Leicester, Leicester, UK

Richard Allen, Michelle Bingham, Terry Brugha, Selina Finney, Rob Free, Don Jones, Claire Lawson, Daniel Lozano-Rojas, Gardiner Lucy, Alistair Moss, Elizabeta Mukaetova-Ladinska, Petr Novotny, Kimon Ntotsis, Charlotte Overton, John Pearl, Tatiana Plekhanova, M. Richardson, Nilesh Samani, Jack Sargant, Ruth Saunders, M. Sharma, Mike Steiner, Chris Taylor, Sarah Terry, C. Tong, E. Turner, J. Wormleighton & Bang Zhao

Liverpool University Hospitals NHS Foundation Trust and University of Liverpool, Liverpool, UK

Lisa Allerton, Ann Marie Allt, M. Beadsworth, Anthony Berridge, Jo Brown, Shirley Cooper, Andy Cross, Sylviane Defres, S. L. Dobson, Joanne Earley, N. French, Kera Hainey, Hayley Hardwick, Jenny Hawkes, Victoria Highett, Sabina Kaprowska, Angela Key, Lara Lavelle-Langham, N. Lewis-Burke, Gladys Madzamba, Flora Malein, Sophie Marsh, Chloe Mears, Lucy Melling, Matthew Noonan, L. Poll, James Pratt, Emma Richardson, Anna Rowe, Victoria Shaw, K. A. Tripp, Lilian Wajero, S. A. Williams-Howard, Dan Wootton & J. Wyles

Sherwood Forest Hospitals NHS Foundation Trust, Nottingham, UK

Lynne Allsop, Kaytie Bennett, Phil Buckley, Margaret Flynn, Mandy Gill, Camelia Goodwin, M. Greatorex, Heidi Gregory, Cheryl Heeley, Leah Holloway, Megan Holmes, John Hutchinson, Jill Kirk, Wayne Lovegrove, Terri Ann Sewell, Sarah Shelton, D. Sissons, Katie Slack, Susan Smith, D. Sowter, Sarah Turner, V. Whitworth & Inez Wynter

Nottingham University Hospitals NHS Trust and University of Nottingham, London, UK

Paula Almeida, Akram Hosseini, Robert Needham & Karen Shaw

Manchester University NHS Foundation Trust and University of Manchester, London, UK

Bashar Al-Sheklly, Cristina Avram, John Blaikely, M. Buch, N. Choudhury, David Faluyi, T. Felton, T. Gorsuch, Neil Hanley, Tracy Hussell, Zunaira Kausar, Natasha Odell, Rebecca Osbourne, Karen Piper Hanley, K. Radhakrishnan & Sue Stockdale

Imperial College London, London, UK

Danny Altmann, Anew Frankel, Luke S. Howard, Desmond Johnston, Liz Lightstone, Anne Lingford-Hughes, William Man, Steve McAdoo, Jane Mitchell, Philip Molyneaux, Christos Nicolaou, D. P. O'Regan, L. Price, Jennifer K. Quint, David Smith, Jonathon Valabhji, Simon Walsh, Martin Wilkins & Michelle Willicombe

Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK

Maria Alvarez Corral, Ava Maria Arias, Emily Bevan, Denise Griffin, Jane Martin, J. Owen, Sheila Payne, A. Prabhu, Annabel Reed, Will Storrar, Nick Williams & Caroline Wrey Brown

British Heart Foundation, Birmingham, UK

Shannon Amoils

NHS Greater Glasgow and Clyde Health Board and University of Glasgow, Glasgow, UK

David Anderson, Neil Basu, Hannah Bayes, Colin Berry, Ammani Brown, Andrew Dougherty, K. Fallon, L. Gilmour, D. Grieve, K. Mangion, I. B. McInnes, A. Morrow, Kathryn Scott & R. Sykes

University of Oxford, Oxford, UK

Charalambos Antoniades, A. Bates, M. Beggs, Kamaldeep Bhui, Katie Breeze, K. M. Channon, David Clark, X. Fu, Masud Husain, Lucy Kingham, Paul Klenerman, Hanan Lamlum, X. Li, E. Lukaschuk, Celeste McCracken, K. McGlynn, R. Menke, K. Motohashi, T. E. Nichols, Godwin Ogbole, S. Piechnik, I. Propescu, J. Propescu, A. A. Samat, Z. B. Sanders, Louise Sigfrid & M. Webster

Belfast Health and Social Care Trust and Queen's University Belfast, Belfast, UK

Cherie Armour, Vanessa Brown, John Busby, Bronwen Connolly, Thelma Craig, Stephen Drain, Liam Heaney, Bernie King, Nick Magee, E. Major, Danny McAulay, Lorcan McGarvey, Jade McGinness, Tunde Peto & Roisin Stone

Airedale NHS Foundation Trust, Keighley, UK

Lisa Armstrong, Brigid Hairsine, Helen Henson, Claire Kurasz, Alison Shaw & Liz Shenton

Wrightington Wigan and Leigh NHS Trust, Wigan, UK

A. Ashish, Josh Cooper & Emma Robinson

Leeds Teaching Hospitals and University of Leeds, Leeds, UK

Andrew Ashworth, Paul Beirne, Jude Clarke, C. Coupland, Matthhew Dalton, Clair Favager, Jodie Glossop, John Greenwood, Lucy Hall, Tim Hardy, Amy Humphries, Jennifer Murira, Dan Peckham, S. Plein, Jade Rangeley, Gwen Saalmink, Ai Lyn Tan, Elaine Wade, Beverley Whittam, Nicola Window & Janet Woods

University of Liverpool, Liverpool, UK

M. Ashworth, D. Cuthbertson, G. Kemp, Anne McArdle, Benedict Michael, Will Reynolds, Lisa Spencer, Ben Vinson, Katie A. Ahmed, Jane A. Armstrong, Milton Ashworth, Innocent G. Asiimwe, Siddharth Bakshi, Samantha L. Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Nicola Carlucci, Emily Cass, Benjamin W. A. Catterall, Jordan J. Clark, Emily A. Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Alejandra Doce Carracedo, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis W. S. Fisher, Lisa Flaherty, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Karl Holden, Anthony Holmes, Rebecca L. Jensen, Christopher B. Jones, Trevor R. Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A. Livoti, Maria Mancini, Hannah Massey, Nicole Maziere, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S. Miah, Joanna Middleton, Joyce Mitchell, Ellen G. Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, P. Matthew Ridley, Debby Sales, Rebecca K. Shears, Benjamin Small, Krishanthi S. Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock & J. Eunice Zhang

University College London, London, UK

Shahab Aslani, Amita Banerjee, R. Batterham, Gabrielle Baxter, Robert Bell, Anthony David, Emma Denneny, Alun Hughes, W. Lilaonitkul, P. Mehta, Ashkan Pakzad, Bojidar Rangelov, B. Williams, James Willoughby & Moucheng Xu

Hull University Teaching Hospitals NHS Trust and University of Hull, Hull, UK

Paul Atkin, K. Brindle, Michael Crooks, Katie Drury, Nicholas Easom, Rachel Flockton, L. Holdsworth, A. Richards, D. L. Sykes, Susannah Thackray-Nocera & C. Wright

East Kent Hospitals University NHS Foundation Trust, Canterbury, UK

Liam Austin, Eva Beranova, Tracey Cosier, Joanne Deery, Tracy Hazelton, Carly Price, Hazel Ramos, Reanne Solly, Sharon Turney & Heather Weston

Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK

Nikos Avramidis, J. Kenneth Baillie, Erola Pairo-Castineira & Konrad Rawlik

Roslin Institute, University of Edinburgh, Edinburgh, UK

Nikos Avramidis, J. Kenneth Baillie & Erola Pairo-Castineira

Newcastle upon Tyne Hospitals NHS Foundation Trust and University of Newcastle, Newcastle upon Tyne, UK

A. Ayoub, J. Brown, G. Burns, Gareth Davies, Anthony De Soyza, Carlos Echevarria, Helen Fisher, C. Francis, Alan Greenhalgh, Philip Hogarth, Joan Hughes, Kasim Jiwa, G. Jones, G. MacGowan, D. Price, Avan Sayer, John Simpson, H. Tedd, S. Thomas, Sophie West, M. Witham, S. Wright & A. Young

East Cheshire NHS Trust, Macclesfield, UK

Marta Babores, Maureen Holland, Natalie Keenan, Sharlene Shashaa & Helen Wassall

Sheffield Teaching NHS Foundation Trust and University of Sheffield, Sheffield, UK

J. Bagshaw, M. Begum, K. Birchall, Robyn Butcher, H. Carborn, Flora Chan, Kerry Chapman, Yutung Cheng, Luke Chetham, Cameron Clark, Zach Coburn, Joby Cole, Myles Dixon, Alexandra Fairman, J. Finnigan, H. Foot, David Foote, Amber Ford, Rebecca Gregory, Kate Harrington, L. Haslam, L. Hesselden, J. Hockridge, Ailsa Holbourn, B. Holroyd-Hind, L. Holt, Alice Howell, E. Hurditch, F. Ilyas, Claire Jarman, Allan Lawrie, Ju Hee Lee, Elvina Lee, Rebecca Lenagh, Alison Lye, Irene Macharia, M. Marshall, Angeline Mbuyisa, J. McNeill, Sharon Megson, J. Meiring, L. Milner, S. Misra, Helen Newell, Tom Newman, C. Norman, Lorenza Nwafor, Dibya Pattenadk, Megan Plowright, Julie Porter, Phillip Ravencroft, C. Roddis, J. Rodger, Peter Saunders, J. Sidebottom, Jacqui Smith, Laurie Smith, N. Steele, G. Stephens, R. Stimpson, B. Thamu, N. Tinker, Kim Turner, Helena Turton, Phillip Wade, S. Walker, James Watson, Imogen Wilson & Amira Zawia

University of Nottingham, Nottingham, UK

David Baguley, Chris Coleman, E. Cox, Laura Fabbri, Susan Francis, Ian Hall, E. Hufton, Simon Johnson, Fasih Khan, Paaig Kitterick, Richard Morriss, Nick Selby, Iain Stewart & Louise Wright

Wirral University Teaching Hospital, Wirral, UK

Elisabeth Bailey, Anne Reddington & Andrew Wight

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK

J. Kenneth Baillie

University of Swansea, Swansea, UK

Steve Bain

University of Southampton, London, UK

David Baldwin, P. C. Calder, Nathan Huneke & Gemma Simons

Royal Brompton and Harefield Clinical Group, Guy's and St Thomas' NHS Foundation Trust, London, UK

R. E. Barker, Daniele Cristiano, N. Dormand, P. George, Mahitha Gummadi, S. Kon, Kamal Liyanage, C. M. Nolan, B. Patel, Suhani Patel, Oliver Polgar, L. Price, P. Shah, Suver Singh & J. A. Walsh

York and Scarborough NHS Foundation Trust, York, UK

Laura Barman, Claire Brookes, K. Elliott, L. Griffiths, Zoe Guy, Kate Howard, Diana Ionita, Heidi Redfearn, Carol Sarginson & Alison Turnbull

NHS Highland, Inverness, UK

Fiona Barrett, A. Donaldson & Beth Sage

Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK

Helen Baxendale, Lucie Garner, C. Johnson, J. Mackie, Alice Michael, J. Newman, Jamie Pack, K. Paques, H. Parfrey, J. Parmar & A. Reddy

University Hospitals of Derby and Burton, Derby, UK

Paul Beckett, Caroline Dickens & Uttam Nanda

NHS Lanarkshire, Hamilton, UK

Murdina Bell, Angela Brown, M. Brown, R. Hamil, Karen Leitch, L. Macliver, Manish Patel, Jackie Quigley, Andrew Smith & B. Welsh

Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Clinical Research Facility and University of Cambridge, Cambridge, UK

Areti Bermperi, Isabel Cruz, K. Dempsey, Anne Elmer, Jonathon Fuld, H. Jones, Sherly Jose, Stefan Marciniak, M. Parkes, Carla Ribeiro, Jessica Taylor, Mark Toshner, L. Watson & J. Worsley

Loughborough University, Loughborough, UK

Lettie Bishop & David Stensel

Betsi Cadwallader University Health Board, Bangor, UK

Annette Bolger, Ffyon Davies, Ahmed Haggar, Joanne Lewis, Arwel Lloyd, R. Manley, Emma McIvor, Daniel Menzies, K. Roberts, W. Saxon, David Southern, Christian Subbe & Victoria Whitehead

Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK

Charlotte Bolton, J. Bonnington, Melanie Chrystal, Catherine Dupont, Paul Greenhaff, Ayushman Gupta, W. Jang, S. Linford, Laura Matthews, Athanasios Nikolaidis, Sabrina Prosper & Andrew Thomas

King's College London, London, UK

Kate Bramham, M. Brown, Khalida Ismail, Tim Nicholson, Carmen Pariante, Claire Sharpe, Simon Wessely & J. Whitney

Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK

Lucy Brear, Karen Regan, Dinesh Saralaya & Kim Storton

South London and Maudsley NHS Foundation Trust and King's College London, London, UK

G. Breen & M. Hotopf

London School of Hygiene and Tropical Medicine, London, UK

Andrew Briggs

Whittington Health NHS Trust, London, UK

E. Bright, P. Crisp, Ruvini Dharmagunawardena & M. Stern

Cardiff and Vale University Health Board, Cardiff, UK

Lauren Broad, Teriann Evans, Matthew Haynes, L. Jones, Lucy Knibbs, Alison McQueen, Catherine Oliver, Kerry Paradowski, Ramsey Sabit & Jenny Williams

Yeovil District Hospital NHS Foundation Trust, Yeovil, UK

Andrew Broadley

University of Birmingham, Birmingham, UK

Mattew Broome, Paul McArdle, Paul Moss, David Thickett, Rachel Upthegrove, Dan Wilkinson, David Wraith & Erin L. Aldera

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

Anda Bularga

University of Cambridge, Cambridge, UK

Ed Bullmore, Jonathon Heeney, Claudia Langenberg, William Schwaeble, Charlotte Summers & J. Weir McCall

NIHR Leicester Biomedical Research Centre-Respiratory Patient and Public Involvement Group, Leicester, UK

Jenny Bunker, Rhyan Gill & Rashmita Nathu

Imperial College Healthcare NHS Trust and Imperial College London, London, UK

L. Burden, Ellen Calvelo, Bethany Card, Caitlin Carr, Edwin Chilvers, Donna Copeland, P. Cullinan, Patrick Daly, Lynsey Evison, Tamanah Fayzan, Hussain Gordon, Sulaimaan Haq, Gisli Jenkins, Clara King, Onn Min Kon, Katherine March, Myril Mariveles, Laura McLeavey, Silvia Moriera, Unber Munawar, Uchechi Nwanguma, Lorna Orriss-Dib, Alexandra Ross, Maura Roy, Emily Russell, Katherine Samuel, J. Schronce, Neil Simpson, Lawrence Tarusan, David Thomas, Chloe Wood & Najira Yasmin

Harrogate and District NHD Foundation Trust, Harrogate, UK

Tracy Burdett, James Featherstone, Cathy Lawson, Alison Layton, Clare Mills & Lorraine Stephenson

Newcastle University/Chair of NIHR Dementia TRC, Newcastle, UK

David Burn

Oxford University Hospitals NHS Foundation Trust, Oxford, UK

A. Burns & N. Kanellakis

Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK

Al-Tahoor Butt, Martina Coulding, Heather Jones, Susan Kilroy, Jacqueline McCormick, Jerome McIntosh, Heather Savill, Victoria Turner & Joanne Vere

University of Oxford, Nuffield Department of Medicine, Oxford, UK

G. Carson

University of Glasgow, Glasgow, UK

Jonathon Cavanagh, S. MacDonald, Kate O'Donnell, John Petrie, Naveed Sattar & Mark Spears

United Lincolnshire Hospitals NHS Trust, Grantham, UK

Manish Chablani & Lynn Osborne

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK

Trudie Chalder

University Hospital of South Manchester NHS Foundation Trust, Manchester, UK

N. Chaudhuri

University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK

Caroline Childs, R. Djukanovic, S. Fletcher, Matt Harvey, Mark Jones, Elizabeth Marouzet, B. Marshall, Reena Samuel, T. Sass, Tim Wallis & Helen Wheeler

King's College Hospital/Guy's and St Thomas' NHS FT, London, UK

A. Chiribiri & C. O'Brien

Barts Health NHS Trust, London, UK

K. Chong-James, C. David, W. Y. James, Paul Pfeffer & O. Zongo

NHS Lothian and University of Edinburgh, Edinburgh, UK

Gaunab Choudhury, S. Clohisey, Andrew Deans, J. Furniss, Ewen Harrison, S. Kelly & Aziz Sheikh

School of Cardiovascular Medicine and Sciences. King's College London, London, UK

Phillip Chowienczyk

Lewisham and Greenwich NHS Trust, London, UK

G. Coakley

Hywel Dda University Health Board, Haverfordwest, UK

S. Coetzee, Kim Davies, Rachel Ann Hughes, Ronda Loosley, Heather McGuinness, Abdelrahman Mohamed, Linda O'Brien, Zohra Omar, Emma Perkins, Janet Phipps, Gavin Ross, Abigail Taylor, Helen Tench & Rebecca Wolf-Roberts

NHS Tayside and University of Dundee, Dundee, UK

David Connell, C. Deas, Anne Elliott, J. George, S. Mohammed, J. Rowland, A. R. Solstice, Debbie Sutherland & Caroline Tee

Swansea Bay University Health Board, Port Talbot, UK

Lynda Connor, Amanda Cook, Gwyneth Davies, Tabitha Rees, Favas Thaivalappil & Caradog Thomas

Faculty of Medicine, Nursing and Health Sciences, School of Biomedical Sciences, Monash University, Melbourne, Victoria, Australia

Eamon Coughlan

Rotherham NHS Foundation Trust, Rotherham, UK

Alison Daniels, Anil Hormis, Julie Ingham & Lisa Zeidan

Salford Royal NHS Foundation Trust, Salford, UK

P. Dark, Nawar Diar-Bakerly, D. Evans, E. Hardy, Alice Harvey, D. Holgate, Sean Knight, N. Mairs, N. Majeed, L. McMorrow, J. Oxton, Jessica Pendlebury, C. Summersgill, R. Ugwuoke & S. Whittaker

Cwm Taf Morgannwg University Health Board, Mountain Ash, UK

Ellie Davies, Cerys Evenden, Alyson Hancock, Kia Hancock, Ceri Lynch, Meryl Rees, Lisa Roche, Natalie Stroud & T. Thomas-Woods

Borders General Hospital, NHS Borders, Melrose, UK

Joy Dawson, Hosni El-Taweel & Leanne Robinson

Aneurin Bevan University Health Board, Caerleon, UK

Amanda Dell, Sara Fairbairn, Nancy Hawkings, Jill Haworth, Michaela Hoare, Victoria Lewis, Alice Lucey, Georgia Mallison, Heeah Nassa, Chris Pennington, Andrea Price, Claire Price, Andrew Storrie, Gemma Willis & Susan Young

University of Exeter Medical School, Exeter, UK

J. Dennis

London North West University Healthcare NHS Trust, London, UK

Shalin Diwanji, Sambasivarao Gurram, Padmasayee Papineni, Sheena Quaid, Gerlynn Tiongson & Ekaterina Watson

Alzheimer's Research UK, Cambridge, UK

Hannah Dobson

Health and Care Research Wales, Cardiff, UK

Yvette Ellis

University of Bristol, Bristol, UK

Jonathon Evans

University of Sheffield, Sheffield, UK

L. Finnigan, Laura Saunders & James Wild

Great Western Hospital Foundation Trust, Swindon, UK

Eva Fraile & Jacinta Ugoji

Royal Devon and Exeter NHS Trust, Barnstaple, UK

Michael Gibbons

Kettering General Hospital NHS Trust, Kettering, UK

Anne-Marie Guerdette, Melanie Hewitt, R. Reddy, Katie Warwick & Sonia White

NIHR Leicester Biomedical Research Centre, Leicester, UK

Beatriz Guillen-Guio

University of Leeds, Leeds, UK

Elspeth Guthrie & Max Henderson

Royal Surrey NHS Foundation Trust, Cranleigh, UK

Mark Halling-Brown & Katherine McCullough

Chesterfield Royal Hospital NHS Trust, Calow, UK

Edward Harris & Claire Sampson

Long Covid Support, London, UK

Claire Hastie, Natalie Rogers & Nikki Smith

King's College Hospital, NHS Foundation Trust and King's College London, London, UK

A. Hayday

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

Simon Heller

NIHR Office for Clinical Research Infrastructure, London, UK

Katie Holmes

Asthma UK and British Lung Foundation Partnership, London, UK

Ian Jarrold & Samantha Walker

North Middlesex University Hospital NHS Trust, London, UK

Bhagy Jayaraman & Tessa Light

Action for Pulmonary Fibrosis, Peterborough, UK

S. Jones

Cardiff University, National Centre for Mental Health, Cardiff, UK

Ian Jones

McPin Foundation, London, UK

Thomas Kabir

Roslin Institute, The University of Edinburgh, Edinburgh, UK

Steven Kerr

The Hillingdon Hospitals NHS Foundation Trust, London, UK

Samantha Kon, G. Landers, Harpreet Lota, Mariam Nasseri & Sofiya Portukhay

Queen Mary University of London, London, UK

Ania Korszun

Swansea University, Swansea Welsh Network, Hywel Dda University Health Board, Swansea, UK

Keir Lewis

Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK

Nazir I. Lone

Barts Heart Centre, London, UK

C. Manisty

Barts Health NHS Trust and Queen Mary University of London, London, UK

Adrian Martineau

Salisbury NHS Foundation Trust, Salisbury, UK

Wadzanai Matimba-Mupaya & Sophia Strong-Sheldrake

University of Newcastle, Newcastle, UK

Hamish McAllister-Williams, Stella-Maria Paddick, Anthony Rostron & John Paul Taylor

Gateshead NHS Trust, Gateshead, UK

W. McCormick, Lorraine Pearce, S. Pugmire, Wendy Stoker & Ann Wilson

Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester, UK

Katherine McIvor

Kidney Research UK, Peterborough, UK

Aisling McMahon

NHS Dumfries and Galloway, Dumfries, UK

Michael McMahon & Paula Neill

Swansea University, Swansea, UK

M. McNarry

MQ Mental Health Research, London, UK

Lea Milligan

BHF Centre for Cardiovascular Science, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

Nicholas Mills

Shropshire Community Health NHS Trust, Shropshire, UK

Sharon Painter, Johanne Tomlinson & Louise Warburton

Somerset NHS Foundation Trust, Taunton, UK

Sue Palmer, Dawn Redwood, Jo Tilley, Carinna Vickers & Tania Wainwright

Francis Crick Institute, London, UK

Markus Ralser

Manchester University NHD Foundation Trust, Manchester, UK

Pilar Rivera-Ortega

Diabetes UK, University of Glasgow, Glasgow, UK

Elizabeth Robertson

Barnsley Hospital NHS Foundation Trust, Barnsley, UK

Amy Sanderson

MRC-University of Glasgow Centre for Virus Research, Glasgow, UK

Janet Scott

Diabetes UK, London, UK

Kamini Shah

British Heart Foundation Centre, King's College London, London, UK

Ajay Shah

King's College Hospital NHS Foundation Trust, London, UK

Ajay Shah

University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK

R. Steeds

Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

R. Touyz

University College London NHS Foundation Trust, London and Barts Health NHS Trust, London, UK

T. Treibel

Northumbria University, Newcastle upon Tyne, UK

Ioannis Vogiatzis

Swansea University and Swansea Welsh Network, Swansea, UK

N. Williams

DUK | NHS Digital, Salford Royal Foundation Trust, Salford, UK

Bob Young

Queen Alexandra Hospital, Portsmouth, UK

Kayode Adeniji

Princess Royal Hospital, Haywards Heath, UK

Daniel Agranoff & Chi Eziefula

Bassetlaw Hospital, Bassetlaw, UK

Ken Agwuh

Darent Valley Hospital, Dartford, UK

Dhiraj Ail

Queen Elizabeth the Queen Mother Hospital, Margate, UK

Ana Alegria

School of Informatics, University of Edinburgh, Edinburgh, UK

Beatrice Alex, Benjamin Bach & James Scott-Brown

North East and North Cumbria Ingerated, Newcastle upon Tyne, UK

Sam Allen

Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Petros Andrikopoulos, Kanta Chechi, Marc-Emmanuel Dumas, Julian Griffin, Sonia Liggi & Zoltan Takats

Section of Genomic and Environmental Medicine, Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UK

Petros Andrikopoulos, Marc-Emmanuel Dumas, Michael Olanipekun & Anthonia Osagie

John Radcliffe Hospital, Oxford, UK

Brian Angus

Royal Albert Edward Infirmary, Wigan, UK

Abdul Ashish

Manchester Royal Infirmary, Manchester, UK

Dougal Atkinson

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK

J. Kenneth Baillie

Section of Molecular Virology, Imperial College London, London, UK

Wendy S. Barclay

Furness General Hospital, Barrow-in-Furness, UK

Shahedal Bari

Hull University Teaching Hospital Trust, Kingston upon Hull, UK

Gavin Barlow

Hillingdon Hospital, Hillingdon, UK

Stella Barnass

St Thomas' Hospital, London, UK

Nicholas Barrett

Coventry and Warwickshire, Coventry, UK

Christopher Bassford

St Michael's Hospital, Bristol, UK

Sneha Basude

Stepping Hill Hospital, Stockport, UK

David Baxter

Royal Liverpool University Hospital, Liverpool, UK

Michael Beadsworth

Bristol Royal Hospital Children's, Bristol, UK

Jolanta Bernatoniene

Scarborough Hospital, Scarborough, UK

John Berridge

Golden Jubilee National Hospital, Clydebank, UK

Colin Berry

Liverpool Heart and Chest Hospital, Liverpool, UK

Nicola Best

Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK

Debby Bogaert & Clark D. Russell

James Paget University Hospital, Great Yarmouth, UK

Pieter Bothma & Darell Tupper-Carey

Aberdeen Royal Infirmary, Aberdeen, UK

Robin Brittain-Long

Adamson Hospital, Cupar, UK

Naomi Bulteel

Royal Devon and Exeter Hospital, Exeter, UK

Tom Burden

Worcestershire Royal Hospital, Worcester, UK

Andrew Burtenshaw

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Gail Carson, Laura Merson & Louise Sigfrid

Conquest Hospital, Hastings, UK

Vikki Caruth

The James Cook University Hospital, Middlesbrough, UK

David Chadwick

Dorset County Hospital, Dorchester, UK

Duncan Chambler

Antimicrobial Resistance and Hospital Acquired Infection Department, Public Health England, London, UK

Meera Chand

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK

Kanta Chechi

Royal Bournemouth General Hospital, Bournemouth, UK

Nigel Chee

Harrogate Hospital, Harrogate, UK

Jenny Child

Royal Blackburn Teaching Hospital, Blackburn, UK

Srikanth Chukkambotla

Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, UK

Richard Clark, Audrey Coutts, Lorna Donelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy & Nicola Wrobel

Torbay Hospital, Torquay, UK

Tom Clark

Northern General Hospital, Sheffield, UK

Paul Collini, Cariad Evans & Gary Mills

Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK

Marie Connor, Jo Dalton, Chloe Donohue, Carrol Gamble, Michelle Girvan, Sophie Halpin, Janet Harrison, Clare Jackson, Laura Marsh, Stephanie Roberts & Egle Saviciute

Department of Infectious Disease, Imperial College London, London, UK

Graham S. Cooke & Shiranee Sriskandan

St Georges Hospital (Tooting), London, UK

Catherine Cosgrove

Blackpool Victoria Hospital, Blackpool, UK

Jason Cupitt & Joanne Howard

The Royal London Hospital, London, UK

Maria-Teresa Cutino-Moguel

MRC-University of Glasgow Centre for Virus Research, Glasgow, UK

Ana da Silva Filipe, Antonia Y. W. Ho, Sarah E. McDonald, Massimo Palmarini, David L. Robertson, Janet T. Scott & Emma C. Thomson

Salford Royal Hospital, Salford, UK

Paul Dark

University Hospital of North Durham, Durham, UK

Chris Dawson

Norfolk and Norwich University Hospital, Norwich, UK

Samir Dervisevic

Intensive Care Unit, Royal Infirmary Edinburgh, Edinburgh, UK

Annemarie B. Docherty & Seán Keating

Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK

Cara Donegan & Rebecca G. Spencer

Salisbury District Hospital, Salisbury, UK

Phil Donnison

National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Gonçalo dos Santos Correia, Matthew Lewis, Lynn Maslen, Caroline Sands, Zoltan Takats & Panteleimon Takis

Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Gonçalo dos Santos Correia, Matthew Lewis, Lynn Maslen, Caroline Sands & Panteleimon Takis

Guy's and St Thomas', NHS Foundation Trust, London, UK

Sam Douthwaite, Michael MacMahon, Marlies Ostermann & Manu Shankar-Hari

The Royal Oldham Hospital, Oldham, UK

Andrew Drummond

European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille University Hospital, University of Lille, Lille, France

Marc-Emmanuel Dumas

McGill University and Genome Quebec Innovation Centre, Montreal, Qeubec, Canada

Marc-Emmanuel Dumas

National Infection Service, Public Health England, London, UK

Jake Dunning & Maria Zambon

Hereford Count Hospital, Hereford, UK

Ingrid DuRand

Southampton General Hospital, Southampton, UK

Ahilanadan Dushianthan

Northampton General Hospital, Northampton, UK

Tristan Dyer

University Hospital of Wales, Cardiff, UK

Chrisopher Fegan

University Hospitals Bristol NHS Foundation Trust, Bristol, UK

Adam Finn

Liverpool School of Tropical Medicine, Liverpool, UK

Tom Fletcher

Leighton Hospital, Crewe, UK

Duncan Fullerton & Elijah Matovu

Manor Hospital, Walsall, UK

Atul Garg

Scunthorpe Hospital, Scunthorpe, UK

Sanjeev Garg

Cambridge University Hospital, Cambridge, UK

Effrossyni Gkrania-Klotsas

West Suffolk NHS Foundation Trust, Bury St Edmunds, UK

Jo Godden

Basingstoke and North Hampshire Hospital, Basingstoke, UK

Arthur Goldsmith

North Cumberland Infirmary, Carlisle, UK

Clive Graham

Paediatric Liver, GI and Nutrition Centre and MowatLabs, King's College Hospital, London, UK

Tassos Grammatikopoulos

Institute of Liver Studies, King's College London, London, UK

Tassos Grammatikopoulos

Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK

Christopher A. Green

Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK

William Greenhalf

Institute for Global Health, University College London, London, UK

Rishi K. Gupta

NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK

Hayley Hardwick, Malcolm G. Semple, Tom Solomon & Lance C. W. Turtle

Warwick Hospital, Warwick, UK

Elaine Hardy

Birmingham Children's Hospital, Birmingham, UK

Stuart Hartshorn

Nottingham City Hospital, Nottingham, UK

Daniel Harvey

Glangwili Hospital Child Health Section, Carmarthen, UK

Peter Havalda

Alder Hey Children's Hospital, Liverpool, UK

Daniel B. Hawcutt

Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK

Antonia Y. W. Ho

Bronglais General Hospital, Aberystwyth, UK

Maria Hobrok

Worthing Hospital, Worthing, UK

Luke Hodgson

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Peter W. Horby

Rotheram District General Hospital, Rotheram, UK

Anil Hormis

Virology Reference Department, National Infection Service, Public Health England, Colindale Avenue, London, UK

Samreen Ijaz

Royal Free Hospital, London, UK

Michael Jacobs & Padmasayee Papineni

Homerton Hospital, London, UK

Susan Jain

Airedale Hospital, Airedale, UK

Paul Jennings

Basildon Hospital, Basildon, UK

Agilan Kaliappan

The Christie NHS Foundation Trust, Manchester, UK

Vidya Kasipandian

University Hospital Lewisham, London, UK

Stephen Kegg

The Whittington Hospital, London, UK

Michael Kelsey

Southmead Hospital, Bristol, UK

Jason Kendall

Sheffield Childrens Hospital, Sheffield, UK

Caroline Kerrison

Royal United Hospital, Bath, UK

Ian Kerslake

Department of Pharmacology, University of Liverpool, Liverpool, UK

Say Khoo

Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK

Paul Klenerman

Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Paul Klenerman

Public Health Scotland, Edinburgh, UK

Susan Knight, Eva Lahnsteiner & Sarah Tait

Western General Hospital, Edinburgh, UK

Oliver Koch

Southend University Hospital NHS Foundation Trust, Southend-on-Sea, UK

Gouri Koduri

Hinchingbrooke Hospital, Huntingdon, UK

George Koshy & Tamas Leiner

Royal Preston Hospital, Fulwood, UK

Shondipon Laha

University Hospital (Coventry), Coventry, UK

Steven Laird

The Walton Centre, Liverpool, UK

Susan Larkin

ISARIC, Global Support Centre, COVID-19 Clinical Research Resources, Epidemic diseases Research Group, Oxford (ERGO), University of Oxford, Oxford, UK

James Lee & Daniel Plotkin

Centre for Health Informatics, Division of Informatics, Imaging and Data Science, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

Gary Leeming

Hull Royal Infirmary, Hull, UK

Patrick Lillie

Nottingham University Hospitals NHS Trust:, Nottingham, UK

Wei Shen Lim

Darlington Memorial Hospital, Darlington, UK

James Limb

Queen Elizabeth Hospital (Gateshead), Gateshead, UK

Vanessa Linnett

Warrington Hospital, Warrington, UK

Jeff Little

Bristol Royal Hospital for Children, Bristol, UK

Mark Lyttle

St Mary's Hospital (Isle of Wight), Isle of Wight, UK

Emily MacNaughton

The Tunbridge Wells Hospital, Royal Tunbridge Wells, UK

Ravish Mankregod

Huddersfield Royal, Huddersfield, UK

Huw Masson

Countess of Chester Hospital, Liverpool, UK

Ruth McEwen & Lawrence Wilson

Frimley Park Hospital, Frimley, UK

Manjula Meda

Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK

Alexander J. Mentzer

Department of Microbiology/Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK

Alexander J. Mentzer

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

Alison M. Meynert & Murray Wham

St James University Hospital, Leeds, UK

Jane Minton

Arrowe Park Hospital, Birkenhead, UK

Kavya Mohandas

Great Ormond Street Hospital, London, UK

Quen Mok

Royal Shrewsbury Hospital, Shrewsbury, UK

James Moon

Addenbrookes Hospital, Cambridge, UK

Elinoor Moore

Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

Shona C. Moore, William A. Paxton & Georgios Pollakis

East Surrey Hospital (Redhill), Redhill, UK

Patrick Morgan

Burton Hospital, Burton, UK

Craig Morris & Tim Reynolds

Peterborough City Hospital, Peterborough, UK

Katherine Mortimore

Kent and Canterbury Hospital, Canterbury, UK

Samuel Moses

Weston Area General Trust, Bristol, UK

Mbiye Mpenge

Bedfordshire Hospital, Bedfordshire, UK

Rohinton Mulla

Glasgow Royal Infirmary, Glasgow, UK

Michael Murphy

Macclesfield General Hospital, Macclesfield, UK

Thapas Nagarajan

Derbyshire Healthcare, Derbyshire, UK

Megan Nagel

Chelsea and Westminster Hospital, London, UK

Mark Nelson & Matthew K. O'Shea

Watford General Hospital, Watford, UK

Lillian Norris & Tom Stambach

EPCC, University of Edinburgh, Edinburgh, UK

Lucy Norris

Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, London, UK

Michael Olanipekun

Imperial College Healthcare NHS Trust: London, London, UK

Peter J. M. Openshaw

Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Anthonia Osagie

Prince Philip Hospital, Llanelli, UK

Igor Otahal & Andrew Workman

George Eliot Hospital - Acute Services, Nuneaton, UK

Mark Pais

Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

Carlo Palmieri

Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK

Carlo Palmieri

Kettering General Hospital, Kettering, UK

Selva Panchatsharam

University Hospitals of North Midlands NHS Trust, North Midlands, UK

Danai Papakonstantinou

Russells Hall Hospital, Dudley, UK

Hassan Paraiso

Harefield Hospital, Harefield, UK

Brij Patel

Lister Hospital, Lister, UK

Natalie Pattison

Musgrove Park Hospital, Taunton, UK

Justin Pepperell

Kingston Hospital, Kingston, UK

Mark Peters

Queen's Hospital, Romford, UK

Mandeep Phull

Southport and Formby District General Hospital, Southport, UK

Stefania Pintus

St George's University of London, London, UK

Tim Planche

King's College Hospital (Denmark Hill), London, UK

Frank Post

Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK

Nicholas Price

Department of Infectious Diseases, Guy's and St Thomas' NHS Foundation Trust, London, UK

Nicholas Price

The Clatterbridge Cancer Centre NHS Foundation, Bebington, UK

David Price

The Great Western Hospital, Swindon, UK

Rachel Prout

Ninewells Hospital, Dundee, UK

Nikolas Rae

Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK

Andrew Rambaut

Poole Hospital NHS Trust, Poole, UK

Henrik Reschreiter

William Harvey Hospital, Ashford, UK

Neil Richardson

King's Mill Hospital, Sutton-in-Ashfield, UK

Mark Roberts

Liverpool Women's Hospital, Liverpool, UK

Devender Roberts

Pinderfields Hospital, Wakefield, UK

Alistair Rose

North Devon District Hospital, Barnstaple, UK

Guy Rousseau

Queen Elizabeth Hospital, Birmingham, UK

Bobby Ruge

Tameside General Hospital, Ashton-under-Lyne, UK

Brendan Ryan

City Hospital (Birmingham), Birmingham, UK

Taranprit Saluja

Department of Pediatrics and Virology, St Mary's Medical School Bldg, Imperial College London, London, UK

Vanessa Sancho-Shimizu

The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK

Matthias Schmid

NHS Greater Glasgow and Clyde, Glasgow, UK

Janet T. Scott

Respiratory Medicine, Institute in The Park, University of Liverpool, Alder Hey Children's Hospital, Liverpool, UK

Malcolm G. Semple

Broomfield Hospital, Broomfield, UK

Aarti Shah

Stoke Mandeville, UK

Prad Shanmuga

University Hospital of North Tees, Stockton-on-Tees, UK

Anil Sharma

Institute of Translational Medicine, University of, Liverpool, Merseyside, UK

Victoria E. Shaw

Royal Manchester Children's Hospital, Manchester, UK

Anna Shawcross

New Cross Hospital, Wolverhampton, UK

Jagtur Singh Pooni

Bedford Hospital, Bedford, UK

Jeremy Sizer

Colchester General Hospital, Colchester, UK

Richard Smith

University Hospital Birmingham NHS Foundation Trust, Birmingham, UK

Catherine Snelson & Tony Whitehouse

Walton Centre NHS Foundation Trust, Liverpool, UK

Tom Solomon

Chesterfield Royal Hospital, Calow, UK

Nick Spittle

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK

Shiranee Sriskandan

Princess Alexandra Hospital, Harlow, UK

Nikki Staines & Shico Visuvanathan

Milton Keynes Hospital, Eaglestone, UK

Richard Stewart

Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

David Stuart

Royal Bolton Hopital, Farnworth, UK

Pradeep Subudhi

Department of Medicine, University of Cambridge, Cambridge, UK

Charlotte Summers

Department of Child Life and Health, University of Edinburgh, Edinburgh, UK

Olivia V. Swann

Royal Gwent (Newport), Newport, UK

Tamas Szakmany

The Royal Marsden Hospital (London), London, UK

Kate Tatham

Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK

Richard S. Tedder

Transfusion Microbiology, National Health Service Blood and Transplant, London, UK

Richard S. Tedder

Department of Medicine, Imperial College London, London, UK

Richard S. Tedder

Queen Victoria Hospital (East Grinstead), East Grinstead, UK

Jo Thomas

Leeds Teaching Hospitals NHS Trust, Leeds, UK

Robert Thompson

Royal Stoke University Hospital, Stoke-on-Trent, UK

Chris Thompson

Whiston Hospital, Rainhill, UK

Ascanio Tridente

Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, UK

Lance C. W. Turtle

Croydon University Hospital, Thornton Heath, UK

Mary Twagira

Gloucester Royal, Gloucester, UK

Nick Vallotton

West Hertfordshire Teaching Hospitals NHS Trust, Hertfordshire, UK

Rama Vancheeswaran

North Middlesex Hospital, London, UK

Rachel Vincent

Medway Maritime Hospital, Gillingham, UK

Lisa Vincent-Smith

Royal Papworth Hospital Everard, Cambridge, UK

Alan Vuylsteke

Derriford (Plymouth), Plymouth, UK

Sam Waddy

St Helier Hospital, Sutton, UK

Rachel Wake

Royal Berkshire Hospital, Reading, UK

Andrew Walden

Royal Liverpool Hospital, Liverpool, UK

Ingeborg Welters

Bradford Royal infirmary, Bradford, UK

Paul Whittaker

Central Middlesex, London, UK

Ashley Whittington

Royal Cornwall Hospital (Tresliske), Truro, UK

Meme Wijesinghe

North Bristol NHS Trust, Bristol, UK

Martin Williams

St. Peter's Hospital, Runnymede, UK

Stephen Winchester

Leicester Royal Infirmary, Leicester, UK

Martin Wiselka

Grantham and District Hospital, Grantham, UK

Adam Wolverson

Aintree University Hospital, Liverpool, UK

Daniel G. Wootton

North Tyneside General Hospital, North Shields, UK

Bryan Yates

Queen Elizabeth Hospital, King's Lynn, UK

Peter Young

Consortia

PHOSP-COVID collaborative group

Kathryn Abel

, H. Adamali

, Davies Adeloye

, Oluwaseun Adeyemi

, Rita Adrego

, Laura Aguilar Jimenez

, Shanaz Ahmad

, N. Ahmad Haider

, Rubina Ahmed

, Nyarko Ahwireng

, Mark Ainsworth

, Asma Alamoudi

, Mariam Ali

, M. Aljaroof

, Louise Allan

, Richard Allen

, Lisa Allerton

, Lynne Allsop

, Ann Marie Allt

, Paula Almeida

, Bashar Al-Sheklly

, Danny Altmann

, Maria Alvarez Corral

, Shannon Amoils

, David Anderson

, Charalambos Antoniades

, Gill Arbane

, Ava Maria Arias

, Cherie Armour

, Lisa Armstrong

, Natalie Armstrong

, David Arnold

, H. Arnold

, A. Ashish

, Andrew Ashworth

, M. Ashworth

, Shahab Aslani

, Hosanna Assefa-Kebede

, Paul Atkin

, Catherine Atkin

, Raminder Aul

, Hnin Aung

, Liam Austin

, Cristina Avram

, Nikos Avramidis

, A. Ayoub

, Marta Babores

, Rhiannon Baggott

, J. Bagshaw

, David Baguley

, Elisabeth Bailey

, J. Kenneth Baillie

, Steve Bain

, Majda Bakali

, M. Bakau

, E. Baldry

, Molly Baldwin

, David Baldwin

, Clive Ballard

, Amita Banerjee

, Dongchun Bang

, R. E. Barker

, Laura Barman

, Perdita Barran

, Shaney Barratt

, Fiona Barrett

, Donna Basire

, Neil Basu

, Michelle Bates

, A. Bates

, R. Batterham

, Helen Baxendale

, Gabrielle Baxter

, Hannah Bayes

, M. Beadsworth

, Paul Beckett

, M. Beggs

, M. Begum

, Paul Beirne

, Murdina Bell

, Robert Bell

, Kaytie Bennett

, Eva Beranova

, Areti Bermperi

, Anthony Berridge

, Colin Berry

, Sarah Betts

, Emily Bevan

, Kamaldeep Bhui

, Michelle Bingham

, K. Birchall

, Lettie Bishop

, Karen Bisnauthsing

, John Blaikely

, Angela Bloss

, Annette Bolger

, Charlotte Bolton

, J. Bonnington

, A. Botkai

, Charlotte Bourne

, Michelle Bourne

, Kate Bramham

, Lucy Brear

, G. Breen

, Jonathon Breeze

, Katie Breeze

, Andrew Briggs

, E. Bright

, Christopher Brightling

, Simon Brill

, K. Brindle

, Lauren Broad

, Andrew Broadley

, Claire Brookes

, Mattew Broome

, Vanessa Brown

, M. Brown

, Jo Brown

, J. Brown

, Ammani Brown

, Angela Brown

, M. Brown

, Jeremy Brown

, Terry Brugha

, Nigel Brunskill

, M. Buch

, Phil Buckley

, Anda Bularga

, Ed Bullmore

, Jenny Bunker

, L. Burden

, Tracy Burdett

, David Burn

, G. Burns

, A. Burns

, John Busby

, Robyn Butcher

, Al-Tahoor Butt

, S. Byrne

, P. Cairns

, P. C. Calder

, Ellen Calvelo

, H. Carborn

, Bethany Card

, Caitlin Carr

, Liesel Carr

, G. Carson

, Penny Carter

, Anna Casey

, M. Cassar

, Jonathon Cavanagh

, Manish Chablani

, Trudie Chalder

, James D. Chalmers

, Rachel Chambers

, Flora Chan

, K. M. Channon

, Kerry Chapman

, Amanda Charalambou

, N. Chaudhuri

, A. Checkley

, Jin Chen

, Yutung Cheng

, Luke Chetham

, Caroline Childs

, Edwin Chilvers

, H. Chinoy

, A. Chiribiri

, K. Chong-James

, N. Choudhury

, Gaunab Choudhury

, Phillip Chowienczyk

, C. Christie

, Melanie Chrystal

, Cameron Clark

, David Clark

, Jude Clarke

, S. Clohisey

, G. Coakley

, Zach Coburn

, S. Coetzee

, Joby Cole

, Chris Coleman

, Florence Conneh

, David Connell

, Bronwen Connolly

, Lynda Connor

, Amanda Cook

, Shirley Cooper

, B. Cooper

, Josh Cooper

, Donna Copeland

, Tracey Cosier

, Eamon Coughlan

, Martina Coulding

, C. Coupland

, E. Cox

, Thelma Craig

, P. Crisp

, Daniele Cristiano

, Michael Crooks

, Andy Cross

, Isabel Cruz

, P. Cullinan

, D. Cuthbertson

, Luke Daines

, Matthhew Dalton

, Patrick Daly

, Alison Daniels

, P. Dark

, Joanne Dasgin

, C. David

, Anthony David

, Ffyon Davies

, Ellie Davies

, Kim Davies

, Gareth Davies

, Gwyneth Davies

, Melanie Davies

, Joy Dawson

, Camilla Dawson

, Enya Daynes

, Anthony De Soyza

, Bill Deakin

, Andrew Deans

, C. Deas

, Joanne Deery

, Sylviane Defres

, Amanda Dell

, K. Dempsey

, Emma Denneny

, J. Dennis

, A. Dewar

, Ruvini Dharmagunawardena

, Nawar Diar-Bakerly

, Caroline Dickens

, A. Dipper

, Sarah Diver

, Shalin Diwanji

, Myles Dixon

, R. Djukanovic

, Hannah Dobson

, S. L. Dobson

, Annemarie B. Docherty

, A. Donaldson

, T. Dong

, N. Dormand

, Andrew Dougherty

, Rachael Dowling

, Stephen Drain

, Katharine Draxlbauer

, Katie Drury

, Pearl Dulawan

, A. Dunleavy

, Sarah Dunn

, Catherine Dupont

, Joanne Earley

, Nicholas Easom

, Carlos Echevarria

, Sarah Edwards

, C. Edwardson

, Claudia Efstathiou

, Anne Elliott

, K. Elliott

, Yvette Ellis

, Anne Elmer

, Omer Elneima

, Hosni El-Taweel

, Teriann Evans

, Ranuromanana Evans

, D. Evans

, R. Evans

, H. Evans

, Rachael A. Evans

, Jonathon Evans

, Cerys Evenden

, Lynsey Evison

, Laura Fabbri

, Sara Fairbairn

, Alexandra Fairman

, K. Fallon

, David Faluyi

, Clair Favager

, Tamanah Fayzan

, James Featherstone

, T. Felton

, V. Ferreira

, J. Finch

, Selina Finney

, J. Finnigan

, L. Finnigan

, Helen Fisher

, S. Fletcher

, Rachel Flockton

, Margaret Flynn

, H. Foot

, David Foote

, Amber Ford

, D. Forton

, Eva Fraile

, C. Francis

, Richard Francis

, Susan Francis

, Anew Frankel

, Emily Fraser

, Rob Free

, N. French

, X. Fu

, Jonathon Fuld

, J. Furniss

, Lucie Garner

, N. Gautam

, John Geddes

, J. George

, P. George

, Michael Gibbons

, Rhyan Gill

, Mandy Gill

, L. Gilmour

, F. Gleeson

, Jodie Glossop

, Sarah Glover

, Nicola Goodman

, Camelia Goodwin

, Bibek Gooptu

, Hussain Gordon

, T. Gorsuch

, M. Greatorex

, Paul Greenhaff

, William Greenhalf

, Alan Greenhalgh

, Neil J. Greening

, John Greenwood

, Rebecca Gregory

, Heidi Gregory

, D. Grieve

, Denise Griffin

, L. Griffiths

, Anne-Marie Guerdette

, Beatriz Guillen-Guio

, Mahitha Gummadi

, Ayushman Gupta

, Sambasivarao Gurram

, Elspeth Guthrie

, Zoe Guy

, Kate Hadley

, Ahmed Haggar

, Kera Hainey

, Brigid Hairsine

, Pranab Haldar

, Lucy Hall

, Ian Hall

, Mark Halling-Brown

, R. Hamil

, Alyson Hancock

, Kia Hancock

, Neil Hanley

, Sulaimaan Haq

, Hayley Hardwick

, Tim Hardy

, E. Hardy

, Beverley Hargadon

, Kate Harrington

, Edward Harris

, Victoria C. Harris

, Ewen Harrison

, Paul Harrison

, Nicholas Hart

, Alice Harvey

, Matt Harvey

, M. Harvie

, L. Haslam

, Claire Hastie

, May Havinden-Williams

, Jenny Hawkes

, Nancy Hawkings

, Jill Haworth

, A. Hayday

, Matthew Haynes

, J. Hazeldine

, Tracy Hazelton

, Liam Heaney

, Cheryl Heeley

, Jonathon Heeney

, M. Heightman

, Simon Heller

, Max Henderson

, Helen Henson

, L. Hesselden

, Melanie Hewitt

, Victoria Highett

, T. Hillman

, T. Hiwot

, Ling-Pei Ho

, Michaela Hoare

, Amy Hoare

, J. Hockridge

, Philip Hogarth

, Ailsa Holbourn

, Sophie Holden

, L. Holdsworth

, D. Holgate

, Maureen Holland

, Leah Holloway

, Katie Holmes

, Megan Holmes

, B. Holroyd-Hind

, L. Holt

, Anil Hormis

, Alexander Horsley

, Akram Hosseini

, M. Hotopf

, Linzy Houchen-Wolloff

, Luke S. Howard

, Kate Howard

, Alice Howell

, E. Hufton

, Rachel Ann Hughes

, Joan Hughes

, Alun Hughes

, Amy Humphries

, Nathan Huneke

, E. Hurditch

, John Hurst

, Masud Husain

, Tracy Hussell

, John Hutchinson

, W. Ibrahim

, F. Ilyas

, Julie Ingham

, L. Ingram

, Diana Ionita

, Karen Isaacs

, Khalida Ismail

, T. Jackson

, Joseph Jacob

, W. Y. James

, W. Jang

, Claire Jarman

, Ian Jarrold

, Hannah Jarvis

, Roman Jastrub

, Bhagy Jayaraman

, Gisli Jenkins

, P. Jezzard

, Kasim Jiwa

, C. Johnson

, Simon Johnson

, Desmond Johnston

, Caroline Jolley

, S. Jones

, H. Jones

, L. Jones

, Ian Jones

, G. Jones

, Heather Jones

, Mark Jones

, Don Jones

, Sherly Jose

, Thomas Kabir

, G. Kaltsakas

, Vicky Kamwa

, N. Kanellakis

, Sabina Kaprowska

, Zunaira Kausar

, Natalie Keenan

, S. Kelly

, G. Kemp

, Steven Kerr

, Helen Kerslake

, Angela Key

, Fasih Khan

, Kamlesh Khunti

, Susan Kilroy

, Bernie King

, Clara King

, Lucy Kingham

, Jill Kirk

, Paaig Kitterick

, Paul Klenerman

, Lucy Knibbs

, Sean Knight

, Abigail Knighton

, Onn Min Kon

, S. Kon

, Samantha Kon

, Ania Korszun

, Ivan Koychev

, Claire Kurasz

, Prathiba Kurupati

, C. Laing

, Hanan Lamlum

, G. Landers

, Claudia Langenberg

, Lara Lavelle-Langham

, Allan Lawrie

, Cathy Lawson

, Claire Lawson

, Alison Layton

, A. Lea

, Olivia C. Leavy

, Ju Hee Lee

, Elvina Lee

, D. Lee

, Karen Leitch

, Rebecca Lenagh

, Victoria Lewis

, Joanne Lewis

, Keir Lewis

, D. Lewis

, N. Lewis-Burke

, X. Li

, Felicity Liew

, Tessa Light

, Liz Lightstone

, W. Lilaonitkul

, Lai Lim

, S. Linford

, Anne Lingford-Hughes

, M. Lipman

, Kamal Liyanage

, Arwel Lloyd

, S. Logan

, D. Lomas

, Nazir I. Lone

, Ronda Loosley

, Janet Lord

, Harpreet Lota

, Wayne Lovegrove

, Daniel Lozano-Rojas

, Alice Lucey

, Gardiner Lucy

, E. Lukaschuk

, Alison Lye

, Ceri Lynch

, S. MacDonald

, G. MacGowan

, Irene Macharia

, J. Mackie

, L. Macliver

, S. Madathil

, Gladys Madzamba

, Nick Magee

, Murphy Magtoto

, N. Mairs

, N. Majeed

, E. Major

, Flora Malein

, M. Malim

, Georgia Mallison

, William Man

, S. Mandal

, K. Mangion

, C. Manisty

, R. Manley

, Katherine March

, Stefan Marciniak

, Philip Marino

, Myril Mariveles

, Michael Marks

, Elizabeth Marouzet

, Sophie Marsh

, M. Marshall

, B. Marshall

, Jane Martin

, Adrian Martineau

, L. M. Martinez

, Nick Maskell

, Darwin Matila

, Wadzanai Matimba-Mupaya

, Laura Matthews

, Angeline Mbuyisa

, Steve McAdoo

, Hamish McAllister-Williams

, Paul McArdle

, Anne McArdle

, Danny McAulay

, Hamish J. C. McAuley

, Gerry McCann

, W. McCormick

, Jacqueline McCormick

, P. McCourt

, Celeste McCracken

, Lorcan McGarvey

, C. McGee

, K. Mcgee

, Jade McGinness

, K. McGlynn

, Andrew McGovern

, Heather McGuinness

, I. B. McInnes

, Jerome McIntosh

, Emma McIvor

, Katherine McIvor

, Laura McLeavey

, Aisling McMahon

, Michael McMahon

, L. McMorrow

, Teresa Mcnally

, M. McNarry

, J. McNeill

, Alison McQueen

, H. McShane

, Chloe Mears

, Clare Megson

, Sharon Megson

, P. Mehta

, J. Meiring

, Lucy Melling

, Mark Mencias

, R. Menke

, Daniel Menzies

, Marta Merida Morillas

, Alice Michael

, Benedict Michael

, C. A. Miller

, Lea Milligan

, Nicholas Mills

, Clare Mills

, George Mills

, L. Milner

, S. Misra

, Jane Mitchell

, Abdelrahman Mohamed

, Noura Mohamed

, S. Mohammed

, Philip Molyneaux

, Will Monteiro

, Silvia Moriera

, Anna Morley

, Leigh Morrison

, Richard Morriss

, A. Morrow

, Paul Moss

, Alistair Moss

, K. Motohashi

, N. Msimanga

, Elizabeta Mukaetova-Ladinska

, Unber Munawar

, Jennifer Murira

, Uttam Nanda

, Heeah Nassa

, Mariam Nasseri

, Rashmita Nathu

, Aoife Neal

, Robert Needham

, Paula Neill

, Stefan Neubauer

, D. E. Newby

, Helen Newell

, J. Newman

, Tom Newman

, Alex Newton-Cox

, T. E. Nichols

, Tim Nicholson

, Christos Nicolaou

, Debby Nicoll

, Athanasios Nikolaidis

, C. Nikolaidou

, C. M. Nolan

, Matthew Noonan

, C. Norman

, Petr Novotny

, Kimon Ntotsis

, Jose Nunag

, Lorenza Nwafor

, Uchechi Nwanguma

, Joseph Nyaboko

, Linda O'Brien

, C. O'Brien

, Natasha Odell

, Kate O'Donnell

, Godwin Ogbole

, G. Ogg

, Olaoluwa Olaosebikan

, Catherine Oliver

, Zohra Omar

, Peter J. M. Openshaw

, D. P. O'Regan

, Lorna Orriss-Dib

, Lynn Osborne

, Rebecca Osbourne

, Marlies Ostermann

, Charlotte Overton

, J. Owen

, J. Oxton

, Jamie Pack

, Edmund Pacpaco

, Stella-Maria Paddick

, Sharon Painter

, Erola Pairo-Castineira

, Ashkan Pakzad

, Sue Palmer

, Padmasayee Papineni

, K. Paques

, Kerry Paradowski

, Manish Pareek

, Dhruv Parekh

, H. Parfrey

, Carmen Pariante

, S. Parker

, M. Parkes

, J. Parmar

, Sheetal Patale

, Manish Patel

, B. Patel

, Suhani Patel

, Dibya Pattenadk

, M. Pavlides

, Sheila Payne

, Lorraine Pearce

, John Pearl

, Dan Peckham

, Jessica Pendlebury

, Yanchun Peng

, Chris Pennington

, Ida Peralta

, Emma Perkins

, Z. Peterkin

, Tunde Peto

, Nayia Petousi

, John Petrie

, Paul Pfeffer

, Janet Phipps

, S. Piechnik

, John Pimm

, Karen Piper Hanley

, Riinu Pius

, Hannah Plant

, S. Plein

, Tatiana Plekhanova

, Megan Plowright

, Krisnah Poinasamy

, Oliver Polgar

, L. Poll

, Julie Porter

, Joanna Porter

, Sofiya Portukhay

, Natassia Powell

, A. Prabhu

, James Pratt

, Andrea Price

, Claire Price

, Carly Price

, L. Price

, D. Price

, L. Price

, Anne Prickett

, I. Propescu

, J. Propescu

, Sabrina Prosper

, S. Pugmire

, Sheena Quaid

, Jackie Quigley

, Jennifer K. Quint

, H. Qureshi

, I. N. Qureshi

, K. Radhakrishnan

, Najib Rahman

, Markus Ralser

, Betty Raman

, Hazel Ramos

, Albert Ramos

, Jade Rangeley

, Bojidar Rangelov

, Liz Ratcliffe

, Phillip Ravencroft

, Konrad Rawlik

, Anne Reddington

, R. Reddy

, A. Reddy

, Heidi Redfearn

, Dawn Redwood

, Annabel Reed

, Meryl Rees

, Tabitha Rees

, Karen Regan

, Will Reynolds

, Carla Ribeiro

, A. Richards

, Emma Richardson

, M. Richardson

, Pilar Rivera-Ortega

, K. Roberts

, Elizabeth Robertson

, Leanne Robinson

, Emma Robinson

, Lisa Roche

, C. Roddis

, J. Rodger

, Natalie Rogers

, Gavin Ross

, Alexandra Ross

, Jennifer Rossdale

, Anthony Rostron

, Anna Rowe

, J. Rowland

, M. J. Rowland

, A. Rowland

, Sarah L. Rowland-Jones

, Maura Roy

, K. Roy

, Igor Rudan

, Richard Russell

, Emily Russell

, Gwen Saalmink

, Ramsey Sabit

, Beth Sage

, T. Samakomva

, Nilesh Samani

, A. A. Samat

, Claire Sampson

, Katherine Samuel

, Reena Samuel

, Z. B. Sanders

, Amy Sanderson

, Elizabeth Sapey

, Dinesh Saralaya

, Jack Sargant

, Carol Sarginson

, T. Sass

, Naveed Sattar

, Kathryn Saunders

, Peter Saunders

, Ruth Saunders

, Laura Saunders

, Heather Savill

, W. Saxon

, Avan Sayer

, J. Schronce

, William Schwaeble

, Janet Scott

, Kathryn Scott

, Nick Selby

, Malcolm G. Semple

, Marco Sereno

, Terri Ann Sewell

, Kamini Shah

, Ajay Shah

, P. Shah

, Manu Shankar-Hari

, M. Sharma

, Claire Sharpe

, Michael Sharpe

, Sharlene Shashaa

, Alison Shaw

, Victoria Shaw

, Karen Shaw

, Aziz Sheikh

, Sarah Shelton

, Liz Shenton

, K. Shevket

, Aarti Shikotra

, J. Short

, Sulman Siddique

, Salman Siddiqui

, J. Sidebottom

, Louise Sigfrid

, Gemma Simons

, Neil Simpson

, John Simpson

, Ananga Singapuri

, Suver Singh

, Claire Singh

, Sally Singh

, D. Sissons

, J. Skeemer

, Katie Slack

, David Smith

, Nikki Smith

, Andrew Smith

, Jacqui Smith

, Laurie Smith

, Susan Smith

, M. Soares

, Teresa Solano

, Reanne Solly

, A. R. Solstice

, Tracy Soulsby

, David Southern

, D. Sowter

, Mark Spears

, Lisa Spencer

, Fabio Speranza

, Louise Stadon

, Stefan Stanel

, R. Steeds

, N. Steele

, Mike Steiner

, David Stensel

, G. Stephens

, Lorraine Stephenson

, M. Stern

, Iain Stewart

, R. Stimpson

, Sue Stockdale

, J. Stockley

, Wendy Stoker

, Roisin Stone

, Will Storrar

, Andrew Storrie

, Kim Storton

, E. Stringer

, Sophia Strong-Sheldrake

, Natalie Stroud

, Christian Subbe

, Catherine Sudlow

, Zehra Suleiman

, Charlotte Summers

, C. Summersgill

, Debbie Sutherland

, D. L. Sykes

, R. Sykes

, Nick Talbot

, Ai Lyn Tan

, Lawrence Tarusan

, Vera Tavoukjian

, Jessica Taylor

, Abigail Taylor

, Chris Taylor

, John Paul Taylor

, Amelie Te

, H. Tedd

, Caroline Tee

, J. Teixeira

, Helen Tench

, Sarah Terry

, Susannah Thackray-Nocera

, Favas Thaivalappil

, B. Thamu

, David Thickett

, David Thomas

, S. Thomas

, Caradog Thomas

, Andrew Thomas

, T. Thomas-Woods

, A. A. Roger Thompson

, Tamika Thompson

, T. Thornton

, Matthew Thorpe

, Ryan S. Thwaites

, Jo Tilley

, N. Tinker

, Gerlynn Tiongson

, Martin Tobin

, Johanne Tomlinson

, C. Tong

, Mark Toshner

, R. Touyz

, T. Treibel

, K. A. Tripp

, Drupad Trivedi

, E. M. Tunnicliffe

, Alison Turnbull

, Kim Turner

, Sarah Turner

, Victoria Turner

, E. Turner

, Sharon Turney

, Lance Turtle

, Helena Turton

, Jacinta Ugoji

, R. Ugwuoke

, Rachel Upthegrove

, Jonathon Valabhji

, Maximina Ventura

, Joanne Vere

, Carinna Vickers

, Ben Vinson

, Ioannis Vogiatzis

, Elaine Wade

, Phillip Wade

, Louise V. Wain

, Tania Wainwright

, Lilian Wajero

, Sinead Walder

, Samantha Walker

, S. Walker

, E. Wall

, Tim Wallis

, Sarah Walmsley

, Simon Walsh

, J. A. Walsh

, Louise Warburton

, T. J. C. Ward

, Katie Warwick

, Helen Wassall

, Samuel Waterson

, L. Watson

, Ekaterina Watson

, James Watson

, M. Webster

, J. Weir McCall

, H. Welch

, Carly Welch

, B. Welsh

, Simon Wessely

, Sophie West

, Heather Weston

, Helen Wheeler

, Sonia White

, Victoria Whitehead

, J. Whitney

, S. Whittaker

, Beverley Whittam

, V. Whitworth

, Andrew Wight

, James Wild

, Martin Wilkins

, Dan Wilkinson

, Nick Williams

, N. Williams

, B. Williams

, Jenny Williams

, S. A. Williams-Howard

, Michelle Willicombe

, Gemma Willis

, James Willoughby

, Ann Wilson

, Imogen Wilson

, Daisy Wilson

, Nicola Window

, M. Witham

, Rebecca Wolf-Roberts

, Chloe Wood

, F. Woodhead

, Janet Woods

, Dan Wootton

, J. Wormleighton

, J. Worsley

, David Wraith

, Caroline Wrey Brown

, C. Wright

, S. Wright

, Louise Wright

, J. Wyles

, Inez Wynter

, C. Xie

, Moucheng Xu

, Najira Yasmin

, S. Yasmin

, Tom Yates

, Kay Por Yip

, Susan Young

, Bob Young

, A. Young

, A. J. Yousuf

, Amira Zawia

, Lisa Zeidan

, Bang Zhao

, Bang Zheng

& O. Zongo

ISARIC investigators

Kayode Adeniji

, Daniel Agranoff

, Ken Agwuh

, Katie A. Ahmed

, Dhiraj Ail

, Erin L. Aldera

, Ana Alegria

, Beatrice Alex

, Sam Allen

, Petros Andrikopoulos

, Brian Angus

, Jane A. Armstrong

, Abdul Ashish

, Milton Ashworth

, Innocent G. Asiimwe

, Dougal Atkinson

, Benjamin Bach

, J. Kenneth Baillie

, Siddharth Bakshi

, Wendy S. Barclay

, Shahedal Bari

, Gavin Barlow

, Samantha L. Barlow

, Stella Barnass

, Nicholas Barrett

, Christopher Bassford

, Sneha Basude

, David Baxter

, Michael Beadsworth

, Jolanta Bernatoniene

, John Berridge

, Colin Berry

, Nicola Best

, Debby Bogaert

, Laura Booth

, Pieter Bothma

, Benjamin Brennan

, Robin Brittain-Long

, Katie Bullock

, Naomi Bulteel

, Tom Burden

, Andrew Burtenshaw

, Nicola Carlucci

, Gail Carson

, Vikki Caruth

, Emily Cass

, Benjamin W. A. Catterall

, David Chadwick

, Duncan Chambler

, Meera Chand

, Kanta Chechi

, Nigel Chee

, Jenny Child

, Srikanth Chukkambotla

, Richard Clark

, Tom Clark

, Jordan J. Clark

, Emily A. Clarke

, Sara Clohisey

, Sarah Cole

, Paul Collini

, Marie Connor

, Graham S. Cooke

, Louise Cooper

, Catherine Cosgrove

, Audrey Coutts

, Helen Cox

, Jason Cupitt

, Maria-Teresa Cutino-Moguel

, Ana da Silva Filipe

, Jo Dalton

, Paul Dark

, Christopher Davis

, Chris Dawson

, Thushan de Silva

, Samir Dervisevic

, Oslem Dincarslan

, Alejandra Doce Carracedo

, Annemarie B. Docherty

, Cara Donegan

, Lorna Donelly

, Phil Donnison

, Chloe Donohue

, Gonçalo dos Santos Correia

, Sam Douthwaite

, Thomas M. Drake

, Andrew Drummond

, Marc-Emmanuel Dumas

, Chris Dunn

, Jake Dunning

, Ingrid DuRand

, Ahilanadan Dushianthan

, Tristan Dyer

, Philip Dyer

, Angela Elliott

, Cariad Evans

, Anthony Evans

, Chi Eziefula

, Cameron J. Fairfield

, Angie Fawkes

, Chrisopher Fegan

, Lorna Finch

, Adam Finn

, Lewis W. S. Fisher

, Lisa Flaherty

, Tom Fletcher

, Terry Foster

, Duncan Fullerton

, Carrol Gamble

, Isabel Garcia-Dorival

, Atul Garg

, Sanjeev Garg

, Tammy Gilchrist

, Michelle Girvan

, Effrossyni Gkrania-Klotsas

, Jo Godden

, Arthur Goldsmith

, Clive Graham

, Tassos Grammatikopoulos

, Christopher A. Green

, William Greenhalf

, Julian Griffin

, Fiona Griffiths

, Philip Gunning

, Rishi K. Gupta

, Katarzyna Hafezi

, Sophie Halpin

, Hayley Hardwick

, Elaine Hardy

, Ewen M. Harrison

, Janet Harrison

, Catherine Hartley

, Stuart Hartshorn

, Daniel Harvey

, Peter Havalda

, Daniel B. Hawcutt

, Ross Hendry

, Antonia Y. W. Ho

, Maria Hobrok

, Luke Hodgson

, Karl Holden

, Anthony Holmes

, Peter W. Horby

, Anil Hormis

, Joanne Howard

, Samreen Ijaz

, Clare Jackson

, Michael Jacobs

, Susan Jain

, Paul Jennings

, Rebecca L. Jensen

, Christopher B. Jones

, Trevor R. Jones

, Agilan Kaliappan

, Vidya Kasipandian

, Seán Keating

, Stephen Kegg

, Michael Kelsey

, Jason Kendall

, Caroline Kerrison

, Ian Kerslake

, Shadia Khandaker

, Say Khoo

, Katharine King

, Robyn T. Kiy

, Paul Klenerman

, Stephen R. Knight

, Susan Knight

, Oliver Koch

, Gouri Koduri

, George Koshy

, Chrysa Koukorava

, Shondipon Laha

, Eva Lahnsteiner

, Steven Laird

, Annette Lake

, Suzannah Lant

, Susan Larkin

, Diane Latawiec

, Lara Lavelle-Langham

, Andrew Law

, James Lee

, Gary Leeming

, Daniella Lefteri

, Tamas Leiner

, Lauren Lett

, Matthew Lewis

, Sonia Liggi

, Patrick Lillie

, Wei Shen Lim

, James Limb

, Vanessa Linnett

, Jeff Little

, Lucia A. Livoti

, Mark Lyttle

, Louise MacGillivray

, Alan Maclean

, Michael MacMahon

, Emily MacNaughton

, Maria Mancini

, Ravish Mankregod

, Laura Marsh

, Lynn Maslen

, Hannah Massey

, Huw Masson

, Elijah Matovu

, Nicole Maziere

, Sarah McCafferty

, Katherine McCullough

, Sarah E. McDonald

, Sarah McDonald

, Laurence McEvoy

, Ruth McEwen

, John McLauchlan

, Kenneth A. Mclean

, Manjula Meda

, Alexander J. Mentzer

, Laura Merson

, Soeren Metelmann

, Alison M. Meynert

, Nahida S. Miah

, Joanna Middleton

, Gary Mills

, Jane Minton

, Joyce Mitchell

, Kavya Mohandas

, Quen Mok

, James Moon

, Elinoor Moore

, Shona C. Moore

, Patrick Morgan

, Kirstie Morrice

, Craig Morris

, Katherine Mortimore

, Samuel Moses

, Mbiye Mpenge

, Rohinton Mulla

, Derek Murphy

, Lee Murphy

, Michael Murphy

, Ellen G. Murphy

, Thapas Nagarajan

, Megan Nagel

, Mark Nelson

, Lisa Norman

, Lillian Norris

, Lucy Norris

, Mahdad Noursadeghi

, Michael Olanipekun

, Wilna Oosthuyzen

, Peter J. M. Openshaw

, Anthonia Osagie

, Matthew K. O'Shea

, Marlies Ostermann

, Igor Otahal

, Mark Pais

, Massimo Palmarini

, Carlo Palmieri

, Selva Panchatsharam

, Danai Papakonstantinou

, Padmasayee Papineni

, Hassan Paraiso

, Brij Patel

, Natalie Pattison

, William A. Paxton

, Rebekah Penrice-Randal

, Justin Pepperell

, Mark Peters

, Mandeep Phull

, Jack Pilgrim

, Stefania Pintus

, Riinu Pius

, Tim Planche

, Daniel Plotkin

, Georgios Pollakis

, Frank Post

, Nicholas Price

, David Price

, Tessa Prince

, Rachel Prout

, Nikolas Rae

, Andrew Rambaut

, Henrik Reschreiter

, Tim Reynolds

, Will Reynolds

, Neil Richardson

, P. Matthew Ridley

, Mark Roberts

, Stephanie Roberts

, Devender Roberts

, David L. Robertson

, Alistair Rose

, Guy Rousseau

, Bobby Ruge

, Clark D. Russell

, Brendan Ryan

, Debby Sales

, Taranprit Saluja

, Vanessa Sancho-Shimizu

, Caroline Sands

, Egle Saviciute

, Matthias Schmid

, Janet T. Scott

, James Scott-Brown

, Malcolm G. Semple

, Aarti Shah

, Manu Shankar-Hari

, Prad Shanmuga

, Anil Sharma

, Catherine A. Shaw

, Victoria E. Shaw

, Anna Shawcross

, Rebecca K. Shears

, Louise Sigfrid

, Jagtur Singh Pooni

, Jeremy Sizer

, Benjamin Small

, Richard Smith

, Catherine Snelson

, Tom Solomon

, Rebecca G. Spencer

, Nick Spittle

, Shiranee Sriskandan

, Nikki Staines

, Tom Stambach

, Richard Stewart

, David Stuart

, Krishanthi S. Subramaniam

, Pradeep Subudhi

, Charlotte Summers

, Olivia V. Swann

, Tamas Szakmany

, Agnieska Szemiel

, Aislynn Taggart

, Sarah Tait

, Zoltan Takats

, Panteleimon Takis

, Jolanta Tanianis-Hughes

, Kate Tatham

, Richard S. Tedder

, Jo Thomas

, Jordan Thomas

, A. A. Roger Thompson

, Robert Thompson

, Chris Thompson

, Emma C. Thomson

, Ryan S. Thwaites

, Ascanio Tridente

, Erwan Trochu

, Darell Tupper-Carey

, Lance C. W. Turtle

, Mary Twagira

, Nick Vallotton

, Libby van Tonder

, Rama Vancheeswaran

, Rachel Vincent

, Lisa Vincent-Smith

, Shico Visuvanathan

, Alan Vuylsteke

, Sam Waddy

, Rachel Wake

, Andrew Walden

, Ingeborg Welters

, Murray Wham

, Tony Whitehouse

, Paul Whittaker

, Ashley Whittington

, Meme Wijesinghe

, Eve Wilcock

, Martin Williams

, Lawrence Wilson

, Stephen Winchester

, Martin Wiselka

, Adam Wolverson

, Daniel G. Wootton

, Andrew Workman

, Nicola Wrobel

, Bryan Yates

, Peter Young

, Maria Zambon

& J. Eunice Zhang

Contributions

F.L. recruited participants, acquired clinical samples, analyzed and interpreted data and cowrote the manuscript, including all drafting and revisions. C.E. analyzed and interpreted data and cowrote this manuscript, including all drafting and revisions. S.F. and M.R. supported the analysis and interpretation of data as well as drafting and revisions. D.S., J.K.S., S.C.M., S.A., N.M., J.N., C.K., O.C.L., O.E., H.J.C.M., A. Shikotra, A. Singapuri, M.S., V.C.H., M.T., N.J.G., N.I.L. and C.C. contributed to acquisition of data underlying this study. L.H.-W., A.A.R.T., S.L.R.-J., L.S.H., O.M.K., D.G.W., T.I.d.S. and A. Ho made substantial contributions to conception/design and implementation of this work and/or acquisition of clinical samples for this work. They have supported drafting and revisions of the manuscript. E.M.H., J.K.Q. and A.B.D. made substantial contributions to the study design as well as data access, linkage and analysis. They have supported drafting and revisions of this work. J.D.C., L.-P.H., A. Horsley, B.R., K.P., M.M. and W.G. made substantial contributions to the conception and design of this work and have supported drafting and revisions of this work. J.K.B. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, has made substantial contributions to conception and design of this work and has supported drafting and revisions of this work. M.G.S. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, sponsor/protocol chief investigator, has made substantial contributions to conception and design of this work and has supported drafting and revisions of this work. R.A.E. and L.V.W. are co-leads of PHOSP-COVID, made substantial contributions to conception and design of this work, the acquisition and analysis of data, and have supported drafting and revisions of this work. C.B. is the chief investigator of PHOSP-COVID and has made substantial contributions to conception and design of this work. R.S.T. and L.T. made substantial contributions to the acquisition, analysis and interpretation of the data underlying this study and have contributed to drafting and revisions of this work. P.J.M.O. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, sponsor/protocol chief investigator and has made substantial contributions to conception and design of this work. R.S.T. and P.J.M.O. have also made key contributions to interpretation of data and have co-written this manuscript. All authors have read and approve the final version to be published. All authors agree to accountability for all aspects of this work. All investigators within ISARIC4C and the PHOSP-COVID consortia have made substantial contributions to the conception or design of this study and/or acquisition of data for this study. The full list of authors within these groups is available in Supplementary Information.

Corresponding authors

Correspondence to Ryan S. Thwaites or Peter J. M. Openshaw.

Ethics declarations

Competing interests

F.L., C.E., D.S., J.K.S., S.C.M., C.D., C.K., N.M., L.N., E.M.H., A.B.D., J.K.Q., L.-P.H., K.P., L.S.H., O.M.K., S.F., T.I.d.S., D.G.W., R.S.T. and J.K.B. have no conflicts of interest. A.A.R.T. receives speaker fees and support to attend meetings from Janssen Pharmaceuticals. S.L.R.-J. is on the data safety monitoring board for Bexero trial in HIV+ adults in Kenya. J.D.C. is the deputy chief editor of the European Respiratory Journal and receives consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Janssen, Novartis, Pfizer and Zambon. A. Horsley is deputy chair of NIHR Translational Research Collaboration (unpaid role). B.R. receives honoraria from Axcella therapeutics. R.A.E. is co-lead of PHOSP-COVID and receives fees from AstraZenaca/Evidera for consultancy on LC and from AstraZenaca for consultancy on digital health. R.A.E. has received speaker fees from Boehringer in June 2021 and has held a role as European Respiratory Society Assembly 01.02 Pulmonary Rehabilitation secretary. R.A.E. is on the American Thoracic Society Pulmonary Rehabilitation Assembly program committee. L.V.W. also receives funding from Orion pharma and GSK and holds contracts with Genentech and AstraZenaca. L.V.W. has received consulting fees from Galapagos and Boehringer, is on the data advisory board for Galapagos and is Associate Editor for the European Respiratory Journal. A. Ho is a member of NIHR Urgent Public Health Group (June 2020-March 2021). M.M. is an applicant on the PHOSP study funded by NIHR/DHSC. M.G.S. acts as an independent external and nonremunerated member of Pfizer's External Data Monitoring Committee for their mRNA vaccine program(s), is Chair of Infectious Disease Scientific Advisory Board of Integrum Scientific LLC, and is director of MedEx Solutions Ltd. and majority owner of MedEx Solutions Ltd. and minority owner of Integrum Scientific LLC. M.G.S.'s institution has been in receipt of gifts from Chiesi Farmaceutici S.p.A. of Clinical Trial Investigational Medicinal Product without encumbrance and distribution of same to trial sites. M.G.S. is a nonrenumerated member of HMG UK New Emerging Respiratory Virus Threats Advisory Group and has previously been a nonrenumerated member of the Scientific Advisory Group for Emergencies (SAGE). C.B. has received consulting fees and/or grants from GSK, AstraZeneca, Genentech, Roche, Novartis, Sanofi, Regeneron, Chiesi, Mologic and 4DPharma. L.T. has received consulting fees from MHRA, AstraZeneca and Synairgen and speakers' fees from Eisai Ltd., and support for conference attendance from AstraZeneca. L.T. has a patent pending with ZikaVac. P.J.M.O. reports grants from the EU Innovative Medicines Initiative 2 Joint Undertaking during the submitted work; grants from UK Medical Research Council, GSK, Wellcome Trust, EU Innovative Medicines Initiative, UK National Institute for Health Research and UK Research and Innovation-Department for Business, Energy and Industrial Strategy; and personal fees from Pfizer, Janssen and Seqirus, outside the submitted work.

Peer review

Peer review information

Nature Immunology thanks Ziyad Al-Aly and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Ioana Staicu was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Additional information

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Graphs show classification error and Area under curve (AUC) from the 50 repeats tenfold nested cross-validation used to optimise and assess the performance of PLR testing associations with each LC outcome relative to Recovered (n = 233): Cardio_Resp (n = 398), Fatigue (n = 384), Anxiety/Depression (n = 202), GI (n = 132), ( e) Cognitive (n = 6). The distributions of classification error and area under curve (AUC) from the nested cross-validation are shown. Box plot centre line represents the Median and boundaries of the box represent interquartile range (IQR), the whisker length represent 1.5xIQR.

( a) Fibrinogen levels at 6 months were compared between pooled LC cases (n = 295) and Recovered (n = 233) and between the Cognitive group (n = 41) and Recovered (n = 233). Box plot centre line represent the Median and boundaries of the box represent interquartile range (IQR), the whisker length represents 1.5xIQR, any outliers beyond the whisker range are shown as individual dots. Median differences were compared using two-sided Wilcoxon signed-rank test *= p < 0·05, **= p < 0·01, ***= p < 0·001, ****= p < 0·0001. Unadjusted p-values are reported. b) Distribution of time from COVID-19 hospitalisation at sample collection applying CDC and NICE definitions of LC (n = 719) ( c) Upset plot of symptom groups. Horizontal coloured bars represent the number of patients in each symptom group: Cardiorespiratory (Cardio_Resp), Fatigue, Cognitive, Gastrointestinal (GI) and Anxiety/Depression (Anx_Dep). Vertical black bars represent the number of patients in each symptom combination group. To prevent patient identification, where less than 5 patients belong to a combination group, this has been represented as '<5'. The Recovered group (n = 250) were used as controls. Forest plots show Olink protein concentrations (NPX) associated with ( d) Cardio_Resp (n = 398), ( e) Fatigue (n = 342), ( f) Anx_Dep (n = 219), ( g) GI (n = 134), and ( h) Cognitive (n = 65). Error bars represent the median accuracy of the model.

Olink measured protein (NPX) were compared to chemiluminescence assays (ECL or ELISA, log2[pg/mL]) to validate our findings, where contemporaneously collected plasma samples were available (n = 58). Results from key mediators associated with LC groups were validated: CSF3, IL1R2, IL2, IL3RA, TNFa, TFF2. R= spearman rank correlation coefficient and shaded areas indicated the 95% confidence interval. Samples that fell below the lower limit of detection for a given assay were excluded and the 'n' value on each panel indicates the number of samples above this limit.

Olink measured plasma protein levels (NPX) between men and women with symptoms, divided by age (<50 or >=50years): (a) shows IL1R2 and MATN2 in the Anxiety/Depression group (<50 n = 55, >=50 n = 133), (b) shows CTSO and NFASC in the Cognitive group (<50 n = 11, >=50 n = 50). Median values were compared between men and women using two-sided Wilcoxon signed-rank test. Box plot centre line represent the Median and boundaries represent interquartile range (IQR), the whisker length represents 1.5xIQR.

Nasal cytokines measured by immunoassay in the CardioResp Group (n = 29) and Recovered (n = 31): ( a) shows IL1a, IL1b, IL-6, APO-2, TGFa, TFF2. Median differences were compared using two-sided Wilcoxon signed-rank test. Box plot centre line represents the Median and boundaries of the box represent interquartile range (IQR), the whisker length represent 1.5xIQR. ( b) Shows cytokines measured by immunoassay in paired plasma and nasal (n = 70). Correlations between IL1a, IL1b, IL-6, APO-2, TGFa and TFF2 in nasal and plasma samples were compared using Spearman's rank correlation coefficient ( R). Shaded areas indicated the 95% confidence interval of R.

Supplementary information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Reprints and permissions

About this article

# data[].attributes.attachment_link.title
Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease - Nature Immunology

# data[].attributes.attachment_link.description
One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered.

# data[].attributes.headline
Factors associated with increased radiation exposure in the fixation of proximal femoral fractures

# data[].attributes.subject
Factors associated with increased radiation exposure in the fixation of proximal femoral fractures

# data[].attributes.attachment_link.readable_text
The .gov means it's official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Abstract

Introduction: When using radiation intraoperatively, a surgeon should aim to keep the radiation dose as low as is reasonably achievable to obtain the therapeutic goal. We aimed to investigate factors associated with increased radiation exposure in fixation of proximal femur fractures.

Methods: We assessed 369 neck of femur fractures over a 1-year period in a district general hospital. All hip fracture subtypes that had undergone surgical fixation were included. We assessed the relationship between type of fracture, implants used and surgeon level of experience with the dose-area product (DAP; cGy/cm 2) and screening time (dS). We also looked at the quality of reduction and fixation and its effect on the radiation exposure.

Results: A total of 184 patients were included in our analysis; 185 patients who were treated with hip arthroplasty were excluded. There was a significant association between higher DAP and fracture subtype ( p = 0.001), fracture complexity ( p < 0.001), if an additional implant was used ( p = 0.001), if fixation was satisfactory ( p = 0.002) and operative time ( p < 0.001). DAP was higher with a proximal femoral nail than with a dynamic hip screw, especially when a long nail was used. There was some evidence of an association between the surgeon's level of experience and DAP exposure, although this was not statistically significant ( p = 0.069).

Conclusions: Increased radiation in proximal femur fractures is seen in the fixation of complex fractures, some subtypes, with certain types of implants used and if an additional implant was required. Surgeon seniority did not result in less radiation exposure, which is in contrast to other published studies.

Keywords: Fixation; Fluoroscopy; Proximal femur fracture; Radiation; Reduction.

PubMed Disclaimer

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Factors associated with increased radiation exposure in the fixation of proximal femoral fractures - PubMed

# data[].attributes.attachment_link.description
Increased radiation in proximal femur fractures is seen in the fixation of complex fractures, some subtypes, with certain types of implants used and if an additional implant was required. Surgeon seniority did not result in less radiation exposure, which is in contrast to other published studies.

# data[].attributes.headline
Surgical trainee experiences from 2013 to 2023 within the United Kingdom as reported by the General Medical Council National Training Survey

# data[].attributes.subject
Surgical trainee experiences from 2013 to 2023 within the United Kingdom as reported by the General Medical Council National Training Survey

# data[].attributes.attachment_link.readable_text
The .gov means it's official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

doi: 10.1016/j.surge.2023.11.005.

Affiliations

1 Department of Surgery, Dartford and Gravesham NHS Trust, Darenth Wood Road, Dartford, DA2 8DA, UK. Electronic address: n.donald@doctors.org.uk.

2 Department of Trauma and Orthopaedics, London North West University Hospitals NHS Trust, UK; Imperial College London, UK.

Free article

Free article

doi: 10.1016/j.surge.2023.11.005.

Affiliations

1 Department of Surgery, Dartford and Gravesham NHS Trust, Darenth Wood Road, Dartford, DA2 8DA, UK. Electronic address: n.donald@doctors.org.uk.

2 Department of Trauma and Orthopaedics, London North West University Hospitals NHS Trust, UK; Imperial College London, UK.

Abstract

Introduction: The General Medical Council (GMC) issues annual surveys to all doctors within the United Kingdom (UK) in a formal postgraduate training scheme. This facilitates the monitoring of experiences for quality assurance purposes. Low job satisfaction has been associated with heightened levels of burnout and staff turnover, alongside deteriorating clinical care and productivity levels.

Methods: We gathered and extracted data from the publicly available online GMC reporting tool. Data ranged from 2013 to 2023 and spanned 12 postgraduate surgical training programmes across all 18 indicators available. In total, 198 individual metrics were recorded, in addition to burnout. We conducted trend analysis and yearly average mean scores for individual metrics, burnout and geographical differences for 141 individual training programmes within the 16 training regions.

Results: Of the 198 metrics analysed, 83 (42 ​%) were found to have statistically significant negative trends (P ​< ​0.05), in comparison to 24 (12 ​%) with positive trends. 5 specialities had over 50 ​% of metrics showing a significant negative trend. Overall satisfaction was negative in all 12 programmes, with eight reaching significance (P ​< ​0.05). Of 141 individual training programmes, 29 ​% showed a significantly negative trend in overall satisfaction, with 1 ​% demonstrating a significant positive trend (P ​< ​0.05).

Conclusion: Our study is the first to explore long-term trends in trainee reported surgical training experiences within the UK. Our data have revealed widespread worsening trainee reported experiences and dissatisfaction across multiple specialities and geographical regions, especially in key areas of overall satisfaction, self-development, and clinical supervision.

Keywords: Burnout; Job satisfaction; Medical education; Personal satisfaction; Physicians; Productivity; Psychology; Surgery; Surveys and questionnaires; Training; United Kingdom.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interest.

Similar articles

Satisfaction of doctors with their training: evidence from UK.

Gregory S, Demartini C. Gregory S, et al. BMC Health Serv Res. 2017 Dec 29;17(1):851. doi: 10.1186/s12913-017-2792-0. BMC Health Serv Res. 2017. PMID: 29284467 Free PMC article.

Building a sustainable rural physician workforce.

Ostini R, McGrail MR, Kondalsamy-Chennakesavan S, Hill P, O'Sullivan B, Selvey LA, Eley DS, Adegbija O, Boyle FM, Dettrick Z, Jennaway M, Strasser S. Ostini R, et al. Med J Aust. 2021 Jul;215 Suppl 1:S5-S33. doi: 10.5694/mja2.51122. Med J Aust. 2021. PMID: 34218436

A new tool to evaluate postgraduate training posts: the Job Evaluation Survey Tool (JEST).

Wall D, Goodyear H, Singh B, Whitehouse A, Hughes E, Howes J. Wall D, et al. BMC Med Educ. 2014 Oct 2;14:210. doi: 10.1186/1472-6920-14-210. BMC Med Educ. 2014. PMID: 25277827 Free PMC article.

Appropriate Medical Staffing Improves Patient Safety, Training and Doctor Wellbeing.

Hunter C, Thorne A, Fallon J, Stevenson AJ. Hunter C, et al. Cureus. 2022 Nov 30;14(11):e32071. doi: 10.7759/cureus.32071. eCollection 2022 Nov. Cureus. 2022. PMID: 36600851 Free PMC article.

Evidence Brief: The Quality of Care Provided by Advanced Practice Nurses [Internet].

McCleery E, Christensen V, Peterson K, Humphrey L, Helfand M. McCleery E, et al. Washington (DC): Department of Veterans Affairs (US); 2014 Sep. Washington (DC): Department of Veterans Affairs (US); 2014 Sep. PMID: 27606392 Free Books & Documents. Review.

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Surgical trainee experiences from 2013 to 2023 within the United Kingdom as reported by the General Medical Council National Training Survey - PubMed

# data[].attributes.attachment_link.description
Our study is the first to explore long-term trends in trainee reported surgical training experiences within the UK. Our data have revealed widespread worsening trainee reported experiences and dissatisfaction across multiple specialities and geographical regions, especially in key areas of overall s ...

# data[].attributes.headline
Conference Abstract - 424 Enhancing patient satisfaction in outpatient hysteroscopy: a comprehensive audit at east kent hospitals

# data[].attributes.subject
Conference Abstract - 424 Enhancing patient satisfaction in outpatient hysteroscopy: a comprehensive audit at east kent hospitals

# data[].attributes.attachment_link.provider_name
International Journal of Gynecologic Cancer

# data[].attributes.attachment_link.title
424 Enhancing patient satisfaction in outpatient hysteroscopy: a comprehensive audit at east kent hospitals

# data[].attributes.attachment_link.description
Introduction/Background This quality improvement project endeavors to evaluate and enhance patient satisfaction in outpatient hysteroscopy procedures at East Kent Hospitals. Our primary objectives include benchmarking against national standards, identifying areas for improvement, and fostering evidence-based decision-making in gynecological care. Methodology We conducted a meticulous audit encompassing outpatient hysteroscopy clinics at WHH, BHD, KCH, and QEQM, involving a diverse sample of 100 patients. The audit spanned from February 2023 to September 2023. Results Pre-Procedure Information: 73% of patients received written information before the procedure, slightly below the national average of 87%. Waiting Area and Facilities: 40% of patients rated our facilities as excellent, while 16% perceived them as poor/fair. Pain Management: 60% received painkillers before their appointments. 12% expressed a wish for painkillers, surpassing the 7% national figure. The mean pain score for our patients was 4.8, indicating a favorable experience compared to the national average of 5.2. Pain Perception: Despite favorable scores, patients reported pain as more intense than their typical menstrual experience. Service Satisfaction: An impressive 83% rated our service 10/10. 5% scored it as 9/10. 5% scored it as 8/10. 7% did not provide a response. Conclusion Our findings reveal commendable patient consultation practices, yet opportunities for improvement in pain management and facility communication. With a focus on personalized care, increased communication regarding painkillers, and addressing facility concerns, we aim to elevate the outpatient hysteroscopy experience for our patients. We believe that sharing these insights at an international medical conference will contribute to the broader discourse on optimizing patient satisfaction in gynecological care. Disclosures .

# data[].attributes.headline
30-day Morbidity and Mortality after Cholecystectomy for Benign Gallbladder Disease (AMBROSE): A Prospective, International Collaborative Cohort Study

# data[].attributes.subject
30-day Morbidity and Mortality after Cholecystectomy for Benign Gallbladder Disease (AMBROSE): A Prospective, International Collaborative Cohort Study

# data[].attributes.attachment_link.readable_text
* Geoffrey Yuet Mun WONG, Royal North Shore Hospital, St Leonards, Australia

† Himanshu WADHAWAN, Forth Valley Royal Hospital, Larbert, United Kingdom

‡ Victor ROTH CARDOSO, University of Birmingham, Birmingham, United Kingdom

§ Laura BRAVO MERODIO, University of Birmingham, Birmingham, United Kingdom

∥ Yashasvi RAJEEV, Royal Brompton Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom

¶ Ricardo David MALDONADO, Power Stats Statistical Consulting, West Ryde, Australia

# Alessandro MARTININO, University of Illinois Chicago, Chicago, Illinois, United States of America

** Vignesh BALASUBRAMANIAM, Ysbyty Gwynedd Hospital, Bangor, United Kingdom

†† Aabid ASHRAF, Maharishi Markandeshwar Medical College And Hospital, Solan, India

‡‡ Adeela SIDDIQUI, Patel Hospital Karachi, Karachi, Pakistan

§§ Ahmad Ghassan AL-SHKIRAT, Jordan University Hospital, Amman, Jordan

∥∥ Ahmed MOHAMMED ABU-ELFATTH, Assiut University Hospital, Assiut, Egypt

¶¶ Ajay GUPTA, Queen Elizabeth Hospital, Gateshead, United Kingdom

## Akram ALKASEEK, Gharyan Central Hospital, Gharyan, Libya

*** Amel OUYAHIA, Medical Research Institute Hospital, Université Ferhat Abbas, Setif, Algeria

††† Amira SAID, Darent Valley Hospital, Dartford, United Kingdom

‡‡‡ Anshuman PANDEY, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India

§§§ Ashwani KUMAR, Government Medical College, Patiala, India

∥∥∥ Baila MAQBOOL, University of New Mexico, Albuquerque, United States of America

¶¶¶ Carlos A. MILLÁN, Hospital San José, Bogota, Colombia

### Cheena SINGH, Maharishi Markandeshwar Medical College And Hospital, Solan, India

**** Diana Alejandra PANTOJA PACHAJOA, Clinica Universitaria Reina Fabiola, Córdoba, Argentina

†††† Dmitry Mikhailovich ADAMOVICH, Gomel State Medical University, Gomel, Belarus

‡‡‡‡ Enrique PETRACCHI, Hospital Dr. Cosme Argerich, Buenos Aires, Argentina

§§§§ Fariha ASHRAF, Patel Hospital, Karachi, Pakistan

∥∥∥∥ Marco CLEMENTI, San Salvatore L'Aquila, University of L'Aquila, L'Aquila, Italy

¶¶¶¶ Francesk MULITA, General University Hospital of Patras, Patras, Greece

#### Gad Amram MAROM, Department of General Surgery, Hadassah Hebrew University Medical Center, Jerusalem, Israel

***** Gamaleldeen ABDULAAL, Southend University Hospital, Southend-on-Sea, United Kingdom

††††† Georgios-Ioannis VERRAS, General Hospital of Patras, Patras, Greece

‡‡‡‡‡ Giacomo CALINI, University Hospital of Udine - Santa Maria della Misericordia, Udine, Italy

§§§§§ Gianluigi MORETTO, Pederzoli Hospital, Peschiera del Garda, Italy

∥∥∥∥∥ Hossam ELFEKI, Mansoura University Hospital, Mansoura, Egypt

¶¶¶¶¶ Hui LIANG, Second Affiliated Hospital of Nanchang University, Nanchang, China

##### Humam JALAAWIY, Ad Dewania Teaching Hospital, Ad Dewania, Iraq

****** Ibrahim ELZAYAT, Aswan University Hospital, Aswan, Egypt

†††††† Jayanta Kumar DAS, Nazareth Hospital, Shillong, India

‡‡‡‡‡‡ Jose Miguel ACEVES-AYALA, Hospital Civil de Guadalajara Dr. Juan I. Menchaca, Guadalajara, Mexico

§§§§§§ Kazi Taslima AHMED, Darent Valley Hospital, Dartford, United Kingdom

∥∥∥∥∥∥ Luca DEGRATE, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy

¶¶¶¶¶¶ Manisha AGGARWAL, Jain Multispeciality Hospital, Khanna, India

###### Mohammed Ahmed OMAR, Qena University Hospital, Qena, Egypt

******* Mounira RAIS, CHU Saadna Abdenour De Sétif, Setif, Algeria

††††††† Muhammed ELHADI, Tripoli University Hospital, Tripoli, Libya

‡‡‡‡‡‡‡ Nasser SAKRAN, Faculty of Medicine, Bar-Ilan University, Ramat Gan, Israel

§§§§§§§ Rajesh BHOJWANI, Santokba Durlabhji Memorial Hospital, Jaipur, India

∥∥∥∥∥∥∥ Ramesh AGARWALLA, Fortis Hospital, West Bengal, India

¶¶¶¶¶¶¶ Samir KANAAN, Tishreen University Hospital, Latakia, Syria

####### Sarnai ERDENE, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia

******** Serge CHOOKLIN, Lviv Regional Clinical Hospital, Lviv, Ukraine

†††††††† Suhail KHUROO, SMVD Narayana Superspeciality Hospital, Katra, India

‡‡‡‡‡‡‡‡ Surrendar DAWANI, Dr. Ziauddin Hospital Clifton campus, Karachi, Pakistan

§§§§§§§§ Syed Tanseer ASGHAR, Kulsum International Hospital, Islamabad, Pakistan

∥∥∥∥∥∥∥∥ Tak Kwan James FUNG, John Radcliffe Hospital, Oxford, United Kingdom

¶¶¶¶¶¶¶¶ Taryel OMAROV, Azerbaijan Medical University, Baku, Azerbaijan

######## Valentin Titus GRIGOREAN, Bagdasar Arseni Emergency Clinical Hospital, Bucharest, Romania

********* Zdenko BORAS, Clinical Hospital Osijek, Osijek, Croatia

††††††††† Georgios V. GKOUTOS, Centre for Health Data Science, University of Birmingham, United Kingdom

‡‡‡‡‡‡‡‡‡ Rishi SINGHAL, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom

§§§§§§§§§ Kamal MAHAWAR, South Tyneside and Sunderland NHS Trust, Sunderland, United Kingdom

Funding Statement: Upper GI Unit, Birmingham Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

Data Access Statement: The anonymized data for this study can be made available upon request.

Author Contributions

Conflict of Interest Declaration: The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interests in the subject matter or materials discussed in this manuscript.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.annalsofsurgery.com.

# data[].attributes.attachment_link.title
30-day Morbidity and Mortality after Cholecystectomy for... : Annals of Surgery

# data[].attributes.attachment_link.description
a gap in the knowledge of the current practice and variations on a global level. Methods: A prospective, international, observational collaborative cohort study of consecutive patients undergoing cholecystectomy for benign gallbladder disease from participating hospitals in 57 countries between January 1 and June 30, 2022, was performed.

# data[].attributes.headline
Real‐world data of a digitally enabled, time‐restricted eating weight management program in public sector workers living with overweight and obesity in the United Kingdom: A service evaluation of the Roczen program

# data[].attributes.subject
Real‐world data of a digitally enabled, time‐restricted eating weight management program in public sector workers living with overweight and obesity in the United Kingdom: A service evaluation of the Roczen program

# data[].attributes.body
weight management program in public sector workers living

with overweight and obesity in the United Kingdom: A

service evaluation of the Roczen program

# data[].attributes.headline
Use of Temporally Validated Machine Learning Models To Predict Outcomes of Percutaneous Nephrolithotomy Using Data from the British Association of Urological Surgeons Percutaneous Nephrolithotomy Audit

# data[].attributes.subject
Use of Temporally Validated Machine Learning Models To Predict Outcomes of Percutaneous Nephrolithotomy Using Data from the British Association of Urological Surgeons Percutaneous Nephrolithotomy Audit

# data[].attributes.attachment_link.description
We have developed a machine learning–based decision aid to provide patient-specific
predictions for counselling patients and perioperative planning before percutaneous
nephrolithotomy. The application is available online at https://endourology.shinyapps.io/PCNL_Demographics/.

# data[].attributes.headline
Strengthening TikTok Content Analysis in Academia Using Follower Count and Engagement

# data[].attributes.subject
Strengthening TikTok Content Analysis in Academia Using Follower Count and Engagement

# data[].attributes.attachment_link.readable_text
Letter to the Editor

1 Urology Department, Darent Valley Hospital, Dartford, United Kingdom

2 Dermatology Department, Barts Health NHS Trust, London, United Kingdom

Corresponding Author:

Serena Ramjee, MBBS

Urology Department

Darent Valley Hospital

Darenth Wood Road

Dartford, DA2 8DA

United Kingdom

Phone: 44 1322 428100

Email: serena.ramjee1@nhs.net

We read with great interest Abdelnour et al's paper titled "Skin of color representation for atopic dermatitis on TikTok: cross-sectional analysis" [] and express our gratitude for the findings.

Using the search term #eczema in July 2022, the study evaluated the representation of patients with skin of color (SoC) and the quality of atopic dermatitis videos on TikTok. A review of 119 eligible videos revealed that physicians produced significantly higher-quality content than nonphysicians but may underrepresent SoC. Viewer count was a secondary measure, with its mean value lower for physicians compared to nonphysicians, though the difference was not significant. The authors noted that this lower viewer count may limit the impact of better SoC representation in physicians' videos. However, we believe that this conclusion cannot be made without further analysis.

Using the viewer count, one may infer that physician content is less popular. However, in instances where there is an insignificant difference in viewer count between sources, this measure alone provides limited information. On TikTok, a view is "counted" within the 3 seconds of playback, meaning a user does not have to view the entire video. Additionally, the viewer count corresponds to the number of times a video has been played rather than unique views []. These factors, coupled with TikTok automatically replaying its videos once they finish, mean the viewer count does not reflect the number of individuals that have viewed a video.

Follower count and engagement (likes, saves, shares, and comments) provide additional context. These measures, alongside viewer count, enable the calculation of a video's engagement rate and reach percentage (view rate). Engagement rate estimates the percentage of viewers that engage with a video (engagement×100/viewer count) [], whereas reach percentage estimates the percentage of a source's followers that view a video (viewer count×100/followers) []. Marketing companies suggest a "good" engagement rate lies between 1% to 5% [] and define the average reach percentage as 14.49% []. To demonstrate the application of these formulas, we reviewed the results from Pagani et al [] below.

This cross-sectional study screened the top 50 videos when searching "slugging" (defined as thickly coating the skin with a petrolatum-based ointment like Vaseline and can form the final step of a nighttime skincare routine []) on TikTok and analyzed their upload source, content, and quality. Videos were categorized by source into health care providers, influencers, and others. Assessing follower count and engagement (likes and comments) revealed that although influencers have a nonsignificantly lower median viewer count than health care providers (94,500 vs 102,150), their videos had a greater reach percentage (65.3% vs 24.9%) and engagement rate (8.1% vs 4.3%). These values suggest that influencers created more engaging content, which may be better promoted by TikTok's algorithm and result in a higher viewer count long term.

We observe that TikTok content analysis is becoming a prevailing means of understanding public dermatology-related information, an unsurprising trend since the platform's video-based format favors dermatology's visual nature, and believe follower count and engagement aid this analysis. Regarding the work of Abdelnour et al [], these measures may assist in determining the impact of improved SoC representation in physician-produced atopic dermatitis videos. If these measures are low, targeted recommendations for improving engagement and reach can be suggested, such as integrating popular trends or cross-promoting content.

Conflicts of Interest

None declared.
Editorial Notice
The corresponding author of "Skin of Color Representation for Atopic Dermatitis on TikTok: Cross-Sectional Analysis" declined to respond to this letter.

‎

Edited by T Leung; This is a non-peer-reviewed article. submitted 05.12.23; accepted 11.01.24; published 30.01.24

©Serena Ramjee, Zeeshaan-ul Hasan. Originally published in JMIR Dermatology (http://derma.jmir.org), 30.01.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Dermatology, is properly cited. The complete bibliographic information, a link to the original publication on http://derma.jmir.org, as well as this copyright and license information must be included.

We read with great interest Abdelnour et al's paper titled "Skin of color representation for atopic dermatitis on TikTok: cross-sectional analysis" [] and express our gratitude for the findings.

Using the search term #eczema in July 2022, the study evaluated the representation of patients with skin of color (SoC) and the quality of atopic dermatitis videos on TikTok. A review of 119 eligible videos revealed that physicians produced significantly higher-quality content than nonphysicians but may underrepresent SoC. Viewer count was a secondary measure, with its mean value lower for physicians compared to nonphysicians, though the difference was not significant. The authors noted that this lower viewer count may limit the impact of better SoC representation in physicians' videos. However, we believe that this conclusion cannot be made without further analysis.

Using the viewer count, one may infer that physician content is less popular. However, in instances where there is an insignificant difference in viewer count between sources, this measure alone provides limited information. On TikTok, a view is "counted" within the 3 seconds of playback, meaning a user does not have to view the entire video. Additionally, the viewer count corresponds to the number of times a video has been played rather than unique views []. These factors, coupled with TikTok automatically replaying its videos once they finish, mean the viewer count does not reflect the number of individuals that have viewed a video.

Follower count and engagement (likes, saves, shares, and comments) provide additional context. These measures, alongside viewer count, enable the calculation of a video's engagement rate and reach percentage (view rate). Engagement rate estimates the percentage of viewers that engage with a video (engagement×100/viewer count) [], whereas reach percentage estimates the percentage of a source's followers that view a video (viewer count×100/followers) []. Marketing companies suggest a "good" engagement rate lies between 1% to 5% [] and define the average reach percentage as 14.49% []. To demonstrate the application of these formulas, we reviewed the results from Pagani et al [] below.

This cross-sectional study screened the top 50 videos when searching "slugging" (defined as thickly coating the skin with a petrolatum-based ointment like Vaseline and can form the final step of a nighttime skincare routine []) on TikTok and analyzed their upload source, content, and quality. Videos were categorized by source into health care providers, influencers, and others. Assessing follower count and engagement (likes and comments) revealed that although influencers have a nonsignificantly lower median viewer count than health care providers (94,500 vs 102,150), their videos had a greater reach percentage (65.3% vs 24.9%) and engagement rate (8.1% vs 4.3%). These values suggest that influencers created more engaging content, which may be better promoted by TikTok's algorithm and result in a higher viewer count long term.

We observe that TikTok content analysis is becoming a prevailing means of understanding public dermatology-related information, an unsurprising trend since the platform's video-based format favors dermatology's visual nature, and believe follower count and engagement aid this analysis. Regarding the work of Abdelnour et al [], these measures may assist in determining the impact of improved SoC representation in physician-produced atopic dermatitis videos. If these measures are low, targeted recommendations for improving engagement and reach can be suggested, such as integrating popular trends or cross-promoting content.

# data[].attributes.attachment_link.title
Strengthening TikTok Content Analysis in Academia Using Follower Count and Engagement

# data[].attributes.attachment_link.description
Letter to the Editor 1 Urology Department, Darent Valley Hospital, Dartford, United Kingdom 2 Dermatology Department, Barts Health NHS Trust, London, United Kingdom Serena Ramjee, MBBS Urology Department Darent Valley Hospital Darenth Wood Road Dartford, DA2 8DA United Kingdom Phone: 44 1322 428100 Email: serena.ramjee1@nhs.net We read with great interest Abdelnour et al's paper titled "Skin of color representation for atopic dermatitis on TikTok: cross-sectional analysis" [] and express our gratitude for the findings.

# data[].attributes.headline
Acute Pancreatitis Masquerading as ST-elevation Myocardial Infarction (STEMI)

# data[].attributes.subject
Acute Pancreatitis Masquerading as ST-elevation Myocardial Infarction (STEMI)

# data[].attributes.body
Infarction (STEMI)

# data[].attributes.headline
Telemedicine Clinics in General and Colorectal Surgery During the COVID-19 Pandemic: Patient Reported Outcomes

# data[].attributes.subject
Telemedicine Clinics in General and Colorectal Surgery During the COVID-19 Pandemic: Patient Reported Outcomes

# data[].attributes.body
Surgery During the COVID-19 Pandemic: PatientReported Outcomes

# data[].attributes.headline
Step forward towards treat-to-target management of giant cell arteritis: patients stratification aiming to targeted remission – updated guidelines

# data[].attributes.subject
Step forward towards treat-to-target management of giant cell arteritis: patients stratification aiming to targeted remission – updated guidelines

# data[].attributes.attachment_link.readable_text
Step forward towards treat-to-target management of giant cell arteritis: patients stratification aiming to targeted remission - updated guidelines

Abstract

Background

The aim of this work is to develop guidelines for health care professionals in the giant cell arteritis diagnosis and management, based on patients' stratification and targeted outcome measures.

Results

Fourteen expert panel had completed the two rounds surveys. After the end of round two, twenty three recommendations were released distributed on 8 domains. The percentage of the agreement on the recommendations was 76.9% to 100%. All 23 key questions were answered at the end of the second round with agreement upon.

Conclusion

Patient stratification facilitate the initiation of an appropriate management approach for patients with giant cell arteritis aiming at achieving targeted disease remission state and prevention of visual loss and/or development of ischaemic events. Treat to Target approach is a new concept in giant cell arteritis management which aims to provide tight control to achieve and maintain disease remission. This work defined the treatment targets in relation to the disease stage.

Background

GCA is a medical emergency as it poses a risk of sudden irreversible loss of vision, stroke, tongue or scalp necrosis or other peripheral limb ischaemic events. However, there has been a misconception by the medical healthcare professionals that GCA is a headache disease of older adults which shows swift and good response to glucocorticoid therapy [ 5]. Such imposing impression of the disease made it less appealing to the medical community particularly the rheumatologists [ 4]. In clinical practice GCA can be multifaceted. This has been attributed to the acute onset and seriousness of the disease, diagnostic obscurity, particularly as the patients tend to seek advice from variable medical specialities, as well as the morbidity associated with GCA treatment [ 5]. Emerging evidence suggests that this naive concept of GCA should be dumped. This has been supported by the advances in the investigation and management of the disease. The definition of a specific ultrasonography (US) pattern in GCA has transformed the management approach of this disease in day-to-day standard practice [ 6, 7, 8].

Over the past decade there has been an increased awareness of GCA. Recent studies have broadened both the GCA diagnostic and treatment spectrum [ 9, 10]. However, despite these fundamental developments, many critical clinical questions remain unanswered for GCA which has affected the key areas of management. Furthermore, there is large heterogeneity in treatment strategies of GCA in clinical practice. These critical gaps in knowledge and medical care highlighted the imperative need to update the current management recommendation and develop improved diagnostic pathways, aiming to set up individualized and targeted management approach for GCA patients. The objective of this guideline is to provide up-to-date, evidence-based recommendations for the targeted assessment and management of GCA.

Methods

Design

Using a multi-step process strategy, the GCA consensus treatment guidelines were produced based on study. The Clinical, Evidence-based, Guidelines (CEG) guideline development methodology, which entails reaching a consensus based on the majority of available scientific data and clinical experience, served as the basis for the study design. With the ultimate aim of offering an expert opinion, the objective is to ascertain the degree of agreement among experts regarding a specific topic. The work complied with the meta-analyses and recommended publishing items for systematic reviews reporting requirements [ 11].

Study teams

Core team

To supervise, plan, and support the development of the project's scope and preliminary clinical questions, as well as the appointment of the expert panel and article drafting. The project's original PICOT clinical questions and project scope were developed with support from the core team. Using the PICOT process helps develop a careful and thoughtful question that makes the search for evidence easier, Formulate the PICOT question in general terms: Based on the EBSCO Health example, while P = GCA patients, I = making consensus via online survey rounds, C = the well-known evidence based previous studies, and O = development of GCA Treat-to-Target management guidelines.

Key questions used to develop the guidelines

A set of structured key questions (supplement 1) that identify the target population, the approach taken in the investigation, the comparison(s) employed, the outcomes used to quantify efficacy, effectiveness, or risk, as well as time (PICOT), served as the focal point of these guidelines [ 12]. The following procedures were followed in order to gather the evidence needed to respond to the clinical questions: developing the clinical questions, organising the questions, looking for evidence, critically assessing and selecting the evidence, presenting the findings, and formulating recommendations. The questions served as the foundation for the methodical literature search, which led to the development of the clinical treatment guidelines.

Literature review team

The extraction of data and the quality of evidence assessment must be completed in order to perform the literature search. The team was guided by an experienced consultant for literature reviews, and an expert in methodology assisted in conducting the study of the literature based on the particular research questions that were selected to centre on GCA management.

Data sources

Using the PubMed/MEDLINE, EMBASE, and Cochrane databases, a systematic literature search was conducted to obtain appropriate evidence-based background knowledge for deliberations. The experts in charge of the literature review revised the data abstraction, published recommendations, and quality of evidence rating [ 13, 14]. They performed this review by providing a comprehensive list of recommendations for the management of GCA, which was based on both their own clinical expertise and the available research evidence. The Oxford Centre for Evidence-based Medicine (CEBM) approach was used to determine the level of evidence for each component (supplement 2) [ 14].

Study selection

Relevant studies were selected by applying inclusion and exclusion criteria to the literature retrieved with the search strategies.

Inclusion criteria

Systematic reviews, uncontrolled trials, randomised controlled trials (RCTs), observational studies (cohort, case control, and cross-sectional), and articles with economic evaluations were among the articles that were included. Trials were considered eligible if participants with GCA from any type of healthcare setting and therapy were included, independent of gender. The classification evidence and recommendations utilised in the included research should be clearly specified. Additionally, the formal procedure (Delphi exercise, panel conference) for formulating recommendations was described.

Exclusion criteria

Editorials, commentary, conference abstracts, narrative/personal reviews that do not rely on evidence, and submissions without an English translation were excluded.

Expert panel

Those are going to be chosen by the core team. In addition to actively participating in GCA-related scientific research, participants should possess professional expertise, training, and experience..

Target audience

The purpose of these guidelines is to support medical professionals who monitor and treat patients with GCA. Additionally, patients and those in charge of commissioning care for patients with GCA in the National Health Service should find the guidelines to be a useful resource.

Delphi

The Delphi procedure is a tried-and-true method designed to find consensus views among experts in the field in order to address research question(s). Its system is built around a sequence of expert-addressed questionnaires, or "rounds" [ 15].

Consensus process

To reach a consensus on the GCA's T2T (Treat to Target) strategy, two Delphi rounds were conducted. The structured Delphi method guarantees that each participant's opinion is given equal weight. Online surveys were used to carry out the Delphi process. Ten items related to the GCA treatment plan were included in the first round of the electronic questionnaire.

Voting process

Voting was conducted in two time-limited rounds via live online delivering. Every task force member received an invitation to participate and advance notice of the start and end times of each voting session. Votes were collected and processed anonymously, and special access links were distributed. During the voting process, feedback on possible ambiguity, unidentified overlaps, and rephrasing of each statement was received. Voting on the statements was restricted to task force members alone.

Chronogram of Delphi rounds

The first round took place between 3rd Feb -8th Feb 2023 (6 days). The aspects about which respondents did not reach consensus in this first round were revised in view of the comments and included in the second round. The second round took place on 19th of Feb 2023 (11 days after the first round) and lasted for 6 days (till 24th of Feb 2023).

Rating

Every statement received a score ranging from 1 to 9, where 1 denoted "complete disagreement" and 9 represented "complete agreement." In general, the numbers 1-3, 4-6, and 7-9 stand for disagreement, uncertainty, and agreement, in that order. No statement required voting, and participants were urged not to vote if they thought a statement was outside their purview. "Uncertainty" in one's vote indicates "discomfort regarding the accuracy of the recommendation." Following each voting session, the scientific committee evaluated the comments that were added to all of the statements. Throughout each vote round, members were encouraged to voice their opinions, especially when there was a disagreement. Because of this, the panel was able to determine when the statement was misunderstood and to remove the vote on it.

Definition of consensus

Developing the clinical care standards framework

In assisting in the standardised identification of guideline components, a structured template was created based on the responses to the structured key questions and the literature research. The information extraction and provision formats for each guideline component have been specified.

Ethical aspects

This study was performed in accordance with the Helsinki Declaration. This was a multistep process which followed the "Clinical, Evidence-based, Guidelines" (CEG) initiative protocol (ethical approval code: 34842/8/21, ethical board Tanta University).

Results

Literature research and evidence selection:

After removing the duplicates, 607 of the 788 records that the search produced were examined (171). We obtained the whole texts of 145 possible documents after filtering. The literature review contained thirty-three documents. The findings were compiled, summarised, and developed into recommendations for the treatment of GCA patients. After that, they were debated, changed, and submitted to a vote.

Expert panel characteristics

The Delphi form was sent to expert panel ( n  = 14), of whom 13 (92.8%) completed the two rounds. The participants were 2 from the USA, 6 from Europe, and 5 from Africa (Egypt). 11 of the experts' panel were rheumatologists in addition to 2 patients.

Delphi round 1

The 23 items in this round, which addressed the major clinical questions, included: all of the clinical questions that were addressed in the rounds that followed. Every domain and question was accepted (all respondents strongly agreed or agreed), and no questions were removed from the list.

Delphi round 2

Based on the literature search, a list of 23 sectioned recommendations were generated using the input from round 1. The response rate for round 2 was 92.8% from the experts' panel (13/14). Wording modifications were suggested for 14 statements. The statements were modified and amended. For all statements the consensus was reached (as ≥ 80% of respondents strongly agreed or agreed). There were no significant differences between the grading of the patients and healthcare professionals. The main differences were regarding the priority of ultrasound scanning (favoured by the European and Egyptian teams) Vs temporal artery biopsy (favoured by the American team).

Statements and grade of recommendations (GOR) for the management of GCA

These are a list of the recommendations made in order to address the main clinical questions. Under each part, there is information on the mean degree of agreement among the expert panel members, the percentage of agreement, the level of evidence (LOE), and the grades of recommendations. A suggestion of an algorithm for the stratification of patients with GCA and the recommended management approach is demonstrated in Table 1. Table 2 shows the Treat to Target proposal for GCA.

Table 1 Suggested algorithm for the GCA patients' stratification

Table 2 Treat to target of giant cell arteritis

Overarching principles

Diagnosis: Q. what is the recommended approach to GCA diagnosis?

Level of evidence: 4C, level of agreement: Mean ± SD: 8.15 ± 1.2, percentage of agreement: 92.3%, Level of agreement: High.

Clinical symptoms (Red Flags)

Key symptoms

New-onset of persistent localised headache, often in the temporal area.

Constitutional symptoms (e.g. weight loss > 2 kg, low-grade fever, fatigue, night sweats).

Jaw pain and/or tongue claudication.

Acute visual symptoms such as amaurosis fugax, acute visual loss, diplopia.

Symptoms of polymyalgia rheumatica.

Limb claudication.

Signs: clinical examination

Cranial disease

Extra-cranial disease

Non-specific manifestations: without evidence of infection or neoplastic disease:

Older age, history of transient visual loss and jaw claudication were independent predictors of visual loss, while fever and rheumatic symptoms were protective [ 21].

Hypertension and ischaemic heart disease were also identified as potential risk factors for cranial ischaemic complications [ 22, 23].

Risk factors for aortic aneurysms:

Diagnostic work-up

Fast Track GCA pathway: Q. is there a role for GCA fast track approach?

Level of evidence: 5D, level of agreement: Mean±SD: 8.07±2.2, percentage of agreement: 92.3%, Level of agreement: High

Immediate treatment of GCA implies that the diagnosis is also confirmed rapidly.

The fast track GCA pathway offers timely evaluation of cranial GCA and has become the gold standard method of assessment and treatment of patients referred with suspected GCA.

Fast track US clinics for GCA offer the suspected GCA patients prompt chance for clinical and sonographic assessment, facilitating immediate initiation of high-dose glucocorticoids (GC), consequently reducing the symptom-to-therapy lag. Therefore, it aims to lessen numbers of negative outcomes as sight loss and subsequently loss of independence and mobility which is associated with increase health care use and cost.

The role of imaging: Q. what is the role of imaging in the diagnosis of GCA?

Level of evidence: 3C, level of agreement: Mean±SD: 8.0±1.2, percentage of agreement: 84.6%, Level of agreement: High

Imaging in clinically suspected cases

Level of evidence: 3C, level of agreement: Mean±SD: 8.15±0.89, percentage of agreement: 92.3%, Level of agreement: High

Imaging modalities

Ultrasound: Q. Should a suspected diagnosis of GCA be confirmed by US imaging?

Level of evidence: 2B, level of agreement: Mean±SD: 7.69±1.6, percentage of agreement: 76.9%, Level of agreement: high

Other imaging modalities: Q. Is there a room for other imaging modalities in the diagnosis of GCA?

Level of evidence: 4C, level of agreement Mean±SD: 7.85±1.63, percentage of agreement: 84.6%, Level of agreement: High

Temporal Artery Biopsy (TAB): Q. Shall Temporal Artery biopsy be considered in every patient with suspected GCA?

Level of evidence: 5, level of agreement Mean±SD: 7.69±1.93, percentage of agreement: 76.9%, Level of agreement: high

Patients' stratification: Q. Can the GCA patients be stratified according to their disease status or the presence of comorbidities?

Level of evidence: 4C, level of agreement: Mean±SD: 8.23±1.1, percentage of agreement: 84.6%, Level of agreement: High

There is not "one size fit all" glucocorticoids regimen for all newly diagnosed GCA patients, with empirical disease-modifying agents added only to patients with an increased risk of steroid-related adverse effects or when a flare occurs.

GCA varies in extent and severity, therefore management should be guided by disease stratification and target the prevention of poor treatment outcomes.

Patients' stratification facilitates the achievement of treatment targets, tailoring the medical management approach and prediction of the disease outcomes.

Patient can be stratified according to: Disease activity, disease severity, chances of accrual damage and the presence of comorbidities (Table 1).

Treat to Target: Q. Can GCA be treated to a target? What are the treatment targets?

Level of evidence: 5D, level of agreement: Mean ± SD: 8.15 ± 1.2, percentage of agreement: 84.6%, Level of agreement: High

Treatment

Can the treatment of GCA be splitted into phases?

Level of evidence: 5D, level of agreement: Mean+SD: 8.31±1.1, percentage of agreement: 84.6%, Level of agreement: High

Induction phase

Maintenance phase

A regimen for glucocorticoids tapering should start once the disease is controlled.

The glucocorticoids tapering regimen must weigh the risk of relapse against the risk of glucocorticoids-related adverse events.

There are several plans for tapering of the glucocorticoids dose. General plan is cut the steroids dose down to a target dose of 15-20 mg/day within 2-3 months and after one year to ≤ 5 mg/day (Table 1).

There is no data available regarding the optimal length of glucocorticoids therapy, it usually takes about two years or more before GCs can be stopped.

In patients receiving GC-sparing therapy, faster glucocorticoids tapering and earlier withdrawal of GCs should be considered on an individual basis.

GCA "patients at risk": Q. Is it important to identify GCA patients who are at risk?

Level of evidence: 5D, level of agreement: Mean±SD: 8.31±0.95, percentage of agreement: 92.3%, Level of agreement: High

Patients at high risk of glucocorticoid toxicity or who have relapsing or refractory disease. These are the:

Patients with a persisting high burden of inflammatory disease, multiple relapses with an inability to wean glucocorticoids, non-response to methotrexate, co‑morbidities or the presence of other factors that increase glucocorticoid-related adverse events, as well as resistance to glucocorticoid therapy.

"Patients at risk" of disease complications and/or treatment-related adverse events.

Management of Relapse: Q. How to manage relapses in GCA?

Level of evidence: 5D, level of agreement: Mean±SD: 8.38±0.77, percentage of agreement: 100%, Level of agreement: High

Relapse rates in the range of 34%-75% may occur in GCA patients treated with glucocorticoids therapy [ 35].

Relapse risk is high particularly after early taper and/or reduction of the glucocorticoids dose below 5 mg/day.

Relapse can be either:

Major Relapse: Recurrence of active disease with either of the following:

Clinical features of ischaemia (including jaw claudication, visual symptoms, visual loss attributable to GCA, scalp necrosis, stroke, limb claudication).

Evidence of active aortic inflammation resulting in progressive aortic or large vessel dilatation, stenosis or dissection.

Minor Relapse:

Recurrence of active disease, not fulfilling the criteria for a major relapse

-Initial treatment is reinstitution or a dose-increase of glucocorticoids which may differ according to whether it is minor (increase GC to last effective dose) or major (increase GC to 40-60mg/day) relapse.

Relapses should warrant the assessment of glucocorticoids benefit: risk ratio as high cumulative GC exposure may lead to an increased risk of glucocorticoids-related adverse events.

Adjunctive therapy, combined with increasing the glucocorticoids dose, should be considered in selected GCA patients (refractory* or relapsing disease, the presence comorbidities or an increased risk of glucocorticoids associated adverse effects or complications). Adding tocilizumab and increasing the dose of glucocorticoids is preferable over methotrexate combined with increasing the glucocorticoids dose for GCA patients who experience disease relapse with cranial or new extra-cranial symptoms while receiving glucocorticoids. Methotrexate can be considered for patients who are unable to tolerate or have limited access to tocilizumab.

Patients who are treated with methotrexate adjunctive therapy: 'treatment failure', is defined as having two or more relapses or having a relapse that was not controlled by an increment of prednisone dose [ 36, 37, 38, 39].

Relapses with symptoms of polymyalgia rheumatica may be controlled by increasing the dose of glucocorticoids alone. If no response, PMR can be considered as a relapse of the GCA.

Refractory GCA: Inability to induce remission (with evidence of reactivation of disease) despite the use of standard care therapy

Glucocorticoids tapering: Q. How to plan for glucocorticoids tapering?

Table 3 shows a suggested regimen for tapering glucocorticoids.

Table 3 Suggested glucocorticoids tapering regimen

Treatment discontinuation: Q. How to plan for treatment discontinuation?

Level of evidence: 5D, level of agreement: Mean+SD: 7.46±1.5, percentage of agreement: 76.9%, Level of agreement: high

Drug-free remission: what is meant by remission?

*Remission

Absence of all clinical signs and symptoms attributable to active LVV and normalisation of ESR and CRP; in addition, for patients with extracranial disease there should be no evidence of progressive vessel narrowing or dilatation (frequency of repeat imaging to be decided on an individual basis)

*Sustained Remission

1.
Remission for at least 6 months.

2.
Achievement of the individual target GC dose.

*Glucocorticoids free remission

1.
Sustained remission

2.
Discontinued GC therapy (but could still be receiving other immunosuppressive therapy)

3.
Drug free remission may be achieved in some patients.

4.
Drug free remission was reported in a cohort of patients treated with Tocilizumab [ 22].

Adjunctive therapy: Q. what is the impact of oral glucocorticoids with non-glucocorticoid immunosuppressive therapy versus oral glucocorticoids alone?

Level of evidence: 4C, level of agreement: Mean±SD: 8.07±1.3, percentage of agreement: 76.9%, Level of agreement: high

Management of patients with comorbidities: Q. What is the impact of identifying the individual patient's comorbidity(ies) at baseline?

Level of evidence: 5D, level of agreement: Mean+SD: 8.15±1.1, percentage of agreement: 84.6%, Level of agreement: High

Diabetes mellitus

Patients with Diabetes Mellitus: use of oral glucocorticoids with methotrexate or tocilizumab can be considered as first line therapy.

Osteoporosis

Consider starting osteoprotective therapy, if the patient has not already started treatment.

Cardiovascular (CVS)

48 who are managing GCA patients should be aware of the increased risk of CVD events, attributable to both disease pathophysiology and glucocorticoid treatment.

GCA patients, should be monitored not only to maintain clinical remission but also to monitor and attempt to prevent CVD events, including strokes, thoracic aortic aneurysms and dissections, ischemic heart disease, and peripheral vascular disease.

Consider imaging to evaluate for active disease and/or development of thoracic aortic aneurysm.

Consider statin and aspirin therapy whenever indicated

If patient is unable to tolerate steroids, consider switching to tocilizumab weekly SC injection.

Infection

The association between high-dose glucocorticoid therapy and opportunistic infections, particularly pneumocystis jirovecii pneumonia (PJP), is now well established in both non-rheumatological and rheumatological diseases. Trimethoprim/sulfamethoxazole (TMP-SMX) has been proved to be effective as a primary prophylaxis for PJP in patients suffering from rheumatological diseases treated with high dose (⩾30 mg/day prednisone) glucocorticoid therapy, with an overall favourable safety profile.

Improving the Benefit: Risk ratio of glucocorticoids: Q. How important is it to optimize the benefit: risk ratio of glucocorticoids?

Level of evidence: 5, level of agreement: Mean±SD: 8.15±0.9, percentage of agreement: 92.3%, Level of agreement: High

Optimizing the benefit: risk ratio of glucocorticoids to minimize adverse events while achieving sustained remission is a vital challenge to be considered whilst treating GCA patients.

Implementation of current treatment recommendations for the optimal use of glucocorticoids could reduce the burden of this treatment

The risk of glucocorticoid-related harm for the majority of patients taking glucocorticoids for a prolonged period (that is, for 3-6 months or more) is:

Low if doses of ≤ 5 mg per day prednisone equivalent are prescribed,

High if doses > 10 mg per day are used.

At doses between 5 and 10 mg per day, patient-specific risk factors determine the probability of harm.

Monitoring: Q. How to monitor GCA patients in standard practice?

Level of evidence: 5D, level of agreement: Mean+SD: 8.23±1.1, percentage of agreement: 84.6%, Level of agreement: High

Baseline assessment

Assessment of medical status

Determination of pre-existing comorbidities such as hypertension, diabetes mellitus, cataract, cardiovascular disease, peptic ulcer disease, osteoporosis and glaucoma is important as the treatment can initiate or worsen disease status.

Assessment of current medications

Checking the list of current medications the patient is taking. Co-medication with non-steroidal anti-inflammatory drugs (NSAIDs) and anti-coagulants is important both for immediate and long-term care in GCA.

Baseline investigations

Consider performing a screen for infection including dipstick urinalysis and chest X-ray (CXR); and a search for mimicking diseases with protein electrophoresis, thyroid function tests, and anti-cytoplasmic neutrophil antibodies. Baseline CXR, echocardiogram or large-vessel imaging are advocated by some centres to assess for large-vessel complications at baseline, in higher risk groups. Occasionally a contrast-enhanced MRI head and orbits may be indicated examining the anterior visual pathways where the cause of an optic neuropathy is not clear.

Frequency of clinical/laboratory monitoring

Imaging monitoring

Level of evidence: 5D, level of agreement: Mean+SD: 8.0±0.8, percentage of agreement: 100%, Level of agreement: High

Surgical management of GCA: Q. what is the role of surgery in the management of GCA?

Level of evidence: 5D, level of agreement: Mean ± SD: 8.53 ± 0.8, percentage of agreement: 92.3%, Level of agreement: High

For any patient requiring surgical vascular intervention for GCA, the type and timing of intervention should be a collaborative decision between the vascular surgeon and rheumatologist.

Patients with severe GCA and worsening signs of limb/organ ischemia who are receiving immunosuppressive therapy, it is advisable to escalate immunosuppressive therapy over surgical intervention.

For GCA patients undergoing vascular surgical intervention (for a GCA associated complication e.g., aneurysm or stenosis), high-dose glucocorticoids should be administered during the periprocedural period, if the patient has active disease.

Elective endovascular interventions or reconstructive surgery should be performed during stable remission. However, arterial vessel dissection or critical vascular ischaemia requires urgent referral to a vascular team.

Disease activity: how to define the disease activity status of GCA?

Level of evidence: 5D, level of agreement: Mean ± SD: 8.07 ± 1.1, percentage of agreement: 84.6%, Level of agreement: High

Definitions for GCA disease activity states:

Defining the specific disease activity states is important for framing this guideline. These are listed in Table 4.

Table 4 Important definitions for GCA diseasea

PROMs: Q. What are the patient reported outcomes important for the assessment and monitoring of GCA patients?

Outcomes: Q. what are the outcome measures for assessment of treatment outcomes in GCA?

Discussion

GCA remains a disease that represents a challenge to both healthcare professionals as well as patients for its ambiguous presentation, approach to diagnosis, or its remarkable risk of flares and chronic damage in the long term. Over the past decade several RCTs and a good number of high-quality diagnostic studies have changed the view of GCA as a short-term steroid responsive illness [ 40, 41, 42, 43]. Such expansion in methodology, understanding of the disease pathogenesis as well as extent and severity of its outcomes highlighted the need for up-to-date recommendations for GCA management. This work was carried out to provide evidence-based recommendations for the evaluation and management of GCA.

The real challenge of giant cell arteritis is not to control the acute inflammatory process, but to ensure long-term, safe prevention of disease relapses and incipient damage. Both the EULAR recommendations [ 35] and the 2021 ACR recommendations for large vessel vasculitis [ 42] suggest treating all newly diagnosed GCA patients in the same strategy, i.e. with the same glucocorticoid regimen, and the option of empirically adding disease-modifying agents to patients with an increased risk of steroid-related adverse effects or when a flare occurs. Such management approach which is based simply on one-size-fits-all strategy leads to overreliance on glucocorticoids and high chance of development of glucocorticoid-associated complications. This recommendation suggests patients' stratification as a new approach to identify and manage the patients tailored to their potential risks. Several patients may have pre-existing, or develop, comorbidities during the course of glucocorticoids therapy, which warrant individualized approach of management. Furthermore, the high likelihood of symptomatic relapse in GCA (34-62%) make these patients prone to longer periods and higher doses of glucocorticoid therapy [ 37]. Furthermore, adding adjunctive therapy such as tocilizumab or methotrexate was reported to achieve superior remission rates in GCA patients and enables faster withdrawal of glucocorticoids therapy [ 42, 43, 44, 45]. Therefore, stratification of GCA would be an ideal strategy particularly for this cohort of patients. A recent article [ 46] highlighted the need to implement disease stratification in standard practice and suggested using clinical, laboratory, histology, and imaging as parameters for stratification. In medicine, stratification is not a new policy. In fact, it is a common approach which has been implement in oncology, haematology [ 45, 46] as well as rheumatology (e.g. SLE and ANCA associated vasculitis) [ 46, 47]. The stratification system is supported by high-quality evidence as a facilitator for the prediction of disease outcome and the tailoring of therapy accordingly [ 47, 48, 49].

This guideline endorsed the Treat to Target concept of GCA. In agreement with the recently published Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatica [ 52], the level of agreement was high among the experts who shared in this study. However, in contrast to Dejaco et al. study [ 50] which considered the GCA treatment target of GCA to be remission, defined as the absence of clinical symptoms and systemic inflammation, this guideline stratified the target according to the disease stage whether early or established. The definition of the Target has also expanded beyond remission state to include also, in addition to clinical remission, avoidance of visual loss or other vascular damage/tissue ischemia, rapid initiation of treatment and achievement of remission, maintenance of remission with the minimal effective dose of therapy, maintain GCA disease related tissue and vascular integrity (whenever appropriate), minimization of glucocorticoid use and relapse prevention, along with avoidance of damage accrual. Patient reported outcomes and Disease activity score (study submitted for publication) have also been added as targets of treatment. T2T recommendations have been endorsed in rheumatology [ 51, 52, 53], and frequently serve as an outcome in clinical trials and observational studies of GCA [ 52].

Limitations of the study

Despite the low level of evidence in the literature, the level of agreement for each of the statements included in this recommendation was consistently high among the expert panel members.

In conclusion, we are embarking now on the era of targeted GCA management approach with several avenues to stratify, diagnose and manage this cohort of patients. Close partnership with other teams that care for those with GCA including rheumatology, medicine, neurology and primary care, will facilitate early diagnosis and improve long-term management. Therefore, to improve the patients' quality of care and effectively manage their disease, we propose that healthcare professionals dealing with GCA will implement these recommendations into their standard clinical practice. Fast-track GCA pathway, patient stratification, US assessment of the temporal artery, patient reported outcomes as well as quantification of the GCA-response to therapy represent the main pillars of GCA management in the coming decade.

Availability of data and materials

The data will be available upon reasonable request.

Abbreviations

ACR:

American College of Rheumatology

CVS:

Cardiovascular

CXR:

Chest X-ray

GCA:

Giant cell arteritis

GC:

Glucocorticoids

GOR:

Grade of recommendations

LV-GCA:

Large vessel-GCA

MRA:

MR angiography

NSAIDs:

Non-steroidal anti-inflammatory drugs

CEBM:

Oxford Centre for Evidence-based Medicine

PJP:

Pneumocystis jirovecii pneumonia

PMR:

Polymyalgia rheumatica

RCTs:

Randomized controlled trials

TAB:

Temporal Artery Biopsy

CEG:

The Clinical, Evidence-based, Guidelines"

EULAR:

The European Alliance of Associations for Rheumatology

LOE:

The level of evidence

TCZ:

Tocilizumab

T2T:

Treat to Target

TMP-SMX:

Trimethoprim/sulfamethoxazole

US:

Ultrasonography

References

Prior JA, Ranjbar H, Belcher J et al (2017) Diagnostic delay for giant cell arteritis - a systematic review and meta-analysis. BMC Med 15:120. https://doi.org/10.1186/s12916-017-0871-z

Patil P, Williams M, Maw WW, Achilleos K, Elsideeg S, Dejaco C, Borg F, Gupta S, Dasgupta B. Fast track pathway reduces sight loss in giant cell arteritis: results of a longitudinal observational cohort study. Clin Exp Rheumatol. 2015;33(2 Suppl 89):S-103-6. Epub 2015 May.

Serling-Boyd N, Stone JH (2020) Recent advances in the diagnosis and management of giant cell arteritis. Curr Opin Rheumatol 32(3):201-207

Article CAS PubMed PubMed Central Google Scholar

OCEBM Levels of Evidence Working Group (2011) The Oxford levels of evidence 2. Oxford Centre for Evidence-Based Medicine, Oxford, UK

Google Scholar

Niederberger M, Spranger J (2020) Delphi technique in health sciences: a map. Front Public Health 8:457. https://doi.org/10.3389/fpubh.2020.00457

Von der Gracht H (2012) Consensus measurement in Delphi studies: review and implications for future quality assurance. Technol Forecast Soc 79(8):1525-1536

Article Google Scholar

Niederberger M, Deckert S (2022) Das Delphi-Verfahren: Methodik, Varianten und Anwendungsbeispiele [The Delphi technique: Methodology, variants and usage examples]. Z Evid Fortbild Qual Gesundhwes 174:11-19. https://doi.org/10.1016/j.zefq.2022.08.007. German

Jaam M, Awaisu A, El-Awaisi A, Stewart D, El Hajj MS (2022) Use of the Delphi technique in pharmacy practice research. Res Social Adm Pharm 18(1):2237-2248. https://doi.org/10.1016/j.sapharm.2021.06.028

Muratore F, Kermani TA, Crowson CS et al (2018) Large-vessel dilatation in giant cell arteritis: a different subset of disease? Arthritis Care Res 70:1406-1411

Article Google Scholar

El Miedany Y, Elgaafary M, Toth M, Azim AA, Palmer D, Dolbear G, Abu-Zaid MH, Affam D, Hassan W, Elnady B, Tabra SA, Saber S. Development of outcome measures for giant cell arteritis for use in clinical trials and standard practice. ClinRheumatol. 2023. https://doi.org/10.1007/s10067-023-06704-7.

Stone JH, Han J, Aringer M et al (2021) Long-term effect of tocilizumab in patients with giant cell arteritis: open-label extension phase of the giant cell arteritis actemra (giacta) trial. Lancet Rheumatol 3:328-336

Article Google Scholar

Stone JH, Tuckwell K, Dimonaco S et al (2019) Glucocorticoid dosages and acute-phase reactant levels at giant cell arteritis flare in a randomized trial of tocilizumab. Arthritis Rheumatol 71:1329-1338

Article CAS PubMed PubMed Central Google Scholar

Tomelleri A, van der Geest KS, Sebastian A, van Sleen Y, Schmidt W, Dejaco C et al (2021) Disease stratification in giant cell arteritis to reduce relapses and prevent long-term vascular damage. Lancet (Rheumatology) 3:886-895

Article Google Scholar

Watson EK, Rose PW, Neal RD et al (2012) Personalised cancer follow-up: risk stratification, needs assessment or both? Br J Cancer 106:1-5

Article CAS PubMed PubMed Central Google Scholar

Dejaco C, Kerschbaumer A, Aletaha D, et al. Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatic. Annals of the Rheumatic Diseases Published Online First: 24 February 2023. https://doi.org/10.1136/ard-2022-223429.

Download references

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

Canterbury Christ Church University, Canterbury, England

Y El Miedany & G Dolbear

Community and Public Health, Ain Shams University, Cairo, Egypt

M El Gaafary

Darent Valley Hospital, Kent, England

M Toth

Cairo University, Giza, Egypt

A Abdel Azim

North Middlesex University Hospital, London, UK

D Palmer

Darent Valley Hospital, Dartford, UK

D Affam

Rheumatology and Rehabilitation, Benha University, Benha, Egypt

W Hassan

Rheumatology and Rehabilitation, Faculty of Medicine, Tanta University, Tanta, Egypt

SA Tabra & MH Abu-zaid

Rheumatology and Rehabilitation, Ain Shams University, Cairo, Egypt

S Saber

Rheumatology and Rehabilitation Department, Tanta Faculty of Medicine, El-Geish Street, Tanta, 31527, Gharbia, Egypt

MH Abu-zaid

Contributions

Conceptualization and design, Yasser El Miedany, Mohammed Hassan Abu-Zaid; Acquisition of data, Yasser El Miedany, Mohammed Hassan Abu-Zaid; Formal analysis, Maha El Gaafary; Investigation, Samar Tabra and waleed hassan; Methodology, all authors; Writing - original draft, Yasser El Miedany, Mohammed Hassan Abu-Zaid; Final approval of the version to be submitted, all authors.

Corresponding author

Correspondence to MH Abu-zaid.

Ethics declarations

Ethics approval and consent to participate

This study was performed in accordance with the Helsinki Declaration. This was a multistep process which followed the "Clinical, Evidence-based, Guidelines" (CEG) initiative protocol (ethical approval code: 34842/8/21, ethical board Tanta University). Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that the corresponding author "Mohammed Hassan Abu-Zaid" is associate editor in the Egyptian Rheumatology and Rehabilitation, Yasser El Miedany, & Waleed Haasn are from editorial board of the journal. There is no financial support and sponsorship.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Reprints and permissions

About this article

Cite this article

El Miedany, Y., El Gaafary, M., Toth, M. et al. Step forward towards treat-to-target management of giant cell arteritis: patients stratification aiming to targeted remission - updated guidelines. Egypt Rheumatol Rehabil 51, 5 (2024). https://doi.org/10.1186/s43166-024-00237-w
Download citation

Received:

Accepted:

Published:

DOI: https://doi.org/10.1186/s43166-024-00237-w

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

# data[].attributes.attachment_link.title
Step forward towards treat-to-target management of giant cell arteritis: patients stratification aiming to targeted remission - updated guidelines - Egyptian Rheumatology and Rehabilitation

# data[].attributes.attachment_link.description
Background The aim of this work is to develop guidelines for health care professionals in the giant cell arteritis diagnosis and management, based on patients' stratification and targeted outcome measures. Results Fourteen expert panel had completed the two rounds surveys. After the end of round two, twenty three recommendations were released distributed on 8 domains.

# data[].attributes.headline
Challenges and options for management of stones in anomalous kidneys: a review of current literature

# data[].attributes.subject
Challenges and options for management of stones in anomalous kidneys: a review of current literature

# data[].attributes.headline
The necessary and neglected work of the soul in healthcare

# data[].attributes.subject
The necessary and neglected work of the soul in healthcare

# data[].attributes.body
Login using OpenAthens

# data[].attributes.headline
Surgical trainee experiences from 2013 to 2023 within the United Kingdom as reported by the General Medical Council National Training Survey

# data[].attributes.subject
Surgical trainee experiences from 2013 to 2023 within the United Kingdom as reported by the General Medical Council National Training Survey

# data[].attributes.attachment_link.description
About ScienceDirect
Shopping cart
Contact and
supportTerms and
conditionsPrivacy policy

# data[].attributes.headline
Worldwide trends of practice and intervention in paediatric endourology: comparison of European versus Non-European responses

# data[].attributes.subject
Worldwide trends of practice and intervention in paediatric endourology: comparison of European versus Non-European responses

# data[].attributes.attachment_link.title
Worldwide trends of practice and intervention in Paediatric Endourology: Comparison of European versus Non-European responses

# data[].attributes.headline
Conference Abstract - Wegener’s vagueness: midfacial granulomatosis with polyangiitis, or cocaine usage?

# data[].attributes.subject
Conference Abstract - Wegener’s vagueness: midfacial granulomatosis with polyangiitis, or cocaine usage?

# data[].attributes.attachment_link.provider_name
Journal of Neurology, Neurosurgery & Psychiatry

# data[].attributes.attachment_link.readable_text
A 45-year-old woman presented with several months of right-sided headache, associated with vocal hoarseness, fever, night sweats and weight loss. Severe right-sided periorbital pain came in episodes lasting several hours, associated with ipsilateral partial ptosis, facial swelling and hyperaesthesia. Indomethacin and greater occipital nerve block were ineffectual; however, a transient symptomatic improvement had coincided with previous steroid treatment.

She had a background of cocaine use. Longstanding sinus complaints were investigated with nasen- doscopy, revealing nasal septal crusting and a hole in the soft palate. Fluctuating lymphadenopathy on previous imaging was investigated with blood tests, showing persistently raised ESR and ANCA positivity. Normal eosinophil counts.

Serial MRI head scans showed evidence of worsening inflammatory, sclerotic and bony erosive changes to the midfacial skull base. The nasal septum and turbinates were obliterated, and maxillary/ethmoid/sphenoid sinuses were persistently effused. Granulomatosis with polyangiitis was diagnosed, and treatment with high-dose steroids and mycophenolate mofetil was commenced. Headache symptoms convinc- ingly improved.

We present a case of headache with atraumatic midline skull base destruction, in a patient satisfying diagnostic criteria for granulomatosis with polyangiitis [1-2]. However, chronic cocaine use can have over- lapping clinical, immunological and radiological features [3-6]. Recent literature is reviewed to evaluate this diagnostic challenge [8-10].

# data[].attributes.attachment_link.title
Wegener's vagueness: midfacial granulomatosis with polyangiitis, or cocaine usage?

# data[].attributes.attachment_link.description
A 45-year-old woman presented with several months of right-sided headache, associated with vocal hoarseness, fever, night sweats and weight loss. Severe right-sided periorbital pain came in episodes lasting several hours, associated with ipsilateral partial ptosis, facial swelling and hyperaesthesia. Indomethacin and greater occipital nerve block were ineffectual; however, a transient symptomatic improvement had coincided with previous steroid treatment.

# data[].attributes.headline
Conference Abstract - A deep dive into a neurological rarity

# data[].attributes.subject
Conference Abstract - A deep dive into a neurological rarity

# data[].attributes.attachment_link.provider_name
Journal of Neurology, Neurosurgery & Psychiatry

# data[].attributes.attachment_link.readable_text
Association of British Neurologists: Annual Meeting Abstracts 2023

Abstract

A 52-year-old fit and well man presented with sudden band like sensation around his chest, eight hours after scuba diving. On movement, he developed abrupt left leg weakness the next day evolving over a few hours, with nadir bilateral leg power 0/5 and urinary retention. He received five hours of hyperbaric oxygen treatment (HBOT) and intravenous immunoglobulin for possible Guillain-Barre syndrome, with no improvement. Cerebrospinal fluid protein was 0.7g/L. Ten days later, on repatriation to the UK, first exam- ination revealed spastic paraparesis with power 2/5, pinprick sensory level at T4 and preserved dorsal column function. Brain imaging was normal but in the spinal cord there was an anterior non-enhancing lesion at T3-4, felt to be ischaemic. He received further prolonged HBOT and methylprednisolone. He suffered a pulmonary embolism, probably provoked by hospital acquired pneumonia, although bloods revealed one positive lupus anticoagulant. Repeat testing returned equivocal with negative anticardiolipin antibodies. Cerebrovascular and cardiovascular abnormalities were not identified on CT-angiogram and bubble echocardiogram. After HBOT there was significant improvement and at 6 months, he can walk with a stick. Neurological complications of scuba diving are rare. This case should alert neurologists to this possible phenomenon and to consider delayed hyperbaric oxygen treatment.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center's RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Read the full text or download the PDF:

# data[].attributes.attachment_link.description
A 52-year-old fit and well man presented with sudden band like sensation around his chest, eight hours after scuba diving. On movement, he developed abrupt left leg weakness the next day evolving over a few hours, with nadir bilateral leg power 0/5 and urinary retention.

# data[].attributes.headline
Venetoclax-based low intensity therapy in molecular failure of NPM1 mutated AML

# data[].attributes.subject
Venetoclax-based low intensity therapy in molecular failure of NPM1 mutated AML

# data[].attributes.attachment_link.title
Venetoclax-based low intensity therapy in molecular failure of NPM1 mutated AML

# data[].attributes.attachment_link.description
Key Points. 84% of patients treated with venetoclax combinations for NPM1mut molecular failure achieved a molecular response and 71% became MRD negativeVenetocl

# data[].attributes.headline
‘Distal-to-proximal’ surgical release of the proximal interphalangeal joint in Dupuytren’s disease

# data[].attributes.subject
‘Distal-to-proximal’ surgical release of the proximal interphalangeal joint in Dupuytren’s disease

# data[].attributes.headline
Lack of regional pathways impact on surgical delay: Analysis of the Orthopaedic Trauma Hospital Outcomes-Patient Operative Delays (ORTHOPOD) study

# data[].attributes.subject
Lack of regional pathways impact on surgical delay: Analysis of the Orthopaedic Trauma Hospital Outcomes-Patient Operative Delays (ORTHOPOD) study

# data[].attributes.headline
Conference Abstract - OGBN P44 Does laparoscopic fundoplication have a role in non-erosive reflux disease? 

# data[].attributes.subject
Conference Abstract - OGBN P44 Does laparoscopic fundoplication have a role in non-erosive reflux disease? 

# data[].attributes.attachment_link.title
OGBN P44 Does laparoscopic fundoplication have a role in non-erosive reflux disease?

# data[].attributes.attachment_link.description
AbstractBackground. Non-erosive reflux disease (NERD) is a sub-group of gastro-oesophageal reflux disease (GORD) characterised by reflux related symptoms withou

# data[].attributes.headline
Characteristics and outcomes of neonates hospitalised with SARS-CoV-2 infection in the UK by variant: a prospective national cohort study

# data[].attributes.subject
Characteristics and outcomes of neonates hospitalised with SARS-CoV-2 infection in the UK by variant: a prospective national cohort study

# data[].attributes.attachment_link.readable_text
Data availability statement

Data are available on reasonable request. The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

Introduction

Children are less severely affected by SARS-CoV-2 than adults, and this pattern has been seen across viral variants. 1 In the neonatal period (first 28 days), neonates can be infected by SARS-CoV-2 or indirectly affected because of maternal infection, for example, through spontaneous or iatrogenic preterm birth. We have previously reported that neonates were more likely than older children to require respiratory support following SARS-CoV-2 infection when the wildtype variant was dominant, 2 but it is not clear if this pattern persisted in later periods. The alpha and delta variants of SARS-CoV-2 resulted in more severe maternal SARS-CoV-2 infection, 3 but there are few studies describing the impact of SARS-CoV-2 viral variants in neonates. 4

Using population-level active surveillance data linked to maternal, neonatal and paediatric intensive care and perinatal mortality data, we aimed to describe the epidemiology, clinical course and short-term outcomes of neonates with confirmed SARS-CoV-2 infection cared for in hospitals in the UK over the first 2 years of the pandemic, stratified by the dominant SARS-CoV-2 variant in circulation at the time of infection.

Methods

This was a national prospective cohort study using the British Paediatric Surveillance Unit (BPSU). 5 From 1 April 2020, senior paediatricians (~4000) in all 155 hospital trusts and health boards in the UK with their associated 190 neonatal units (NNUs) received a weekly (until March 2021) then monthly electronic BPSU reporting card asking them to report any baby who had laboratory-confirmed SARS-CoV-2 infection in the first 28 days after birth and received inpatient care on a postnatal ward, NNU, paediatric inpatient ward or paediatric intensive care unit (PICU). Well neonates born in the UK remained with their mother on postnatal wards until mother and baby were fit for discharge; neonates with asymptomatic SARS-CoV-2 on postnatal wards and asymptomatic cases detected through screening were not reported. Monthly reporting cards sought confirmation that all eligible neonates in the previous month had been reported, and that any reports of no infected neonates were accurate (active negative surveillance). To maximise case ascertainment, we linked to national testing data from Public Health England and Health Protection Scotland between 1 March 2020 and 31 March 2021, as well as the Paediatric Intensive Care Audit Network, 6 United Kingdom Obstetric Surveillance System (UKOSS) data 7 and MBRRACE-UK national perinatal mortality surveillance data. 8 Additional details can be found in the online supplemental methods. Intensive care was defined using British Association of Perinatal Medicine categories of care 9 for neonatal admissions, or any admission to a PICU. Severe disease was defined as having received respiratory support. Very preterm birth was defined as birth at <32 gestational weeks.

Neonatal deaths were verified with the MBRRACE-UK national surveillance of perinatal deaths. 10 Neonatal deaths were attributed to SARS-CoV-2 if the treating paediatrician reported that SARS-CoV-2 infection contributed to the baby's death; we also recorded if the referring clinician reported that maternal SARS-CoV-2 infection led to spontaneous or iatrogenic preterm birth.

UK SARS-CoV-2 testing policy among pregnant women and neonates evolved during the study. Initially, only symptomatic women and neonates were tested. Routine screening of all obstetric admissions was recommended by the Royal College of Obstetricians and Gynaecologists on 29 May 2020 and neonatal testing recommended for symptomatic neonates of mothers with a SARS-CoV-2 infection; testing of asymptomatic neonates varied. Confirmation of neonatal SARS-CoV-2 infection required at least two positive samples, including one at least 72 hours after birth. 11 UK policy was that well neonates of SARS-CoV-2-infected mothers should be cared for alongside their mother in the postnatal ward and not routinely tested.

This analysis presents characteristics and outcomes for neonates reported as having confirmed SARS-CoV-2 infection in the first 28 days after birth, between 1 March 2020 and 1 April 2022, and for whom complete data had been received by 30 July 2022. To provide a complete description of the first two pandemic years, this report includes neonates with SARS-CoV-2 infection between 1 March 2020 and 30 April 2020 previously reported. 2

As individual-level SARS-CoV-2 variant data were not recorded in medical records, the outcomes were compared across four proxy groups according to the period in which the original wildtype, alpha variant, delta variant or omicron variant was the dominant circulating strain in the UK.

The original wildtype period included neonates diagnosed from 1 March to 30 November 2020, the alpha variant period from 1 December 2020 to 15 May 2021, the delta variant period from 16 May 2021 to 14 December 2021 and the omicron variant period from 15 December 2021 to 1 April 2022. We chose cut-off dates for the delta and omicron periods using data on variant sequencing from Public Health England to identify the week when these variants first contributed >50% of SARS-CoV-2 infections nationally. 12 Since genomic data on the variant were less widely available at the start of the pandemic, Public Health England modelled proxy data and reported that the alpha variant reflected the substantial majority of infections across all areas of England during December 2020; therefore, 1 December 2020 was used as an estimated cut-off date. 13

Results

Monthly BPSU card returns were received between 91.3% (3748/4070, April 2020) and 71.9% (3110/4298, February 2022) of UK paediatricians over the surveillance period. In total, 1192 potentially eligible neonates were reported to the BPSU system over the study period and 116 non-duplicate neonates were identified from other sources ( figure 1). Linkage with data held in the NNRD was achieved for 99% (132/134) of neonates reported through the BPSU system who received NNU care. Three hundred and forty-four neonates were diagnosed with SARS-CoV-2 infection in the first 28 days after birth and received inpatient care, predominantly in the wildtype-dominant and alpha-dominant periods, with numbers dropping in subsequent variant periods: 146 neonates were reported in the wildtype period, 123 in the alpha period, 57 in the delta and 18 in the omicron periods ( figure 2). Three hundred and twenty cases were in England, 16 cases in Scotland, 6 in Wales or Northern Ireland; country data were missing for 2 cases.

Median age at diagnosis was 9 days (IQR 3-17 days); 44.5% (153/344) of the neonates were diagnosed in the first 7 days after birth; of these, 66.7% (102/153) were born to a mother with confirmed SARS-CoV-2 infection within 7 days before or after giving birth. The age distribution at diagnosis was similar across different dominant circulating variant periods ( online supplemental figure 1). Respiratory signs were common along with poor feeding or vomiting and fever ( online supplemental figure 2); 15% of neonates were asymptomatic.

Neonates in hospital with neonatal SARS-CoV-2 infection were more commonly preterm and male when compared with all live births in England and Wales and this was consistent across all variant epochs, although sex differences were less marked in the alpha period ( table 1). The highest proportions of very preterm births were seen in the delta-predominant period. An over-representation of non-white ethnic groups among neonatal SARS-CoV-2 infections in the wildtype period was not seen with later variants ( table 1).

Most neonates in hospital with neonatal SARS-CoV-2 infection did not require high-level care; however, 44.7% required some form of respiratory support and 21.8% received intensive care ( table 2). Higher numbers and proportions of neonates in hospital with neonatal SARS-CoV-2 in the delta period required intensive care or invasive respiratory support, compared with other variant periods ( figure 3). Infection following suspected nosocomial transmission, excluding vertical transmission, affected 7.8% of neonates overall. Outcomes following neonatal SARS-CoV-2 infection were generally good; however, 11 deaths occurred in neonates who tested positive for SARS-CoV-2, 4 of which were attributed either directly or indirectly to neonatal SARS-CoV-2 infection (case fatality 4/344, 1.2% 95% CI 0.3% to 3.0%). Three of these four neonates had been born preterm due to maternal COVID-19. All four SARS-CoV-2-related neonatal deaths were in the delta period.

As expected in any neonatal population, degree of prematurity was strongly linked with receipt of respiratory support with all extremely preterm neonates infected with SARS-CoV-2 requiring ventilation; this highlights the challenges separating severe manifestations of SARS-CoV-2 infection from conditions related to preterm birth ( online supplemental table 1).

Discussion

Using population-level active surveillance data from March 2020 to April 2022 and spanning wildtype, alpha, delta and omicron variant-predominant periods during which there were approximately 1.4 million births recorded in the UK, 14-16 we confirm that the need for inpatient care for neonates with SARS-CoV-2 infection was rare and outcomes were generally good. Neonatal SARS-CoV-2 infection led to severe disease in a minority of neonates, with death related to neonatal SARS-CoV-2 infection occurring in 1.2% of hospitalised neonates. During the delta variant-predominant period, higher numbers of neonates had severe disease associated with SARS-CoV-2 infection, defined as requiring respiratory support, compared with other variant epochs. We believe this is the first study to present descriptive data from a national cohort on neonatal deaths reported as related to SARS-CoV-2 infection, all of which occurred in the delta-predominant period in the UK.

The pattern of more serious neonatal disease in the delta period described here may be explained by the higher number and proportion of neonates born very preterm with neonatal SARS-CoV-2 infection during this period. More severe maternal infection and higher rates of preterm birth have been described in the delta-predominant wave in the UK 3 and internationally 17; it is unclear whether this pattern of more severe maternal disease was related to changing characteristics of the viral variant or changes in behaviour and low vaccination rates among pregnant women in the UK during this period. Similarly, it is not possible to determine from these data presented whether the delta variant was more pathogenic in neonates, or whether adverse neonatal outcomes were a result of more severe maternal SARS-CoV-2 disease leading to more preterm births, a well-described risk factor for neonatal infection. 18

There have been very few population-based studies of neonates infected with SARS-CoV-2 infection, and data describing neonatal SARS-CoV-2 infection by variant are even more sparse. Population-level data from Germany describing paediatric SARS-CoV-2 infection show higher rates of COVID-19-related hospitalisation and intensive care unit admission for children under 5 years in the delta-predominant period compared with alpha-predominant, wildtype-predominant and omicron-predominant periods, 19 although data from the UK did not report a higher rate of intensive care admissions for children under 5 with delta compared with earlier viral variants. 20 Data covering approximately 10% of the US population found similar rates of intensive care admissions of infants <6 months of age with the delta and omicron variants. 21 A further study examining administrative data representing approximately 20% of US hospital admissions found that COVID-19 among newborns is rare but is associated with newborn critical care outcomes like invasive ventilation, and that risks for invasive compared with non-invasive ventilatory support were higher in delta compared with pre-delta periods, 22 consistent with the UK data we present here. Single-centre case-series have also reported more severe SARS-CoV-2 infection in infants and neonates in delta-predominant compared with other variant-predominant periods, 4 supporting a link between infection with the delta variant and more severe neonatal disease.

Although there have been multiple registries describing neonatal SARS-CoV-2 infection, 23 24 there have been very few representative population-level studies and those that have published have been limited by low case numbers. 25 The population-level data we present here include and build on previously published neonatal surveillance data from the UK from the first weeks of the SARS-CoV-2 pandemic when the wildtype variant predominated. 2 These updated data describe the presentation and clinical course of neonatal SARS-CoV-2 infection in the largest number of neonates reported to date. Consistent with early data, 2 we confirm that while respiratory signs were widespread, symptomatic neonatal SARS-CoV-2 most commonly presented with poor feeding or other gastrointestinal signs. Fever and respiratory signs were also common but did not predominate as in other paediatric groups. 26 Data from Switzerland in one of the few other population-level surveillance studies found fever and respiratory signs most common at presentation in the 73 neonates reported, 25 possibly reflecting the non-specific nature of these neonatal signs. The large number of neonatal cases we report compared with other neonatal studies provide confidence in our key findings that while receipt of respiratory support is relatively common among neonates hospitalised with neonatal SARS-CoV-2, this is generally seen in the context of preterm birth. Almost half of hospitalised neonates with SARS-CoV-2 infection received some form of respiratory support. We also report reassuring short-term outcomes following neonatal SARS-CoV-2 infection consistent with Swiss national data 25 and international registry data. 27 28

The high rate of presumed nosocomial transmission reported throughout the study (7.8%) is of concern. This likely reflects the challenges of limiting viral exposure in NNUs with few isolation facilities, in the context of a pandemic with high rates of staff and parent infection.

Conclusions

Inpatient care for neonates infected with SARS-CoV-2 was uncommon throughout the first 2 years of the pandemic and short-term outcomes were generally good. Severe disease was more common, although still rare, during the delta variant period; this may have been influenced by more severe maternal disease resulting in more very preterm neonates. Rapidly established and ongoing national surveillance was essential to understand the neonatal impact of the evolving SARS-CoV-2 pandemic, highlighting the key role of established systems such as the BPSU, UKOSS and MBRRACE-UK perinatal mortality surveillance. The long-term effects of early life exposure to SARS-CoV-2 are unknown, and ongoing data collection, linkage and developmental follow-up remain crucial.

Data availability statement

Data are available on reasonable request. The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We acknowledge the assistance of Jacob Avis, Richard Lynn and Farhana Ahmed at the BPSU, the BPSU reporting clinicians, the NIHR Clinical Research Networks and other people without whose support this research would not have been possible in such a timely manner.

# data[].attributes.attachment_link.title
Characteristics and outcomes of neonates hospitalised with SARS-CoV-2 infection in the UK by variant: a prospective national cohort study

# data[].attributes.attachment_link.description
Objective Neonatal infection with wildtype SARS-CoV-2 is rare and good outcomes predominate. We investigated neonatal outcomes using national population-level data to describe the impact of different SARS-CoV-2 variants. Design Prospective population-based cohort study. Setting Neonatal, paediatric and paediatric intensive care inpatient care settings in the UK.

# data[].attributes.headline
Beyond the symptoms: Personalizing giant cell arteritis care through multidimensional patient reported outcome measure

# data[].attributes.subject
Beyond the symptoms: Personalizing giant cell arteritis care through multidimensional patient reported outcome measure

# data[].attributes.attachment_link.readable_text
The .gov means it's official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

doi: 10.1016/j.semarthrit.2023.152285. Online ahead of print.

Affiliations

1 Professor Canterbury Christ Church University, England; H. Senior Clinical Lecturer, King's College London, England. Electronic address: secretary@rheumatology4u.com.

2 Professor Community and Public Health, Ain Shams University, Cairo, Egypt.

3 H. Senior Clinical Lecturer, King's College London, England; Darent Valley Hospital, Kent, England.

4 North Middlesex University Hospital, London, England.

5 Darent Valley Hospital, Kent, England.

6 Professor of Internal Medicine/Rheumatology, College of Medicine, King Abdulaziz University, Saudi Arabia.

7 Professor Rheumatology, Physical Medicine and Rehabilitation, Assiut University, Egypt.

8 Professor Rheumatology and Rehabilitation, Benha University, Benha, Egypt.

9 Assistant Professor Rheumatology and Rehabilitation, Tanta University, Tanta, Egypt.

10 Rheumatology and Rehabilitation, Ain Shams University, Cairo, Egypt.

11 Lectuer Rheumatology and Rehabilitation, Alexandria University, Alexanrdia, Egypt.

doi: 10.1016/j.semarthrit.2023.152285. Online ahead of print.

Affiliations

1 Professor Canterbury Christ Church University, England; H. Senior Clinical Lecturer, King's College London, England. Electronic address: secretary@rheumatology4u.com.

2 Professor Community and Public Health, Ain Shams University, Cairo, Egypt.

3 H. Senior Clinical Lecturer, King's College London, England; Darent Valley Hospital, Kent, England.

4 North Middlesex University Hospital, London, England.

5 Darent Valley Hospital, Kent, England.

6 Professor of Internal Medicine/Rheumatology, College of Medicine, King Abdulaziz University, Saudi Arabia.

7 Professor Rheumatology, Physical Medicine and Rehabilitation, Assiut University, Egypt.

8 Professor Rheumatology and Rehabilitation, Benha University, Benha, Egypt.

9 Assistant Professor Rheumatology and Rehabilitation, Tanta University, Tanta, Egypt.

10 Rheumatology and Rehabilitation, Ain Shams University, Cairo, Egypt.

11 Lectuer Rheumatology and Rehabilitation, Alexandria University, Alexanrdia, Egypt.

Abstract

Background: Giant Cell Arteritis (GCA) is the commonest form of systemic vasculitis in people over the age of 50. Published research highlighted the lack of a disease-specific patient reported outcomes (PROMs) for GCA.

Objectives: To assess the validity, reliability and responsiveness to change of a devised disease specific patient self-reported outcome measures questionnaire for Giant Cell Arteritis (GCA).

Methods: The GCA-PROMs was conceptualized based on frameworks outlined in the OMERACT developed core set of Outcome Measures for Large-Vessel Vasculitis and the guiding principles of the FDA guidance. Initially, cognitive interviews were conducted to identify item pool of questions. Item selection and reduction was achieved based on patients as well as an interdisciplinary group of specialists. Rasch and internal consistency reliability analyses were implemented.

Results: A total of 54 GCA patients completed the questionnaire. The GCA-PROMs questionnaire was reliable as demonstrated by a high standardized alpha (0.878-0.983). Content construct assessment of the GCA-PROMs functional disability and QoL revealed significant correlation (p< 0.01) with both HAQ and EQ-5D. Changes in functional disability, QoL showed significant (p< 0.01) variation with diseases activity status in response to therapy.

Conclusions: The developed GCA-PROMs questionnaire is a reliable and valid instrument for assessment of GCA patients. A stratified treatment regimen depending on the individual patient's risk factors as well as preferences and associated comorbidities is the best approach to tailored patient management.

Keywords: Benefit/risk ratio; GCA; GCA-PROMs; Giant cell arteritis; PROMs; Patient education; Patient stratification.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest Authors declare no conflicts of interest.

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Beyond the symptoms: Personalizing giant cell arteritis care through multidimensional patient reported outcome measure - PubMed

# data[].attributes.attachment_link.description
The developed GCA-PROMs questionnaire is a reliable and valid instrument for assessment of GCA patients. A stratified treatment regimen depending on the individual patient's risk factors as well as preferences and associated comorbidities is the best approach to tailored patient management.

# data[].attributes.headline
Conference Abstract - Metastatic lung cancer: another symptom of Long COVID?

# data[].attributes.subject
Conference Abstract - Metastatic lung cancer: another symptom of Long COVID?

# data[].attributes.attachment_link.title
Metastatic lung cancer: another symptom of Long COVID?

# data[].attributes.attachment_link.description
National data indicates fewer lung cancer diagnoses in 2020 than 2019 in England, but post-pandemic outcomes are not yet available (https://www.rcplondon.ac.uk/projects/outputs/nlca-annual-report-2022). We aimed to identify trends in lung cancer diagnosis in our hospital before, during and after the COVID-19 pandemic, ahead of national data.

# data[].attributes.headline
The implications when offering percutaneous nephrostomy for the management of malignant obstructive uropathy secondary to urological malignancy: can we be more selective?

# data[].attributes.subject
The implications when offering percutaneous nephrostomy for the management of malignant obstructive uropathy secondary to urological malignancy: can we be more selective?

# data[].attributes.headline
New-Onset Rheumatic Immune-Mediated Inflammatory Diseases Following SARS-CoV-2 Vaccinations until May 2023: A Systematic Review

# data[].attributes.subject
New-Onset Rheumatic Immune-Mediated Inflammatory Diseases Following SARS-CoV-2 Vaccinations until May 2023: A Systematic Review

# data[].attributes.attachment_link.title
New-Onset Rheumatic Immune-Mediated Inflammatory Diseases Following SARS-CoV-2 Vaccinations until May 2023: A Systematic Review

# data[].attributes.attachment_link.description
A comprehensive, up-to-date systematic review (SR) of the new-onset rheumatic immune-mediated inflammatory diseases (R-IMIDs) following COVID-19 vaccinations is lacking. Therefore, we investigated the demographics, management, and prognosis of new R-IMIDs in adults following SARS-CoV-2 vaccinations. A systematic literature search of Medline, Embase, Google Scholar, LitCovid, and Cochrane was conducted.

# data[].attributes.headline
Efficacy and Safety of Hyaluronic Acid and Platelet-Rich Plasma Combination Therapy Versus Platelet-Rich Plasma Alone in Treating Knee Osteoarthritis: A Systematic Review

# data[].attributes.subject
Efficacy and Safety of Hyaluronic Acid and Platelet-Rich Plasma Combination Therapy Versus Platelet-Rich Plasma Alone in Treating Knee Osteoarthritis: A Systematic Review

# data[].attributes.headline
Taking a Break? The Growing Trend of FY3: Why More Junior Doctors are Taking Time Out after the Foundation Programme and What They Elect to Do?

# data[].attributes.subject
Taking a Break? The Growing Trend of FY3: Why More Junior Doctors are Taking Time Out after the Foundation Programme and What They Elect to Do?

# data[].attributes.attachment_link.readable_text
There is a growing trend of UK doctors taking time out of clinical training following completion of the Foundation Programme. At a time when NHS services are facing unparalleled demand, considering the reasons why early career clinicians are deciding to delay entry into specialist training is paramount. Here, we describe some of the push and pull factors contributing to the "FY3" year phenomenon as well as the avenues doctors explore. Within the NHS, clinical fellowships can offer more flexibility in terms of rota and location compared to specialty training posts whilst also providing clinical experience and the chance to develop highly sought-after skills in teaching, research, and leadership. Similarly, locum rotas can be negotiated and usually offer significantly enhanced pay. Outside of the NHS, healthcare systems in Australia, New Zealand, and Canada actively seek out UK doctors, incentivising them with better work-life balance, increased pay, and improved working conditions, leading many doctors who had intended to return to the NHS to stay abroad. Doctors are also becoming increasingly aware of their transferable skills and the value they can bring to non-clinical roles in the pharmaceutical industry, management consulting, and medical law. Although the FP was originally introduced to address issues surrounding career progression and poor training experiences, current push factors for taking an "FY3" including increasing competition for specialty training posts, an imbalance towards service provision versus training, and high workload suggest systemic issues within the UK health service are undermining this aim and ultimately leading doctors to take time out of training.

# data[].attributes.attachment_link.title
Taking a Break? The Growing Trend of FY3: Why More Junior Doctors are Taking Time Out after the Foundation Programme and What They Elect to Do?

# data[].attributes.attachment_link.description
There is a growing trend of UK doctors taking time out of clinical training following completion of the Foundation Programme. At a time when NHS services are facing unparalleled demand, considering the reasons why early career clinicians are deciding to delay entry into specialist training is paramount.

# data[].attributes.headline
Reconstruction of the ‘Foot at Risk’ during Acute Charcot Neuroarthropathy

# data[].attributes.subject
Reconstruction of the ‘Foot at Risk’ during Acute Charcot Neuroarthropathy

# data[].attributes.headline
Streams, rivers and data lakes: an introduction to understanding modern electronic healthcare records

# data[].attributes.subject
Streams, rivers and data lakes: an introduction to understanding modern electronic healthcare records

# data[].attributes.attachment_link.readable_text
Abstract

As foundation doctors, we have often found ourselves informing patients that a certain aspect of their medical information cannot be immediately found, either because it is on an electronic system we cannot access, or it is in a hospital that is unlinked to our own. Unsurprisingly, this frequently leaves patients flabbergasted and confused. We started to wonder: if patients' data are entered onto an electronic system: where do those data go? If medical data are searched for, where do those data come from? Why are there so many hidden sources of information that clinicians cannot access? In an ever-increasing digital sphere, electronic data will be the future of holistic health and social care planning, impacting every clinician's day-to-day role. From electronic healthcare records to the use of artificial intelligence solutions, this article will serve as an introduction to how data flows in modern healthcare systems.

What makes electronic healthcare records differ from one another?

Healthcare data can be defined as patient information that is entered by clinical or non-clinical individuals. Traditionally written in paper format (eg discharge letters, test results, appointments and clinical notes), patient records could become multiple volumes of healthcare data. Electronic healthcare records (EHR) are defined as a data system that stores patient healthcare data. Although a clinician might believe that they are interacting with a single EHR, in reality, most hospitals use multiple types (Table 1).

EHR software brands can vary by hospital and are often divided into two categories: (1) bespoke ('lots of little' EHRs or 'best of breed') models: where many single systems are designed for specific departments needs and data communicates between them; or (2) monolithic models: where one EHR system is used for the whole hospital serving every clinical department or scenario.

The benefit of monolithic EHRs is that they directly link healthcare data without the need to open new software or use multiple single sign-on tools. However, monolithic EHRs can be difficult to specialise to the needs of every clinical department. For foundation doctors, this manifests as a clear difference in usability from one EHR system to another.

Data fragmentation and integration: where are my patients' data?

EHRs that are entirely unlinked to other healthcare software are termed 'data silos'. Data silos represent a closed-off, unintegrated source of clinical information and include data used in research, private healthcare, genomics and in wearable devices (eg digital watches that monitor heart rate). Historically, when EHRs were deployed, not enough consideration was put into how those data could be shared or integrated into other systems. From a foundation doctor's perspective, this means fragmented or missing data, which require accessing multiple systems to retrieve (eg by making laborious calls and sending emails to clinical secretaries or on-call doctors at another institute or NHS Trust).

Another way in which healthcare data become fragmented and lost is when a clinician attempts to adapt an EHR to fit their clinical need. This occurs via the frontend-backend disconnect: what a clinician sees on the user interface (frontend) does not encompass all the data stored (backend). It is relatively easy for clinicians to alter the frontend with new electronic forms. However, without altering the backend, these forms are stored in an unusable form; moreover, these alterations require specialist knowledge often lacking in NHS Trusts. Therefore, healthcare records mirror a library without an indexing catalogue, where anyone can just throw a book inside (Fig 1).

Preventing this 'library-with-no-index' scenario, where data cannot be easily retrieved, requires data linkage and integration. This has been attempted for more than 20 years and is currently happening via the integrated care systems (ICS), outlined in the NHS 2019 Long-Term Plan. Unfortunately technological barriers exist that prevent data linkage and integration, preventing clinicians from accessing healthcare data, thereby worsening the socioeconomic burden on healthcare systems.

Streams and rivers: how do my patients' data move through EHR systems?

For clinicians, understanding data flows is key to understanding how data are shared between different EHRs. When healthcare data are entered, like a stream it can flow one way, whereas a turbulent data river can flow both ways, allowing for data exchange. Data can also differ in language and structure; therefore, if they are not standardised, the flow becomes a torrent of garbled unstructured data, useless to clinicians seeking a source of accurate, succinct and timely information (like fishing in murky waters). For communication between different EHR systems, the data need to be standardised; hence, the common data term: interoperability. Interoperability is defined as the ability of different EHR systems to share healthcare data, and is achieved through standardisation of semantics and syntax: semantic standardisation organises via language, referring to the meaning of content, whereas syntactic standardisation organises via structure, referring to the ordering of words, phrases or messages.

Semantic standardisation is traditionally achieved through clinical coding. Clinical coding is performed by GPs in GP practices, and by clinical coders in hospitals. Clinical coders read and interpret clinical text to assign relevant codes that reflects a patient's care during a hospital visit. Correct and efficient clinical coding is essential for service evaluation, research and medical billing. Inaccuracies in coding (eg if a procedure that was carried out is missed) leads to the misallocation of staff, funds and resources, resulting in inefficiencies and waste. For foundation doctors, this often means the frustrating task of filling in structured proformas or checklists to help inform clinical coders before an administrative task is complete or a patient is discharged. The major coding system currently used for diseases is the International Classification of Diseases version 10 (ICD-10). Office of Population and Census survey version 4 (OPCS-4) is the coding classification used for interventions and procedures. Another newer ontological coding system is called Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT): this covers diseases, procedures as well as many other biomedical and healthcare concepts (eg anatomy, occupation, etc.). Unlike other coding systems, SNOMED-CT has a larger, more detailed vocabulary and, therefore, it better reflects the language of clinicans.

Syntactic standardisation allows for formal data structuring. For example, if a message states 'NHS number', the recipient knows that the next 10 digits is the NHS number; similarly, dates follow a date-month-year format. The area in healthcare that has most effectively standardised itself is radiology, via Digital Imaging and Communications in Medicine (DICOM). Given that DICOM standards were decided early, different hospitals could easily share imaging. In the rest of healthcare, the main data messaging standard is Health Level Seven (HL7): a universal packaging system and a standard of transmitting data to allow different EHR systems to communicate. The latest HL7 incorporates a flexible data structure called 'fast healthcare interoperability resources' (FHIR) (Fig 2). Unfortunately for foundation doctors, many EHR systems were installed without implementing adequate data syntactic standardisation because of cost, effort and inability to gain consensus; therefore, patients' data can easily get lost or confined inside a difficult to access system. Moreover, owing to data protection legislation, healthcare data need to be retained for access for up to 25 years; therefore, data can be trapped for decades in old systems that function poorly on modern computers.

Machine learning, artificial intelligence and data lakes: how can my patients' data be better utilised?

Foundation doctors who use EHR certainly understand the inefficient ways in which patients' data are utilised; however, newer innovative approaches are on the horizon, such as by using an open-source artificial intelligence (AI) framework called CogStack, which can extract data from unstandardised EHR and data silos. CogStack syphons out data, bringing them into one place: the data lake. Databases store data, data lakes represent large pooled databases and data warehouses represent organised data lakes. Data lakes contain millions of data sets, termed 'big data', sourced from a myriad of databases. Data that clinicians enter can be structured (ie lab results) or unstructured (ie clinical entries in the form of free text). Around 80% of big data are unstructured; this vital raw information cannot be used to a fraction of its worth. Big data require filtering: simplified into essential components ('abstraction'), converted into a suitable format ('transformation') and standardised via terminology ('harmonisation'). Filtering requires a natural language processing (NLP) system, a subset of machine learning (ML) and AI.

AI uses advanced statistical approaches and computer models to mimic the organisation of the human brain. ML is a subset of AI, first introduced during the 1990s; it algorithmically derives patterns and 'learns' from past data without explicit programming. Deep learning is a subset of ML and uses big data to feed machines with large amounts of these raw data, developing its own representations needed for pattern recognition. For clinicians, a ML solution could provide a single user interface that is accessible across all systems simultaneously. The ML concept of NLP allows data to be 'read' quickly by using a combination of text-mining and terminology recognition (Fig 3). An illustration of an open-source NLP that uses big data is the medical concept annotation toolkit (MedCAT). MedCAT uses SNOMED-CT as a source of clinical terminology, but can use any standardised vocabulary.

For clinicians, data are most valuable when they are cleaned and usable; NLP can help sanitise data before use. For foundation doctors looking at clinical entries or writing a discharge letters, it can be time consuming to look through a set of complex patient records. Imagine an NLP system in which your patient's genomics, wearables and other standard clinical information were easily accessible and analysable at the point of entry. This could prevent inefficiencies and be invaluable for patients who cannot fully communicate their own care needs, such as non-native speakers or the cognitively impaired.

Ethical considerations of big data: how can I protect my patients' data?

If AI is to serve as a trusted clinical aid, it must be robust, accurate and as free as possible from bias. Moreover, big data in AI represents the personal information of millions of individuals; thus, respect of privacy via consenting and prevention of data breaches via secure storage embody important safeguarding strategies. Safeguarding data by only including individuals who actively provide consent can appear fair but cause bias because certain socioeconomic classes, ethnic groups and others (eg those with a learning disability) are under-represented in consenting. Opt-out strategies, as well as ensuring openness and honesty, might be the most logical approaches to handling big data in these scenarios.

Anonymising data (all identifiers removed) or pseudonymising data (all identifiers replaced) could reduce the risk of re-identification breaches, especially in research. However, these strategies can lead to vital information, such as demographics, ethnicity or age, being lost, producing biases through missing data. For example, if poorer outcomes are experienced in a certain postcode but that location information is lost via anonymising, research outcomes that appear fair might in fact be biased. Bias does not imply intent; it might simply be unrepresentative of the entire patient population. A solution could be to establish a trusted research environment in which data are more openly used by trusted organisations; this was successful deployed during the coronavirus pandemic, allowing real-time data analysis in a fast-evolving situation.

Conclusion

As EHRs continue to grow, high-quality patient care will require foundation doctors to have a detailed understanding of digital healthcare systems. It will also become essential to teach all doctors about EHR design as well as to train them regarding how best to exploit modern data strategies to efficiently process, extract and utilise raw data obtained at the point of entry. There is a danger of creating AI that has built-in bias; however, with the hindsight of knowing how EHRs have historically worked, there is a unique opportunity to create a system built by design rather than necessity: this requires being conscious in its creation. Health inefficiencies and health inequality continue to represent huge socioeconomic burdens. Establishing EHR interoperability, instituting integrated monolithic EHRs and utilising machine learning tools represent extremely exciting future solutions to these conundrums.

Acknowledgements

We thank Rudy Harris, Klara De Baerdemaeker and Hani Salih for helping to sense check this piece for junior doctors and the general reader.

# data[].attributes.attachment_link.title
Streams, rivers and data lakes: an introduction to understanding modern electronic healthcare records

# data[].attributes.attachment_link.description
As foundation doctors, we have often found ourselves informing patients that a certain aspect of their medical information cannot be immediately found, either because it is on an electronic system we cannot access, or it is in a hospital that is unlinked to our own. Unsurprisingly, this frequently leaves patients flabbergasted and confused.

# data[].attributes.headline
A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning

# data[].attributes.subject
A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning

# data[].attributes.attachment_link.readable_text
1. Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. A definite diagnosis of AD can only be made post-mortem and by neuropathological confirmation of extracellular amyloid plaques. These plaques are composed of fibrillar amyloid and intracellular tau tangles, containing hyperphosphorylated tau [ 1].

Since the brain is inaccessible during life, the AD field has relied on imaging and cerebrospinal fluid (CSF) biomarkers to support clinical diagnosis, classify individuals for research studies or to interrogate and track pathophysiology [ 2, 3]. With the development of new disease-modifying therapies, it has become critically urgent to develop biomarkers that will identify individuals who are most likely to benefit from them. Thus, we need to develop tests that are simple to obtain, less invasive, high throughput and cost effective so we can test widely.

Currently, several fluid biomarkers are now validated to support clinical diagnosis in CSF [ 4]. These include the use of the ratio of the beta-amyloid peptides Aβ1-42/1-40, P-tau a marker of tau pathology, and neurofilament light (NfL), a biomarker of neuroaxonal damage [ 5, 6]. There are also promising biomarkers of amyloid, tau and neurodegeneration in plasma [ 7] and they are in the process of being validated in real life populations, with plasma P-tau 217 looking particularly promising [ 8, 9, 10, 11]. However, all these tests are expensive to perform, require invasive procedures, have to be pre-handled and centrifuged at source, and analyses performed in specialist laboratories.

CSF is obtained by lumbar puncture (LP), which is safe and generally well tolerated. However, it is not possible to perform this procedure on everyone, for instance those on blood-thinning agents, and is an invasive procedure that carries a 5-10% risk of post-LP syndrome [ 12]. Although blood is more accessible, it still remains invasive, and requires strict pre-handling practices with rapid centrifugation at source, to provide reliable results [ 13]. Therefore, there is considerable interest and a need for developing biomarkers in novel and non-invasive biological fluids such as urine that are easier and cheaper to collect, store, process and analyse. This could potentially be collected in the home environment and shipped to a lab through the post with no sample preparation required. Sampling is likely to be more acceptable to patients and could be widely used for earlier screening in mid-life populations outside of specialist centres and in any geographical location.

Despite extensive progress in CSF and serum biomarkers, research into biomarkers for brain diseases in urine is lagging behind. This is due to the significantly lower protein concentrations making detection more difficult and that urine is more distant from the brain compared with CSF and plasma. However, with technological advances in mass spectrometry, the increasing use of triple quadrupole mass spectrometers in chemical pathology and their unique ability to perform targeted proteomic analyses of multiple biomarkers at once, it is now conceivable that urinary biomarkers of AD can be measured. Urine has been explored previously for its potential for AD diagnosis particularly for metabolite changes [ 14, 15, 16, 17, 18]; however, the urinary metabolome can be highly variable so we have looked at the potential of urinary proteins. Conventionally most urinary protein is thought to be kidney derived but it has been shown to contain many membrane and extracellular proteins not just from the renal system but also from other distant organs [ 19, 20]. More recently its potential is being explored for neurological conditions such as brain cancer [ 21], Parkinson's disease [ 22] and AD [ 23, 24, 25, 26]

Furthermore, the use of machine learning and AI approaches is revolutionising diagnostics as we move to use multiple biomarkers to refine prognosis and diagnosis [ 27]. Therefore, in this study we tested the hypothesis that individuals with AD would have a different urinary proteomic profile to healthy controls and that these could reflect changes in relevant pathobiological pathways. The aims of this exploratory study were to:

Screen the urine proteome in participants with AD and compare with healthy controls using untargeted proteomics to identity pathways and potential AD biomarkers;

Create a translational and rapid test to validate any biomarkers using a multiplexed, targeted proteomic approach in an independent cohort;

Use machine learning techniques to develop a 'panel' of biomarkers that could be used to help diagnose AD.

2. Results

As expected, a significantly greater proportion of AD individuals in the discovery cohort were APO ε4-positive compared to controls in both cohorts. CSF amyloid concentration was lower in those with AD, and T-tau and P-tau were higher. MMSE scores were unsurprisingly lower in the AD group. These individuals were in the mild to moderate stage of the disease. The discovery and validation cohorts are described in full in Table 1.

2.1. Biomarker Discovery and Pathway Analyses: Comparison of Urinary Proteomic Analyses from AD Patients and Healthy Controls

The discovery cohort was composed of eleven individuals: six participants fulfilled clinical criteria for typical AD, and five were healthy controls. Label free proteomics and bioinformatic analyses identified a total of 1525 proteins. Comparison between the AD and control patient group identified a total of 42 proteins demonstrating changes in expression of protein between both groups (see Supplementary Table S1 for details). As described in the methods section, all proteins ranked A, B and C and demonstrating changes in expression, designated as showing a statistical significance of p < 0.05, were analysed using the Ingenuity Pathway analyses bioinformatics package (Qiagen, Venlo, The Netherlands).

Ingenuity canonical pathways analyses identified proteins activated by oxysterol ligands, cholesterol and bile acid metabolism (LXR/FXR/RXR activation) to be significantly changed in the urine of AD patients. Other changes observed included those involved in protein synthesis or folding and also changes in energy metabolism. Remarkably, disease function analyses identified nine proteins previously described as being altered in AD and amyloidosis diseases (APOA4, HSPA5, RNASET2, PLD3, FRMD4B, B2M, HPX, SERPINC1, OLR1). The functional pathway amyloidosis and familial amyloidosis being the first and third most significant pathways changed, with AD being the second and eighth most significantly relevant disease identified for each pathway, respectively. Figure 1 shows a summary of the results from the discovery phase.

2.2. Development of a Targeted and Multiplex Assay to Validate Potential Urinary Proteomic Biomarkers of AD

Unlike the pathway analyses of potential disease-modifying proteins in AD where all significant, differentially expressed proteins are taken into account, the development of a validatory and high-throughput test requires only those biomarkers with high confidence identification being taken forward. Figure 2 shows the 29 high-confidence proteins identified in this Rank A group that were taken forward for evaluation from the discovery analyses. These potential biomarkers were augmented into our in-house neuroinflammatory targeted proteomic panel [ 28], which was constructed from a mixture of literature reviews, known biomarkers of neurodegeneration and inflammatory factors. Therefore, a total of 88 protein biomarkers were developed into a scheduled, 17 min, multiplexed and targeted proteomic test. This panel of potential hypothesis-driven and hypothesis-generated biomarkers were then analysed in a total of 21 patients which constituted of 9 individuals with AD and 12 healthy, age-matched controls.

2.3. Individual Biomarkers and Univariate Analyses for the Diagnosis of AD

Out of the total of 88 biomarkers analysed in the multiplexed validatory test, we could detect reliably 61 proteins. We applied elastic net regression to pinpoint the most influential proteins in the discrimination between AD and healthy controls. We identified a total of five proteins which demonstrated potential for being put forward as possible biomarkers for AD ( Figure 3a). These included the four proteins, REG1B, VCAM1, TNF-beta and MIEN1, which were observed to be present in lower concentrations in AD urine. The protein, ABAC7, was the only potential biomarker to be elevated, with a 1.5-mean fold increase in concentration in the AD group compared to the controls ( Figure 3a,b). However, of all the biomarkers only MIEN1 demonstrated a statistically significant change in concentration compared to the control group ( Figure 3b). The biomarkers ABAC7 and MIEN1 (FC = −1.8) which demonstrated the greatest fold-change relative to one another, was further evaluated by looking at their relationship to one another in each patient. By ratioing the biomarkers MIEN1/ABAC7, we were able to further increase the statistical significance between the AD and controls even further ( Figure 3 c, p = 0.01).

2.4. Multilinear Regression and Machine Learning Analyses of Multiple Biomarkers for Improving the Specificity and Sensitivity for Diagnosing AD

To improve accuracy and sensitivity of the assay, we modelled the proteins using linear regression ( Figure 4). The AD and control samples were initially assessed using the significantly different protein MIEN1 alone; prediction of the samples in the model demonstrated an overall classification accuracy of 71% (56% sensitivity). To evaluate if the classification strength could be improved by using more predictors, we included the proteins which had been chosen in the elastic net feature selection performed to find the most relevant proteins to discriminate between AD and controls. This rendered us with a model including MIEN1, TNFB, VCAM1, REG1B and ABCA7. These five proteins were applied as predictors in a multiple linear regression model and when the samples were once more predicted, the overall classification accuracy was 86%, demonstrating a 15% improvement as compared to using the protein MIEN1 alone. Given the small sample size, we opted for performing k-fold cross validation on the model, where we utilised ten splits of the data. This resulted in six out of nine samples being accurately predicted as AD, and eight out of twelve samples accurately predicted as control.

3. Discussion

In this exploratory study, we used untargeted proteomic profiling to identify proteins that were differentially expressed in affected AD patients compared to unaffected control urine. We were able to detect differences in a number of proteins known to be implicated in AD pathology and related biological pathways. Furthermore, we developed a targeted proteomics panel and validated our findings in an independent cohort. Our findings suggest that this approach could have potential as a test in clinical practice for first tier screening or potentially to monitor new treatments. Since many of the proteins we identified are implicated in brain amyloidosis, a pathophysiological process which predates symptom onset in AD by ~25 years [ 29], we postulate that this biomarker panel has potential as an early pre-symptomatic screening tool for AD.

Finding biomarkers for early and accurate diagnosis of AD has become an urgent priority in the dementia field, now that three immunotherapies against fibrillar amyloid have demonstrated utility in slowing cognitive progression in mild to moderate AD [ 30, 31]. Inclusion in these studies requires demonstration of amyloidosis and tauopathy in the brain, either by cerebrospinal fluid analysis or PET scanning, and this is likely to remain the gold standard for providing accurate individual biomarkers support for a diagnosis of AD. However, the infrastructure for carrying out LPs and PET scans in the general population is very limited [ 32]. Tools for screening and risk stratification in the general population will be extremely important, particularly in countries without access to advanced diagnostics for dementia [ 33, 34]. Blood biomarkers are currently reasonably advanced in their development, with plasma P-tau 217 (particularly the P-T217/T217 ratio [ 35, 36]) proving to be a strong predictive marker of amyloid burden and tau deposition, in real life populations [ 37, 38] and plasma Aβ42/40 ratio allowing for reasonable separation of AD from non-AD individuals [ 39]. Yet, one limitation of blood biomarkers is the need for strict pre-handling protocols so that samples are centrifuged rapidly to avoid the effects of proteases degrading proteins of interest [ 40]. This is likely to limit its use in regional memory clinics and geographically isolated healthcare environments. It is also likely to be a barrier for home self-testing. In this study, we collected urine from a mid-stream sample. No early aliquoting or centrifugation was required at the point of collection, and very limited instructions were provided to participants, even those with moderately severe cognitive impairment. This means that collection is likely to be feasible across populations in developed and developing countries, making it an attractive screening tool and urine should be considered a more 'liquid gold' biofluid rather than just a waste product.

Using a univariate analysis only one protein, migration and invasion enhancer 1 (MIEN1), demonstrated a clear and statistically significant change in expression between the AD and control groups. MIEN1 is an intracellular protein located to the cytosol and centriole, that is expressed in many tissues but has a particularly high expression in the basal ganglia and cerebellum of the brain. MIEN1 is known to be a negative regulator of apoptosis and a positive regulator of cell migration and has gained significant interest in its role in breast cancer. However, MIEN1 variants have also been associated with early onset AD [ 41]. The exact mechanism of action is unclear, but MIEN1 is postulated to both interact with glutathione peroxidase and plays a significant role in the regulation of apoptosis through control of caspase 3 (CASP3). Variants in both these proteins are known to be associated strongly with AD, in particular CASP3 which cleaves beta amyloid 4a protein which is strongly associated with neuronal cell death observed in AD patients. Although individual statistical significance was not achieved with the other elevated proteins identified in this study, we were able to demonstrate that the diagnostic classification accuracy increases by 15% when utilising a panel of five proteins as compared to one protein alone. This highlights the strength of a carefully selected biomarker panel to improve the diagnostic and predictive ability of discriminant models. Our study is limited by the small sample size, but we anticipate that with increased sample numbers and statistical power, we could improve classification accuracy. Further, the five predictor proteins are involved in a range of biological processes that are plausibly relevant to AD pathophysiology, generally implicating lipid metabolism and inflammation pathways. Metabolomic-wide studies (MWAS) have demonstrated utility in elucidating the molecular mechanisms by which individual genes confer risk for AD. A recent study demonstrated that variations in ABCA7 are linked to increased risk of AD through altered sphingolipid metabolism [ 42]. Using disease and functional analyses, we have identified changes in a number of biomarkers involved in amyloidosis and AD including PLD3. Importantly, a previous urine proteomics study found that PLD3 is associated with AD [ 43]. Future MWAS studies may compliment the current study and other proteomics studies in the manipulation of therapeutic targets for AD.

A strength of this study is the well-phenotyped clinical characterisation of the discovery cohort, carried out at a national specialist centre, with diagnosis supported by imaging and CSF biomarkers. Although the number of individuals was small, we were able to provide an independent discovery and validation cohort. Unusually we had access to 'ideal' healthy controls who were the relatives of patients with AD. This meant that they were age matched, did not have cognitive symptoms, and agreed to have a LP as part of another observational study [ 44], which allowed us to confirm that they did not have biochemical evidence of brain amyloid pathology. Conversely, the validation cohort had limited clinical information, based on the restrictions of the ethics under which these individuals were recruited and therefore the individuals included could be at a different stage of the disease. However, the results obtained in this work are extremely promising and should be replicated in much larger cohorts of samples from patients across a range of neurodegenerative diseases and across AD disease course, especially during the pre-clinical phase to understand the assay's potential as a pre-symptomatic screening tool.

In summary, we have identified and validated differences in the urinary proteome between patients diagnosed with AD and healthy age-matched controls. The use of a machine learning approach in combination with a multiplexed panel of biomarkers, allowed us to improve the power of the assay to correctly identify the majority of AD patients analysed in this study. This provides proof of concept that a multiplex of AD-related proteins can be detected in urine using mass spectrometry and demonstrates the potential utility of high-throughput panels of urinary biomarkers to aid clinical diagnosis of AD.

4. Materials and Methods

4.1. Discovery Cohort

Individuals who fulfilled clinical research criteria for AD were prospectively recruited from a specialist cognitive disorders clinic as previously described [ 44]. All individuals underwent mini-mental state examination (MMSE; [ 45]) brain MRI, detailed neuropsychological assessments and had a LP. Controls were prospectively recruited and were age and sex matched (spouses or friends of those with AD), had no cognitive complaints, MMSE scores ≥ 28 and non-AD CSF profiles. Apolipoprotein E (APOE) ε2/ε3/ε4 genotype status was determined as previously described [ 44].

4.2. Validation Cohort

Individuals who fulfilled consensus criteria for AD were prospectively recruited from a diagnostic LP clinic. We included individuals who fulfilled clinical research criteria for AD [ 46], but CSF and other clinical data were not available for inclusion in this study. Controls were accompanying family or friends and reported no cognitive problems. Only basic demographic data were collected.

4.3. CSF Sample Collection, Pre-Analytical Handling, and Analysis

CSF samples were prospectively collected in the discovery cohort according to a standard operating procedure. Aβ1-42, T-tau, and P-tau assays were performed in batches according to local laboratory standard operating procedures to achieve inter-day coefficients of variation (CV) < 10% as previously described [ 47].

4.4. Urine Sample Collection and Pre-Clinical Handling

Individuals were asked to provide a midstream sample of urine during their research visit and to fill a 100 mL polypropylene screw-top container (Starstedt, product code: 75.1354.001). Samples were collected between 0800 and 1200. Samples were collected at room temperature and transferred directly to a −80 freezer within 2 h.

4.5. Urinary Creatinine Measurements

Creatinine concentration was measured for each urine sample using mass spectrometry as previously described [ 48].

Discovery proteomics: Samples were thawed at room temperature and vortexed for five seconds prior to aliquoting of 2 mL urine into 5 mL centrifuge tubes from Eppendorf. The 2 mL aliquots were centrifuged at room temperature at 3761× g for 30 min to separate the urinary sediment from solution using a Sorvall Legend RT centrifuge. The supernatant was transferred to Amicon Ultra-4 10 kDa molecular weight cut-off filters from Merck Millipore (Burlington, MA, USA) and 2 mL Milli-Q water was added to give a final volume of 4 mL. To concentrate the urinary proteins, the samples were centrifuged at room temperature for one hour at 4444× g (Sorvall Legend RT). The concentrate was transferred to a 1.5 mL centrifuge tube (Eppendorf). To ensure maximum recovery, the filters were washed with 100 μL 50 mM ammonium bicarbonate which was pooled with the concentrate. 800 μL ice-cold acetone was added to the pooled concentrate and the samples were vortexed for five seconds before overnight incubation in −20 °C. To separate the supernatant from the protein pellet, the samples were centrifuged for 10 min at +4 °C and 16,900× g using a Micro-centrifuge 5424 R (Eppendorf). The supernatant was carefully pipetted off and discarded. The pellet was air-dried in a fume hood for 20 min to evaporate residual acetone. 100 μL Milli-Q water was added to the samples and the protein pellet broken up by vigorous vortexing. The samples were thereafter freeze-dried overnight, followed by tryptic digestion with overnight incubation, solid phase extraction to purify the peptides and overnight evaporation of solvents [ 49]. The digested and SPE-cleaned samples were reconstituted in 50 μL 3% acetonitrile, 0.1% TFA and a peptide assay was performed. The peptide concentration in the samples was normalised to 1000 ng/μL before instrumental proteomics discovery analysis by 2D-LC-MS.

The peptides were separated using a 2D-NanoAquity liquid chromatography system (Waters, Manchester, UK). All samples were fractionated online into ten fractions over a 12-h period as previously described [ 50]. After acquisition, data were imported to Progenesis QI for proteomics (Waters) and the fractions 1-10 were individually processed before all results were merged into one experiment. The Ion Accounting workflow was utilised, with UniProt Canonical Human Proteome (exported 2017) as database. The digestion enzyme was set as trypsin. Carbamidomethyl on cysteines was set as a fixed modification; deamidation of glutamine and asparagine, oxidation of tryptophan and pyrrolidone carboxylic acid on the N-terminus were set as variable modifications. The identification tolerance was restricted to at least two fragments per peptide, three fragments per protein and one peptide per protein. A false discovery rate of 4% or less was accepted. The individual fractions were combined in Progenesis, using the multifraction experiment workflow. At least two unique peptides per protein and an identification confidence score larger than 15 were set as thresholds for classifying a protein as a confident identification.

4.6. Development of a High-Throughput, Multiplexed and Targeted Proteomic Assay

Potential biomarkers and those proteins demonstrating significant changes in protein expression were further subdivided and ranked into three groups A, B and C. Rank A biomarkers consisted of protein identifications where at least two unique peptides were observed and had a confidence score higher than 15. Other proteins were ranked B by having at least two unique peptides were identified/confidence score higher than 15, and C ranking indicates that one unique peptide was observed and the confidence score was lower than 15. All proteins, regardless of confidence rank, were then included in bioinformatic analyses where we looked for statistically significant changes in expression and fold change. However, only proteins ranked as A and identified by this high stringency analysis, thus more likely to better and more robust biomarkers, were taken forward for validation using a targeted proteomic approach.

The sample cohort for the targeted validation study was prepared using the same method as the discovery cohort but using 4 mL of urine and with 150 ng whole protein ENO1 (yeast) added as an internal standard to account for losses during sample preparation and for quantitation. The concentrated, digested and SPE-cleaned urine samples were reconstituted in 50 μL 3% acetonitrile, 0.1% TFA, containing 0.1 μM of stable heavy isotope labelled peptides or 'AquaPeptides' (ALDOA, C3, GSTO1, RSU1 and TSP1) prior to analysis by UPLC-MS/MS. The analytical settings have been described previously [ 28]. The MRM method consisted of 189 unique peptides and was split over two injections to ensure adequate acquisition of the transitions. A table detailing MRM transitions is available in Supplementary Table S2. After acquisition, data were peak picked using an in-house developed Python-based guided user interface (GUI) and peak picking application [ 51] or the MassLynx (version 4.1) module TargetLynx (Waters). In the GUI application workflow, the raw instrument files were converted to text files using the application MSConvert from ProteoWizard [ 52] and imported to the application. Peaks were aligned if necessary, and thereafter integrated. When TargetLynx was used, data were imported to the application and quantitative methods were created and applied to the data. The targeted raw data are available via the Panorama repository https://panoramaweb.org/AD_Urine_Proteomics.url (accessed on 27 August 2023). A complete summary of the workflow and methodology is described in Figure 5.

4.7. Statistical Analysis

Most of the statistical analyses were performed in Python (version 3.6) [ 53]. The proteins detected in the discovery analysis transformed to normality using a Box-Cox transformation (boxcox) from SciPy's stats package (version 1.11.0). Student's t-test with a nominal p-value threshold of 0.05 was applied to determine differential protein expression between the groups. Correlation analyses were performed using Pearson correlation (SciPy). The data were visualised using the Seaborn library (version 0.12.2) and the multivariate tool principal component analysis in the software SIMCA, version 17 (Umetrics Sartorius Stedim, Umeå, Sweden).

Linear regression models of proteins analysed in the targeted workflow were built using Scikit-learn (version 1.2.2). Feature selection was performed using a 5-fold cross validated elastic net regression (Scikit-learn) to pinpoint the variables of greatest importance to discriminate between AD and control samples. A multiple linear regression model was built using the panel of selected proteins. Cross validation was performed using KFold cross validations from Scikit-learn with ten splits of the data.

4.8. Pathway Analysis

The proteins expressing a nominally significant difference (p < 0.05) between the AD and the control groups were investigated using the expression analysis workflow in Ingenuity Pathway Analysis (Qiagen, Venlo, The Netherlands). To determine up- or downregulation of a protein in the AD group, the average fold-change compared to the control group was calculated.

4.9. Ethics

Ethical approval was obtained from the National Hospital for Neurology and Neurosurgery Research Ethics Committee (12 LO 1504, Dec 2012, Queen Square ethics committee) and written informed consent was obtained from all participants.

Supplementary Materials

Author Contributions

J.H.: Conceptualization, data acquisition, data curation, formal analysis, methodology and writing-original draft. R.C.P.: Data curation, formal analysis, methodology and writing-original draft. W.E.H.: Data curation, formal analysis, methodology and writing-original draft. J.C.: Writing-original draft. A.J.M.F.: Writing-review & editing. C.F.S.: Data acquisition, writing-review & editing. C.A.L.: Writing-review & editing. E.C.M.: Writing-review & editing. H.Z.: Conceptualization and writing-review & editing. J.M.S.: Conceptualization and writing-review & editing. K.M.: Conceptualization, methodology, formal analysis, funding acquisition, project administration, resources, supervision and writing-original draft. R.W.P.: Conceptualization, methodology, formal analysis, funding acquisition, project administration, resources, supervision and writing-original draft. All authors have read and agreed to the published version of the manuscript.

Funding

R.C.P. is supported by the UK Dementia Research Institute [award number MC_PC_17114] which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme-Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship AACSF-20-685780, the University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL.

Informed Consent Statement

Informed consent was given by all participants in this study.

Data Availability Statement

Acknowledgments

We wish to thank the participants who contributed to this study and to Iceland Foods Ltd.

Conflicts of Interest

H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). RWP is co-lead for the Neurofilament light consortium, and industry funded academic collaboration funded by Abbvie, Biogen, Bristol Myers Squibb and Roche.

References

Therriault, J.; Servaes, S.; Tissot, C.; Rahmouni, N.; Ashton, N.J.; Benedet, A.L.; Karikari, T.K.; Macedo, A.C.; Lussier, F.Z.; Stevenson, J. Equivalence of plasma p-tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease. Alzheimer's Dement. 2023. [Google Scholar] [CrossRef]

Jchallqvist/mrmIntegrate. Available online: https://github.com/jchallqvist/mrmIntegrate (accessed on 4 April 2023).

Python. Available online: https://www.python.org/ (accessed on 18 June 2023).

Figure 1. Discovery urine proteomics of AD versus healthy age-matched controls. ( A) Volcano plot showing the nominally differentially expressed (p < 0.05) proteins in blue and non-significantly different proteins in red. Ingenuity pathway analyses of those proteins observed to have differential expression in the urine of AD patients versus normal, age-matched controls; ( B) Canonical pathway analysis demonstrating that significant differences are observed in lipid and cholesterol homeostasis which is a hallmark of AD; ( C) Disease and functional analyses clearly identifies that there is significant changes in biomarkers involved in amyloidosis and AD, indicating that proteins present in the urine identify underlying disease processes occurring in the brain.

Figure 2. Summary of the biomarker discovery experiment and the identification of those proteins to be put forward as evaluation as potential biomarkers capable of distinguishing AD from controls. Proteins identified with high confidence and amenable to tandem mass spectral analyses are shown as large green circles (downregulated in AD) and pink circles (upregulated in AD).

Figure 3. ( a) Identification of the five proteins that demonstrated significant elevation or were present in lower amounts in the urine of patients with a confirmed AD diagnosis (MIEN1, TNF-beta, VCAM1, REG1B and ABCA7). ( b) Univariate analyses of the two proteins most up- and down regulated, ABCA7 and MIEN1, respectively, with MIEN1 being statistically significantly elevated (p = 0.03). ( c) By looking at the ratio of the biomarkers ABAC7 and MIEN1 to one another, increases the statistical significance between AD and controls even further (p = 0.01). The whiskers show the minimum and maximum and the boxes show the 25th percentile, the median and the 75th percentile. Values outside 1.5 fold the interquartile are represented by dots. x represents the mean.

Figure 4. Figure showing the power of multilinear regression and multiplex biomarker panel analyses to increase accuracy and sensitivity of the test by using four biomarkers in addition to the best performing biomarker (MIEN1).

Figure 5. Methodology Workflow: shows methodology workflow for the discovery cohort protein analysis (stage 1) and the development of a high-throughput, multiplexed and targeted proteomic assay (stage 2).

Table 1. ( a): Demographics, cognitive profiles and cerebrospinal fluid biomarker profiles of the discovery cohort. Abbreviations: AD, Alzheimer's disease; MMSE, mini mental score exam; CSF, cerebrospinal fluid. All data are shown as the mean ± standard deviation unless otherwise stated. ( b): Demographics and cognitive profiles of the validation cohort. Abbreviations: AD, Alzheimer's disease. All data are shown as the mean ± standard deviation unless otherwise stated.

Hällqvist J, Pinto RC, Heywood WE, Cordey J, Foulkes AJM, Slattery CF, Leckey CA, Murphy EC, Zetterberg H, Schott JM, et al. A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning. International Journal of Molecular Sciences. 2023; 24(18):13758. https://doi.org/10.3390/ijms241813758

Chicago/Turabian Style

Hällqvist, Jenny, Rui C. Pinto, Wendy E. Heywood, Jonjo Cordey, Alexander J. M. Foulkes, Catherine F. Slattery, Claire A. Leckey, Eimear C. Murphy, Henrik Zetterberg, Jonathan M. Schott, and et al. 2023. "A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning" International Journal of Molecular Sciences 24, no. 18: 13758. https://doi.org/10.3390/ijms241813758

# data[].attributes.attachment_link.title
A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning

# data[].attributes.attachment_link.description
As disease-modifying therapies are now available for Alzheimer's disease (AD), accessible, accurate and affordable biomarkers to support diagnosis are urgently needed. We sought to develop a mass spectrometry-based urine test as a high-throughput screening tool for diagnosing AD.

# data[].attributes.headline
Transperineal laser ablation as a new minimally invasive surgical therapy for benign prostatic hyperplasia: a systematic review of existing literature

# data[].attributes.subject
Transperineal laser ablation as a new minimally invasive surgical therapy for benign prostatic hyperplasia: a systematic review of existing literature

# data[].attributes.attachment_link.title
Transperineal Laser Ablation for Benign Prostatic Enlargement: A Systematic Review and Pooled Analysis of Pilot Studies

# data[].attributes.attachment_link.description
Transperineal laser ablation (TPLA) of the prostate is a new minimally invasive treatment option in men with lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE). The aim of this systematic review was to investigate the efficacy and safety of TPLA in the management of BPE. T…

# data[].attributes.headline
Contemporary Considerations in the Evolution of Wearable Technology for Arrhythmia Detection

# data[].attributes.subject
Contemporary Considerations in the Evolution of Wearable Technology for Arrhythmia Detection

# data[].attributes.attachment_link.readable_text
Arrhythmias are an increasingly common cause of hospital admissions worldwide. Late detection of arrhythmias is associated with a significantly increased risk of cardiovascular complications. Early identification and management of life-threatening arrhythmias is paramount to reduce mortality. Wearable technologies are now widespread among the general population, providing a continuous output of healthcare data. However, this data are not routinely integrated into clinical practice. Here, we begin by outlining the current landscape in wearable technology for aiding arrhythmia detection; we then consider the clinical impact of wearable technology for both clinicians and patients; we further highlight the latest and emerging trials in wearable technology for arrhythmia detection and finally postulate the wider implications of the expansion of such cardiac devices.

Keywords: Arrhythmia, monitoring, wearables, technology, cardiovascular complications, cardiac devices.

# data[].attributes.attachment_link.keywords[]
contemporary considerations in the evolution of wearable technology
for arrhythmia detection

# data[].attributes.attachment_link.title
Contemporary Considerations in the Evolution of Wearable Technology for Arrhythmia Detection

# data[].attributes.attachment_link.description
Arrhythmias are an increasingly common cause of hospital admissions worldwide. Late detection of arrhythmias is associated with a significantly increased risk of cardiovascular complications. Early identification and management of life-threatening arrhythmias is paramount to reduce mortality. Wearable technologies are now widespread among the general population, providing a continuous output of healthcare data.

# data[].attributes.headline
Preventing the overdiagnosis of chest sepsis in children: A quality improvement project

# data[].attributes.subject
Preventing the overdiagnosis of chest sepsis in children: A quality improvement project

# data[].attributes.headline
Conference Abstract - 369 Should We Be Group and Save Testing for Laparoscopic General Surgical Procedures? a Retrospective Audit of Transfusion Rates at a District General Hospital 

# data[].attributes.subject
Conference Abstract - 369 Should We Be Group and Save Testing for Laparoscopic General Surgical Procedures? a Retrospective Audit of Transfusion Rates at a District General Hospital 

# data[].attributes.attachment_link.title
369 Should We Be Group and Save Testing for Laparoscopic General Surgical Procedures? a Retrospective Audit of Transfusion Rates at a District General Hospital

# data[].attributes.attachment_link.description
AbstractIntroduction. The risk of bleeding in surgery makes the requirement for transfusion a pertinent consideration for all clinical staff involved in the car

# data[].attributes.headline
Variability in the presentation of complicated jejunal diverticulosis

# data[].attributes.subject
Variability in the presentation of complicated jejunal diverticulosis

# data[].attributes.headline
Urinary bladder melanosis with complete resolution case report

# data[].attributes.subject
Urinary bladder melanosis with complete resolution case report

# data[].attributes.attachment_link.readable_text
Bladder melanosis is a rare condition that has been incidentally reported in a limited number of cases during cystoscopies performed for the investigation of LUTS [ 2]. Moreover, bladder melanosis associated with transitional cell carcinoma has been reported in less than 5 cases worldwide. Our case is unique because bladder melanosis was associated with low-grade TCC and had complete resolution within one year.

There have been four reported cases in the literature of patients diagnosed with bladder melanosis and urothelial carcinoma (Table 1). In three out of four reported cases, patients presented initially with haematuria [ 3, 4, 5]. In one case, the patient originally presented with recurrent UTI's, and was found to have bladder melanosis. She represented one year later with haematuria and was then found to have TCC [ 6].

Table 1 A table demonstrating the key features of patients who have been found to have concurrent melanosis and urothelial carcinoma

All patients had cystoscopy, which in all the cases demonstrated dark pigmentation. Four out of five cases, including our case, underwent a TURBT [ 3, 5, 6]. One patient underwent a laparoscopic nephroureterectomy as they were found to have a ureteric tumour [ 4]. Regarding follow-up, three out of five cases, including our case, had regular surveillance cystoscopy [ 4, 6].

To date, the clinical presentation of bladder melanosis has been non-specific, with symptoms varying from recurrent cystitis and dysuria, to more concerning symptoms like gross haematuria, acute renal failure, and palpable mass [ 5]. Due to the rarity of the condition, it is yet unknown whether any of these symptoms are caused by bladder melanosis or whether, in itself, bladder melanosis is asymptomatic and only incidentally reported in cystoscopies [ 7].

Bladder melanosis is reported during cystoscopies as a velvety appearance of the urothelium with brown-black deposits which can be found in any area of the bladder. Moreover, the lesions can be flat or can have a small punctate appearance [ 6]. It is paramount for biopsies of the lesions to be taken to rule out any other aetiologies for dark pigmentation. To date, bladder melanosis is considered to be a benign condition. However, as mentioned above, its presence has been reported in conjunction with malignant proliferation, either as a predecessor or simultaneous. Further research is needed to better understand bladder melanosis's true significance.

The presence of bladder melanosis is proven histopathologically with Fontana-Masson staining. The melanin granules have the capacity to reduce the ammoniacal silver nitrate, resulting in black appearance. Furthermore, adding strong oxidizing agents bleaches the specimen, confirming the presence of melanin [ 6].

The differential diagnosis includes malignant melanoma, which is distinguished by proliferation of melanocytes, which are positive for S-100 and HMB-45 (which would be negative in melanosis). As there is no proliferation of melanocytes, there is nothing to suggest that surveillance with cystoscopy follow-up would be of much benefit for melanosis. In our case, there was no evidence of melanin pigment in the bladder biopsy taken after one year.

Few theories have been proposed with regards to bladder melanosis formation, but the pathophysiological mechanism of the condition is still obscure. The bladder urothelium does not normally contain melanocytes. The question of how does the urothelium gain melanocytic cells has been raised. Most of the published reports assume that: 1. During embryological development, the melanocytes have an aberrant migration; 2. Local transdifferentiating of urothelial stem cells [ 8]. None of the above theories has a solid research background, making the validity of the proposals questionable. Furthermore, it has been proposed that bladder melanosis is the result of an abnormal reaction of the mucosal nerve plexus or resulted secondary to the plasticity of the urothelium [ 8]. Only one case reported the presence of melanosis after bladder Botox therapy but it is yet unknown whether the innervation of the bladder was the culprit [ 8].

# data[].attributes.attachment_link.title
Urinary bladder melanosis with complete resolution case report - African Journal of Urology

# data[].attributes.attachment_link.description
Background Melanosis of the bladder is a rare condition characterized by multifocal, diffuse melanin pigmentation of the urothelial mucosa or lamina propria without any proliferation of melanocytes. Less than 25 cases have been reported so far of which only four patients had concurrent urothelial carcinoma.

# data[].attributes.headline
Development of outcome measures for giant cell arteritis for use in clinical trials and standard practice

# data[].attributes.subject
Development of outcome measures for giant cell arteritis for use in clinical trials and standard practice

# data[].attributes.attachment_link.readable_text
Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

Szekeres D, Al OB (2022) Current developments in the diagnosis and treatment of giant cell arteritis. Front Med 13(9):1066503. https://doi.org/10.3389/fmed.2022.1066503

Article Google Scholar

Rimland CA, Quinn KA, Rosenblum JS, Schwartz MN, Bates Gribbons K, Novakovich E, Sreih AG, Merkel PA, Ahlman MA, Grayson PC (2020) Outcome measures in large vessel vasculitis: relationship between patient-, physician-, imaging-, and laboratory-based assessments. Arthritis Care Res 72(9):1296-1304. https://doi.org/10.1002/acr.24117

Article Google Scholar

Saw SM, Ng TP (2001) The design and assessment of questionnaires in clinical research. Singap Med J 42(3):131-135

Carmines EG, Zeller RA (1979) Reliability and validity assessment (Vol. 17). Sage publications

Shi J, Mo X, Sun Z (2012) Content validity index in scale development. Zhong Na Da Xue Xue Bao Yi Xue Ban 37(2):152-155. https://doi.org/10.3969/j.issn.1672-7347.2012.02.007

Article Google Scholar

Park JR, Jones JG, Hazleman BL (1981) Relationship of the erythrocyte sedimentation rate to acute phase proteins in polymyalgia rheumatica and giant cell arteritis. Ann Rheum Dis 40:493-495. https://doi.org/10.1136/ard.40.5.493

Delecoeuillerie G, Joly P, Cohen de Lara A, Paolaggi JB (1988) Polymyalgia rheumatica and temporal arteritis: a retrospective analysis of prognostic features and different corticosteroid regimens (11 year survey of 210 patients). Ann Rheum Dis 47:733-739. https://doi.org/10.1136/ard.47.9.733

Kyle V, Cawston TE, Hazleman BL (1989) Erythrocyte sedimentation rate and C reactive protein in the assessment of polymyalgia rheumatica/giant cell arteritis on presentation and during follow up. Ann Rheum Dis 48:667-671. https://doi.org/10.1136/ard.48.8.667

Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ (2000) Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 43:1041-1048. https://doi.org/10.1002/1529-0131(200005)43:5<1041::AID-ANR12>3.0.CO;2-7

Dejaco C, Kerschbaumer A, Aletaha D, Bond M, Hysa E, Camellino D et al (2023) Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatica. Ann Rheum Dis:ard-2022-ar223429. https://doi.org/10.1136/ard-2022-223429

Download references

Acknowledgements

The authors acknowledge the kind cooperation and help of Miss. Sara Tousson Mohamed, Specialist librarian, Faculty of Medicine, Alexandria University, and Ms. Genny Franklin, Librarian, Darent Valley Hospital, Dartford, Kent, England, for their support in doing the review of the literature process.

Author information

Authors and Affiliations

Canterbury Christ Church University, Canterbury, England

Yasser El Miedany & Gillian Dolbear

King's College London, London, England

Yasser El Miedany & Mathias Toth

Ain Shams University, Cairo, Egypt

Maha Elgaafary & Sally Saber

Darent Valley Hospital, Kent, England

Mathias Toth & Dora Affam

Cairo University, Giza, Egypt

Atef Abdel Azim

North Middlesex University Hospital, London, England

Deborah Palmer

Tanta University, Tanta, Egypt

Mohamed Hassan Abu-zaid & Samar abdAlhamed Tabra

Benha University, Benha, Egypt

Waleed Hassan & Bassant Elnady

Contributions

All authors contributed in the study methodology, analysis, and interpretation of the data and outcomes as well as the manuscript writing, reading, and approval of the final version.

Corresponding author

Correspondence to Yasser El Miedany.

Ethics declarations

Ethics approval and consent to participate

Local ethical and methodological protocols for approval of the study were followed and accepted by the research ethical committee of Tanta University (approval number 36264PR45/1/23). All the participants were kept anonymous, in compliance with data protection regulations. Written informed consent from all participants was obtained in accordance with the local ethical committee.

Consent for publication

NA

Disclosures

None.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Reprints and Permissions

About this article

Cite this article

El Miedany, Y., Elgaafary, M., Toth, M. et al. Development of outcome measures for giant cell arteritis for use in clinical trials and standard practice. Clin Rheumatol (2023). https://doi.org/10.1007/s10067-023-06704-7
Download citation

Get shareable link

Keywords

Disease activity

GCA

Giant cell arteritis

Outcome measures

Patient global assessment

Physician global assessment

Ultrasound

Validity

# data[].attributes.attachment_link.title
Development of outcome measures for giant cell arteritis for use in clinical trials and standard practice - Clinical Rheumatology

# data[].attributes.attachment_link.description
Background Developments in outcome measures in the rheumatic diseases are promoted by the development of successful treatments. Giant cell arteritis (GCA) is a multifaceted disorder and, therefore, measurement of multiple outcomes is relevant to this illness. It is a privilege to analyze and monitor/transfer long-term patients' management outcomes particularly if the same outcomes are used in practice and in trials.

# data[].attributes.headline
Incidence and trends in workplace violence within emergency departments in the United Kingdom 2017-2022: an observational time series analysis

# data[].attributes.subject
Incidence and trends in workplace violence within emergency departments in the United Kingdom 2017-2022: an observational time series analysis

# data[].attributes.attachment_link.readable_text
Department of Surgery, Dartford and Gravesham NHS Trust, Dartford, United Kingdom

Department of Trauma and Orthopaedics, London North West University Hospitals NHS Trust, London, United Kingdom

Imperial College London, London, United Kingdom

Background: Workplace violence (WPV) is a notable issue facing healthcare services and workers globally. WPV impacts upon the well-being of staff and can put healthcare provision at risk with detrimental effects on patient care. This study aims to investigate and quantify, at national and regional levels, the incidence and trends of WPV within emergency departments (EDs).

Methods: We requested data relating to WPV from all 152 trusts with an ED in the United Kingdom from January 2017-March 2022. We applied interrupted time series and trend analysis to check for significant differences in WPV across the COVID-19 pandemic.

Results: We conducted time series analysis on 58 million attendances and detected statistically significant increases in WPV in March 2020-5.06/100,000 attendances (95% CI 1.59/100,000-8.53/100,000 p < 0.01) and May 2020-20.63/100,000 attendances (95% CI 9.39-31.87 p < 0.01). Rises in incidents of 0.37/100,000 attendances per month (95% CI 0.21-0.53 p < 0.0001) were found January 2017-March 2020. We analyzed 96 million attendances for yearly trends, which revealed statistically significant increasing trends of WPV in London and North-West England ( p < 0.05), and physical WPV in the North West England ( p  < 0.05).

Conclusion: There have been dramatic increases in incidents of WPV in United Kingdom EDs over the last 5 years with concerning rises during the COVID-19 period. Our findings highlight the potential to further demoralize a workforce already under significant strain, resulting in increased absences for physical or mental health and an exodus of staff. Therefore, trusts should ensure there are robust systems in place to protect and safeguard staff.

Introduction

Workplace violence (WPV) against healthcare workers (HCWs) is a notable and widespread healthcare issue with a high global prevalence ( 1). WPV is an umbrella term that is defined by the World Health Organization (WHO) as "incidents involving work-related abuse, threats or assaults among HCWs including physical, sexual, verbal, psychological abuse and workplace harassment." ( 1) The World Medical Association (WMA) has condemned the increase in cases of WPV perpetrated against HCWs and has labeled the surge in violence over the last decade as a healthcare emergency. Further, the WMA has called on the WHO and member states to take urgent action against WPV ( 2). The WHO has similarly acknowledged the impact of WPV on the physical and psychological health of HCWs and their subsequent job motivation, potentially compromising patient care and putting healthcare provision at risk ( 3).

Liu et al. recently quantified rates of WPV in healthcare and concluded that 62% of HCWs have been exposed to WPV. Liu et al. further noted that violence varied by geographic location and hospital department, with an increased prevalence in Asia and North America, and in the Emergency Department (ED) and psychiatric wards ( 4). Moreover, in their review articles exploring WPV specifically within an ED setting, Aljohani et al. postulated that 77% of ED staff members had been exposed to WPV, and Nikathil et al. suggested a rate of 36 violent patients for every 10,000 attendances ( 5, 6).

Aljohani et al. further explored the breakdown of WPV by role in their review and meta-analysis. They found that the majority of ED workers involved in WPV were nurses (55.7%) followed by physicians (36.5%), and that the primary instigators of WPV were family members (52%) followed by patients themselves (27%).

Many factors can lead to exposure to WPV, the causes of which have been extensively studied. The majority of studies note that nurses are the group most likely to be victims of abuse. Studies have also shown that increasing age, and a longer duration of employment are risk factors ( 7, 8). The association with gender and WPV is less clear, with some studies reporting men to experience higher rates of WPV, whereas a systematic review of studies in the African healthcare setting showed females to be at higher risk of WPV ( 8, 9).

Recent literature suggests that during the COVID-19 pandemic, there has been an alarming increase in WPV. For example, Chiroco et al. reported that WPV during this period was excessively high ( 10). Similarly, McGuire et al. found that, within one North American hospital referral region, violent incidents during the pandemic increased to 2.53/1000 visits compared to 1.13/1000 in the 3 months prior and 1.24/1000 in the year prior ( 11).

From a British perspective, the 2021 UK NHS Staff Survey revealed that within the previous 12 months, 14% of all NHS staff had experienced some sort of physical violence. A further 28% of the approximately 600,000 responses had experienced non-physical violence ( 12). Of frontline staff in hospitals with frequent patient contact, 19% were exposed to physical violence and 35% to non-physical violence. Results of the survey also indicated that only 42% of respondents reported an episode of violence. According to the survey, the groups most exposed to physical violence within the last 12 months were nursing and healthcare assistants (35.5%), followed by registered nurses and midwives (23.7%), and lastly medical and dental staff (11.4%). This was in contrast to harassment/bullying/verbal abuse where the groups most exposed were nurses and midwives (39.3%), followed by nursing axillary (38.0%), and finally medical and dental (34.2%). Two recent surveys conducted during the pandemic found that, over a one-month period, 30% of hospital doctors and 50% of General Practitioners had experienced verbal abuse, while the second survey found 35% of doctors had been subjected to verbal or physical abuse during the pandemic ( 13, 14).

The negative association of WPV with HCWs' well-being has been extensively documented, particularly its role in depression, lifestyle changes, anxiety, PTSD and burnout ( 15- 18). The 2022 GMC survey revealed that Emergency Medicine (EM) staff were at the highest risk of burnout, with 32% and 26% rates for trainees and trainers, respectively. Higher turnover of physicians has been reported in staff who have experienced WPV. This phenomenon is especially impactful in EM, which has a higher level of attrition than other specialities ( 19). Indeed, a review by McDermid et al. highlighted workplace aggression and violence as major themes in EM nurses ( 20). Moreover, a recent survey by the Royal College of Emergency Medicine reported that a large percentage of EM staff were considering altering working hours or leaving the field ( 21).

With this in mind, the aim of this study was to investigate and quantify trends in WPV within NHS EDs in the UK during the five-year period that included the COVID-19 pandemic. Since 2017 with the disbandment of NHS Protect, there has been no formalized national data collection on WPV for hospital trusts; therefore, this study serves to fill that knowledge gap, and provide justification for NHS trust-level policies to prevent WPV and support staff who fall victim to it.

Methods

We sent Freedom of Information requests to all 152 trusts within England, Scotland, Wales and Northern Ireland that included a Type 1 department defined by NHS England as "A major Accident and Emergency (A&E) department - A consultant led 24-h service with full resuscitation facilities and designated accommodation for the reception of accident and emergency patients" and/or a Type 2 department defined as "a consultant led single speciality A&E service (e.g., ophthalmology, dental) with designated accommodation for the reception of emergency patients" ( 22).

We requested specific information on WPV, including physical assaults resulting in injury and non-injury, verbal abuse, sexual harassment/abuse, and other abuse not falling into these categories. Trusts were given a minimum of 80 working days to respond to the request. Trusts were requested to provide data on patient, relative or visitor violence on HCWs. Where patient/visitor on patient/visitor, HCW on HCW or HCW on patient/visitor information was provided, these were excluded from the analysis.

We requested aggregate data if we could not obtain exact numbers based on confidentiality exemptions. Where, due to low numbers and confidentiality concerns, only ranges were provided, the most conservative figure was used. For example, a range of five to ten was recorded as five.

We gathered monthly ED attendance data from publicly and freely available governmental sources; NHS England, Public Health Scotland, StatsWales and Northern Ireland Department of Health websites ( 23- 26). For trusts that merged during the data collection period, data from the constituent trusts were consolidated for the new trusts. A&E attendances were defined by all 4 sources as 'unplanned new' or 'unplanned review' attendances whether they were admitted or not ( 22, 24- 26).

Ratios were calculated by incidents reported compared to total attendance figures, and we only used attendance figures for the trusts reporting for that time period.

Descriptive data were collected and analyzed using Microsoft Excel®.

Ethical statement

The UK Freedom of Information Act (2000) provides a right of access to information held by UK public authorities including the UK National Health Service. Individual trusts that responded to Freedom of Information (FOI) request replied with anonymized data in line with the UK Data Protection Act (2018) and UK GDPR legislation preventing release of third party data to the general public. Responsibility for the release of WPV data in the form of Freedom of Information requests to the general public is the responsibility of the individual trust releasing the data and identifiable information is exempt from FOI requests under Section 40 of the FOI act ( 27).

As analysis was run on publicly available data sets, in keeping with the principles of data protection and anonymity outlined above, no ethics committee approval was required.

Statistical analysis

We conducted time series analysis using Stata/IC version 15. Yearly trend analysis was conducted using the Mann-Kenall test. We conducted a region-stratified analysis to detect variation by locality, and conducted subgroup analysis on specific categories of WPV (physical violence, sexual harassment/abuse).

Only complete years 2017-2021 were included in the analysis to prevent the possibility of seasonality impacts on the data.

To further elicit any effect of the pandemic, a monthly interrupted time series analysis (ITSA) using Prais-Winsten regression analysis was utilized as previously described ( 28). Our interrupted time series model was built around two key time points, the onset and offset of the UK lockdown. On March 16 2020, the UK government advised against all non-essential travel with a stay-at-home order and on May 10 2020, the first relaxation of lockdown rules occurred with an allowance to return to work. For all models, the distribution of residuals was inspected for approximation to normality. Due to the heteroscedastic nature of our data, we applied the generalized least squares model to our data over the ordinary least squares model, which can be statistically inefficient ( 29).

Results

A total of 133 (88%) trusts responded to our FOI requests. Six trusts could not provide data due to confidentiality or storage issues (4%). Therefore, data were available from 127 (84%).

Monthly analysis

At the time of manuscript submission, 75 trusts were able to provide monthly data. NHS records show that across the UK from January 2017 to March 2022, A&E attendances totaled 119,197,489. We received data for 58,459,667 or 49.0% of total A&E attendances throughout the UK during the period of interest ( 20- 23). Monthly total WPV data are summarized, alongside total attendances for all UK trusts, in Table 1. Where possible, incident rates per 100,000 attendances have been calculated. It was not possible to calculate incident rates for trusts unable to provide monthly data.

Table 1. Monthly breakdown for attendances, total number of incidents and incidents/100,000 attendances.

Prior to March 2020, from January 2017, there was a statistically significant though small trend of an estimated increase of 0.37/100,000 attendances per month (95% CI 0.21/100,000-0.53/100,000 p < 0.0001) from an estimated 51.38/100,000 baseline determined by the model (95% CI 48.31/100,000-54.45/100,000). Incidents in March 2020, which coincided with the government-mandated stay at home lockdown order, increased by 5.06/100,000 (95% CI 1.59/100,000-8.53/100,000 p < 0.01) and remained high during the lockdown period with no detectable trend. During May 2020, when the government announced the lifting of lockdown and the return to work order, incidents increased by a further 20.63/100,000 (95% CI 9.39/100,000-31.87/100,000 p < 0.01). Following May 2020, although there was a decrease, this was not statistically significant-1.23/100,000 per month (95% CI-4.39/100,000-1.92/100,000 p = 0.48). These figures equate to a rise of approximately 50% in WPV over a roughly 2-year period. The levels of WPV at the end of our study, as predicted by the model, remain higher than pre-lockdown levels and far higher than the levels witnessed at the start of our study in January 2017. The graphical representation of the Prais-Winsten analysis is depicted in Figure 1.

Figure 1. ITSA for monthly data of total WPV per 100,000 attendances.

Yearly analysis

One hundred twenty seven out of one hundred fifty seven trusts provided yearly data. Of those, 99 provided complete data with exact figures (65%), 20 provided ranges only due to low numbers (13%), 7 were only able to provide certain time periods (5%), and 1 provided only a certain time period and range (0.7%).

From January 2017 to December 2021, out of a total of 113,294,985 ED visits, we received data covering 96,595,484 attendances allowing us to analyze 81.0% of all attendances within the UK during that time period.

The total number of incidents, rates per 100,000 attendances and p values for the presence of a statistically significant trend using Mann-Kendall analysis are detailed in Table 2.

Table 2. Total National and Regional WPV incidents, total number of incidents and incidents/100,000 attendances 2017-2021.

Throughout the UK, the rate of WPV per 100,000 attendances rose from 57/100,000 in 2017 to 79/100,000 in 2021, an increase of 39% over 5 years. Initial data collection from the first 3 months of 2022 suggests a rate of 77/100,000. The largest yearly change was seen during 2019-2020 from 61/100,000 to 79/100,000.

Wales had the highest number of incidents per 100,000 attendances, reaching a peak of 122/100,000 in 2021; initial data from 2022 suggests a reduction to 77/100,000.

On a country level, no statistically significant detectable trend existed for any of the Home Nations. However, the UK as a whole, as well as England and Northern Ireland are approaching significance with the presence of a trend ( p  < 0.1).

Regional analysis with geographical groupings as described by NHS England revealed a considerable increase in incidents per 100,000 in 5 regions - South East (60%), London (78%), North East and Yorkshire (83%), North West (112%) and South West (23%) and a decrease in 2 regions - Midlands (-17%) and East of England (-6%) as detailed in Table 2 and depicted graphically in Figure 2.

Figure 2. WPV incidents per total 100,000 attendances within regions of England.

Trend analysis showed statistically significant rising trends in London and the North-West of England ( p < 0.05). Regions approaching statistically significant trends were the North-East England, South-East England and the South-West England (p < 0.1). Mann-Kendall analyses for the presence of a statistically significant trend over the 5 years are also presented in Table 2.

Subgroup analysis

Physical abuse

Eighty one trusts provided data on physical violence. We received data covering 80,872,878 ED attendances, 71.3% of all ED attendances during that period.

A breakdown of physical violence is shown in Table 3. Overall from 2017 to 2021, there was an increase of 27% in incidents per 100,000 (18/100,000 to 23/100,000) down 9% from a peak of 25/100,000 in 2020. There were increases in physical abuse rates per 100,000 in England (26%), Wales (61%) and Northern Ireland (159%) and a decrease in Scotland (19%).

Table 3. National and Regional physical violence incidents, total number of incidents and per 100,000 attendances.

North-West England recorded a statistically significant trend for increased physical violence ( p  < 0.05), London, North-East England and Yorkshire and Northern Ireland all approached significance (p < 0.1).

Further sub-group analysis on physical violence and sexual abuse and harassment from January 2017-March 2022 can be found in the supplementary files.

Two trusts changed their reporting procedures during the request time period. These were Northern Lincolnshire and Goole NHS Foundation Trust (January 2018) and Manchester University NHS Foundation Trust (March 2018). Data derived from the old methods were excluded due to significant variance in incidents pre and post reporting method change.

Discussion

This study presents the results of a large, multicentre investigation of WPV within EDs, at a regional and country level. To our knowledge, this is the first study to investigate the country-wide associations of WPV, the COVID-19 pandemic and the subsequent lockdown.

Of great concern is that our study has shown that WPV has persisted above pre-pandemic levels both in the total number of incidents and per attendance, a change that is statistically significant. While there were small detectable increases prior to COVID-19, there was a notable increase in violence at the start of the lockdown period and a further drastic and significant increase when the lockdown was eased.

Our results corroborate the results of an Israeli study noting HCWs' perception of increasing WPV during the pandemic ( 30). Our data are also in keeping with the findings of the McGuire et al. study, which demonstrated an increase in WPV during COVID-19. Albeit, the increase in WPV described in our study throughout the COVID period was 50%, compared to 200% in the paper by McGuire et al. ( 8) A similar increase in WPV has been documented in primary care within the UK, with violent incidents doubling in 5 years ( 31).

Our study also demonstrates regional variation in WPV, both within the Home Nations as well as the English regions. For example, the rate of WPV in Scotland decreased over the COVID period, as did WPV in the Midlands and East of England regions. By contrast, WPV increased significantly in London (64.17/100,000 to 114.27 p < 0.05) and the North West of England (41.00/100,000 to 86.72/100,000 p  < 0.05). Furthermore, physical violence increased significantly in the North West of England (13.01/100,000 to 35.65/100,000 p < 0.05). Although the factors contributing to this regional variation are beyond the scope of this study, it represents an interesting area for further research. Nonetheless, policymakers should be mindful of areas with an increased incidence of violence and prioritize these areas for the implementation of anti-violence policies and campaigns.

Additionally, we have identified certain regions where there is an increasing trend of physical violence. Specific policies designed to mitigate the effect of physical abuse, where strategies can differ from other types of abuse, should be targeted to these regions at risk ( 32).

As previously noted in the NHS staff survey, not all WPV incidents are reported. Indeed, 25-50% of all incidents go unreported ( 12). Therefore, the true incidence and, by extension, the impact of WPV is likely to be higher than that posited in this paper.

Academics have hypothesized several potential precipitants of WPV against HCWs. Previous studies identified the following as potential triggers: long wait times to see a clinician or receive medication, a shortage of staff, exposure to pain, high-stress levels and feelings of anger, frustration and unmet patient needs ( 33, 34). These proposed triggers provide an interesting comparison to our own study, which spanned the COVID-19 pandemic. NHS data revealed the height of the pandemic to be a period of low attendance and improved wait times within EDs ( 35). On that basis, therefore, one would expect violence levels to have fallen as the aforementioned precipitants were largely addressed, inadvertently or otherwise. This, however, was not the finding in our study. Therefore, explaining the increase in violence is not as simple as blaming the pandemic. By logical extension, a 'return-to-normal' cannot be expected to be the sole antidote.

More recently the NHS has been experiencing a retention crisis with healthcare workers of all disciplines leaving the field, including 34,000 nurses leaving their posts and 10,000 doctors giving up their license to practice in 2022 ( 36, 37). Worryingly in a survey of 4,500 junior doctors in the UK a third planned to work abroad in the next 12 months, and 40% would leave the NHS as soon as they found another job ( 38). Job dissatisfaction has recently manifested itself with the most widespread industrial action within the NHS. A recent meta-analysis of 6,400 nurses showed that WPV was associated with nursing turnover ( 39). Furthermore, recent studies concluded that perceived organizational support reduced the effect of WPV upon turnover ( 40, 41).

For a nationalized health service like the NHS, which already suffers from 133,000 vacancies (9.7% of the total workforce) in England alone, the impact of increasing violence against HCWs could be catastrophic toward this retention crisis ( 42). The negative psychological effects, such as stress and burnout, of WPV on HCWs have been well documented ( 15- 18). With a steep rise in WPV, it is highly likely that the collective morale of the workforce has plummeted, and their well-being suffered. Within a cohort of ED nurses, there was shown to be a direct correlation between experiencing WPV and reduced job satisfaction and increased turnover ( 43).

Additionally, poor staff morale and widespread rota gaps could lead to worsening service provision capability, which can have significant detrimental effects on patient care and outcomes, as well as triggering further WPV; a vicious cycle ensues.

Previously, efforts to reduce the incidence of WPV and its effects on HCWs have been targeted toward security interventions, support groups and staff training, which have all been discussed as positive and useful interventions ( 44- 46). In view of the findings of our study, these and other interventions to safeguard staff would benefit from increased resource allocation and implementation within the NHS.

In 2020 NHS England released the Violence Prevention and Reduction standard ( 47). Despite this, WPV remains concerningly high, and our results should provide policymakers with evidence that further efforts are needed to halt and reverse this worrying trend. In the current climate of widespread industrial action over working conditions within the NHS, WPV should be an area that is focused on nationally in light of this study's findings. We further suggest that reducing WPV and increasing support for WPV victims would have an immediate effect on staff morale and well-being, and improve efforts at reducing staff turnover. This should be done expeditiously in view of the current NHS staffing crisis.

Limitations

Due to a large number of trusts and incident reporting systems, there is the potential for a wide variation in the way incidents have been reported and recorded by each individual trust, which could impact results. Twenty trusts were unable to provide exact figures; however, as this was the case only if incident numbers were low, the figures are judged to have a small impact on the overall validity of the results and would lead to an under-represented number of WPV incidents. Further due to the anonymized nature of the data sets released via the FOI requests and publicly available attendance data, we did not receive any demographic data on any of the participants involved in the violence. Therefore, specific commentary on the representativeness of the data to the entire UK population is limited. Due to the small number of time points, particularly in regard to yearly data analysis, the potential for Type II statistical errors with no trend detected is elevated. Further data gathering covering more time points in the future could mitigate this potential.

Conclusion

Our study has demonstrated that there has been a dramatic rise of 50% in the number of WPV incidents recorded throughout 2017-2022 in the UK, with significant, drastic increases over the COVID lockdown period. WPV critically impacts upon staff morale and well-being, resulting in problems related to staff retention, recruitment and the efficient running of the department. Ultimately, patient outcomes are put at risk. There is some regional and geographical variance in rates of violence, the cause of which is uncertain. Further investigation is required.

We believe that the findings of this study highlight an emergency in WPV, and should serve as a precipitant for targeted reduction strategies. This paper provides evidence to encourage healthcare leaders to accelerate the formulation and implementation of policies to safeguard HCWs in a period of particularly low morale and well-being as shown by large-scale industrial action within the workforce. With the ongoing retention crisis within the NHS, a reduction in WPV will provide an immediate boost to an increasingly dejected and demoralized workforce.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

ND contributed to conceptualization, methodology, and data collection. TL contributed to software and formal statistical analysis. All authors contributed to manuscript draft and review. All authors have read and agreed to the published version of the manuscript.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh.2023.1211471/full#supplementary-material

References

9. Njaka, S, Edeogu, OC, Oko, CC, Goni, MD, and Nkadi, N. Work place violence (WPV) against healthcare workers in Africa: a systematic review. Heliyon. (2020) 6:e04800. doi: 10.1016/j.heliyon.2020

CrossRef Full Text | Google Scholar

27. Health Bodies (England). (2000). Definition document for health bodies in England (this will include all NHS trusts, clinical commissioning groups and special health authorities). (Version 4.0).
Google Scholar
28. Turner, SL, Karahalios, A, Forbes, AB, Taljaard, M, Grimshaw, JM, and McKenzie, JE. Comparison of six statistical methods for interrupted time series studies: empirical evaluation of 190 published series. BMC Med Res Methodol. (2021) 21:134. doi: 10.1186/s12874-021-01306-w

CrossRef Full Text | Google Scholar

33. Algwaiz, W, and Alghanim, S. Violence exposure among health care professionals in Saudi public hospitals. A preliminary investigation. Saudi Med J. (2012) 33:76-82.

PubMed Abstract | Google Scholar

# data[].attributes.attachment_link.title
Incidence and trends in workplace violence within emergency departments in the United Kingdom 2017-2022: an observational time series analysis

# data[].attributes.attachment_link.description
BackgroundWorkplace violence (WPV) is a notable issue facing healthcare services and workers globally. WPV impacts upon the well-being of staff and can put healthcare provision at risk with detrimental effects on patient care.

# data[].attributes.headline
Predicting long-term risk of reoperations following abdominal and pelvic surgery: a nationwide retrospective cohort study

# data[].attributes.subject
Predicting long-term risk of reoperations following abdominal and pelvic surgery: a nationwide retrospective cohort study

# data[].attributes.attachment_link.readable_text
Introduction

Highlights

One in seven patients has a reoperation in the 5 years after abdominal surgery.

Important risk factors for reoperation are mesh, infection, and colorectal surgery.

Individual risk for reoperation can be determined based on the prediction model.

The prediction model can improve patient information and the informed consent procedure.

In contemporary surgical practice, approximately half of all elective abdominal procedures are reoperations. Reoperations have an inherent increased risk of complications, related to anatomical changes and the formation of adhesions in particular. These risks apply to patients undergoing emergency surgery for obstruction related to adhesions, as well as patients undergoing (elective) reoperation for indications unrelated to adhesions. After previous laparotomy up to 90% of patients undergoing a reoperation require adhesiolysis to gain access to the operative area. Following a laparoscopy, the overall incidence of adhesions is 60 and 44% of patients have adhesions at the previous operative site. Adhesiolysis at reoperation increases the operative time by a median of 18 min and is associated with 6-10% risk of iatrogenic bowel injury. Adhesiolysis is associated with a higher risk of infectious complications even if no bowel injury occurred. Incremental hospital costs associated with adhesiolysis are estimated to be $4500 higher per operation compared with similar procedures without the need for adhesiolysis.

Identifying patients at high risk for future reoperations is considered difficult because most reoperations are not related to the previous procedure. Therefore, surgeons are often not directly confronted with the reoperations and subsequent adhesion-related complications. Moreover, risk factors for reoperations are not yet fully elucidated. A national survey demonstrated surgeons and gynecologists underestimate risk factors for adhesion formation that impact the need for adhesiolysis during reoperation.

Surgeons often fail to inform patients about the future risk of reoperation and other adhesion-related complications during informed consent. Understanding the risk factors for future reoperation results in a more detailed informed consent and could guide the application of adhesion prevention strategies such as the use of adhesion barriers.

The aim of this study was to construct an evidence-based prediction model based on the risk of future reoperation using data from the nationwide SCAR update study cohort. Models were fitted for the overall risk of reoperation, a reoperation in the same surgical area, and a reoperation in the same surgical area after more than 30 days. Most reoperations within 30 days are performed because of short-term complications of surgery such as anastomotic leakage or abscesses. These risks are often mentioned as such in informed consent. Patients reoperated after more than 30 days in the same surgical area are also the most likely to benefit from adhesion prevention strategies.

Materials and methods

Patients

For this study, the data from the SCAR update study were used. Data for this study were retrieved from the Scottish Medical Record Linkage Database of the Scottish National Health Service (NHS Scotland). The data from the NHS Scotland includes all data from inhabitants of Scotland, with no opt-out. All patients (including minors) who underwent initial open or laparoscopic abdominal or pelvic surgery between June 2009 and June 2011 were included both elective and emergency operations. Patients with a history of previous abdominal or pelvic surgery were not selected. Abdominal and pelvic operations were identified by the Office of Population Censuses and Surveys Classification of Interventions and Procedures version 4 (OPCS-4) codes. Readmissions were defined by OPCS-4 codes combined with the International Classification of Disease, 10th Revision (ICD-10) diagnostic codes. All pelvic and abdominal reoperations during 5 years of follow-up were reviewed for this study. The most frequent indications for reoperations are described. More detailed information on this cohort can be found in a previous publication.

Variables

The variables incorporated in the prediction model were extracted from the OPCS-4 and ICD-10 codes. Demographics comprised age and sex and surgical variables were surgical approach (laparoscopic/open), surgical area of operation (abdominal wall, small pelvis, right upper quadrant, right lower quadrant, left upper quadrant or left lower quadrant), type of surgical procedure (liver, retroperitoneal, urological, upper gastrointestinal, gall bladder, appendix, gynecological uterus-sparing, gynecological with hysterectomy, rectum, colon or other), presence of inflammatory bowel disease (IBD), malignancy as an indication for initial surgery, previous radiotherapy, intra-abdominal infection, presence of a registered endometriosis diagnosis and mesh placement at initial surgery. Relevant ICD-10 codes for intra-abdominal infection have been listed in Appendix Table B (Supplemental Digital Content 2, https://links.lww.com/JS9/A323). For any single surgical procedure more than one surgical area could be scored, for example, right hemicolectomy was considered as the right lower quadrant and right upper quadrant.

Statistical analysis

Nomograms were built based on prediction models that were fitted using Cox regression analysis. A prediction model was built for the overall risk of reoperation 2 and 5 years after initial surgery, for reoperations in the same anatomical area, and finally for reoperations after 30 days in the same anatomical area. The multivariable prognostic model carried out in the Regression Modeling Strategies package in R (version 3.5.1) was used.

To fit the prediction model we started with univariable Cox regression analysis, analyzing the difference between demographics, presence of IBD or malignancy, operated organ domain, and operation type. The incidence of repeat surgery and hazard ratios (HRs) with 95% CIs was calculated. Statistically significant differences were defined as a P-value of less than 0.05. All significant predictors for reoperations in the univariable analysis were included in the multivariable analysis. Using backward selection, variables were removed from the model in case of a P-value greater than 0.20.

The c-statistic was used to quantify accuracy in terms of predictive discrimination. A c-statistics 0.65-0.70 were considered moderately predictive, 0.70-0.79 good prediction, 0.80-0.89 excellent prediction, and more than 0.9 outstanding. To prevent overestimation with fitting on a single cohort, the validity of the created prediction model was evaluated by internal cross‐validation using a bootstrap procedure. The bootstrap procedure is the recommended method for internal validation of the predictive accuracy of prediction models. From the bootstrap resampling procedure the adjusted c-statistic was calculated. The difference in the compared c-statistics is described as optimism. In case of optimism below 0.01, the original model was considered accurate and consequently retained.

Furthermore, subgroup analysis was performed to verify the consistency of the subgroups. The subgroups are benign versus malignant indications for initial surgery, open versus laparoscopic initial surgery, and reoperation before and after 30 days after the initial surgery.

To predict the risk of reoperation in the individual patient the nomogram was used by filling in the independent risk factors which corresponded to a number of points on the scale. The aggregated points of the risk factors translated to the prediction of the 2-year and 5-year risk of reoperation.

The study is registered on Clinicaltrials.gov number NCT05516420.

Ethical consideration

The research proposal was approved by the board of the Electronic Data Research and Innovation Service of Public Health Scotland (PHS). This study is conducted and reported in line with the STROCSS criteria (Supplemental Digital Content 1, https://links.lww.com/JS9/A322).

Results

Overall, 72 270 patients underwent their initial abdominal or pelvic surgery during the study period; reoperations were performed in 10 467 (14.5%) patients in the 5 years after the initial surgery ( Fig. 1). In 9497 (13.1%) patients reoperation was performed in the same anatomical area. Reoperations were performed during a mean follow-up of 70.2 months (SD=22.2, range: 0-95.1). Table 1 displays the baseline characteristics. During the study period, 21 519 (29.7%) patients underwent a laparoscopic procedure. All other operations (50 751, 70.2%) were open procedures. In 16.0% of procedures (11 560 of 72 270) malignancy was the indication for the initial surgery.

There was wide variation in the indications for reoperation. In Table A (Supplemental Digital Content 2, https://links.lww.com/JS9/A323), the 10 most common indications for reoperation after laparotomy or laparoscopy are presented. These 10 indications were related to 60% of reoperations after open initial surgery and 91% of reoperations after laparoscopic procedures. Most reoperations were unrelated to the initial surgery. Some reoperations were related but unplanned, such as the correction of abdominal wall hernia and adhesiolysis for obstruction. Only 18.5% of these common reoperations could be identified as a possibly planned reoperation (i.e. reoperations that could be anticipated at the initial procedure such as ileostomy closure). Reoperations for disease recurrence were relatively uncommon and not included in the list of common procedures for reoperation.

Risk factors for reoperation overall

Almost all variables significantly impacted the risk for reoperation overall in the univariable (Table C, Supplemental Digital Content 2, https://links.lww.com/JS9/A323) and multivariable analyses ( Table 2) and were entered into the prediction model ( Fig. 2). Only endometriosis was excluded from the multivariable analysis through backward selection.

Figure 2:

Nomogram to calculate the risk for reoperation overall. By drawing a vertical line from each variable to the point axis on top and summing the individual points for all variables, the total score is calculated. From the total score axis perpendicular to the bottom, the linear predictor and the 2-year and 5-year risk for reoperation are determined. An example of a calculation using the nomogram (Fig. 2); male patient, 50 years old (23 points), laparoscopic (0 points) right hemicolectomy (colon 71 points) due to malignancy (14 points) as initial surgery (taken the highest surgical area, seen right hemicolectomy is performed in right upper quadrant (55 points) and right lower quadrant (16 points). Summed up a total of 179 points, translating to a 14% risk for reoperation in 2 years postoperative and an 18% 5-year risk. GI, gastrointestinal; IBD, inflammatory bowel disease.

Placement of mesh at initial surgery had the highest impact on the risk of reoperation overall (35.2%, HR=7.06, 95% CI: 6.60-7.55). Other relevant risk factors were operations involving the rectum (30.2%, HR=5.40, 95% CI: 4.19-6.96) or colon (18.7%, HR=3.39, 95% CI: 2.63-4.36) and intra-abdominal infection (17.6%, HR=2.24, 95% CI: 2.10-2.50). Following open procedures, more patients (15.0%) underwent reoperation (HR=1.30, 95% CI: 1.23-1.39) compared with laparoscopic procedures (8.6%). Reoperations were performed more often in women (13.4%) compared with men (12.3%, HR=1.15, 95% CI: 1.10-1.21).

The results were robust in subgroup analysis, comparing benign with malignant indications for initial surgery (Tables D, Supplemental Digital Content 2, https://links.lww.com/JS9/A323 and E, Supplemental Digital Content 2, https://links.lww.com/JS9/A323) and open with laparoscopic approach (Tables F, Supplemental Digital Content 2, https://links.lww.com/JS9/A323 and G, Supplemental Digital Content 2, https://links.lww.com/JS9/A323). The only noticeable difference between subgroups was the impact of sex in the subgroups of malignant surgery. The risk for reoperation was increased in men with malignancy as an indication for initial surgery. In all other subgroups, women had a higher risk for reoperation. In the subgroup of laparoscopic initial operations, intra-abdominal infection was excluded as a risk factor for reoperation from the multivariable analysis through backward selection.

The nomogram for reoperation overall ( Fig. 2) had good prognostic accuracy with a c-statistic of 0.72. The accuracy of the model remained the same after internal validation through bootstrapping ( c-statistic=0.72). Due to optimism in the model of 0.001, the original model could be retained.

Risk factors for reoperation in the same surgical area

Univariable analysis was performed on all variables (Table H, Supplemental Digital Content 2, https://links.lww.com/JS9/A323). Through backward selection endometriosis and intra-abdominal infection were excluded from multivariable analysis ( Table 3). Consequently, the remaining variables were entered into the prediction model.

The type of surgical procedure had the greatest impact on the risk for reoperation in the same surgical area with the highest reoperation rate after rectal surgery (26.0%, HR=9.48, 95% CI: 6.79-13.22), followed by uterus-sparing gynecological procedures (14.5%, HR=4.73, 95% CI: 3.37-6.64) and colonic surgery 14.1% (HR=5.44, 95% CI: 3.90-7.59). After open surgery 5773 of 50 751 (11.4%) patients underwent reoperation (HR=1.42, 95% CI: 1.32-1.54) compared with 966 of 21 519 (4.5%) after laparoscopic procedures. When mesh was placed during the initial surgery, reoperation was higher (14.4%, HR=2.48, 95% CI: 2.25-2.74) than after surgery without mesh placement (9.0%).

The subgroup of malignant indications for initial surgery showed the intra-abdominal infection was retained in the multivariable analysis and IBD was excluded through backward selection in the multivariable analysis for the risk of reoperation in the same area (Tables I, Supplemental Digital Content 2, https://links.lww.com/JS9/A323 and J, Supplemental Digital Content 2, https://links.lww.com/JS9/A323). The male sex had an increased risk in the malignant subgroup analysis compared with the female sex in the main analysis. In the laparoscopic subgroup, sex was excluded for multivariable analysis through backwards selection. All other variables were maintained in the multivariable subgroup analysis of the open versus laparoscopic approach (Tables K, Supplemental Digital Content 2, https://links.lww.com/JS9/A323 and L, Supplemental Digital Content 2, https://links.lww.com/JS9/A323). However, endometriosis and radiotherapy did not impact the risk of reoperation in the same area in the open approach subgroup significantly.

The predictive accuracy of the nomogram for reoperation in the same surgical area was good ( c-statistic=0.72) and remained the same after internal validation through bootstrapping ( c-statistic=0.72). Consequently, the optimism of less than 0.001 did not require adjustment of the original model.

Risk factors for early or late reoperation in the same surgical area

After univariable analysis on all variables (Table M, Supplemental Digital Content 2, https://links.lww.com/JS9/A323), intra-abdominal infection and endometriosis were excluded from multivariable analysis (Table N, Supplemental Digital Content 2, https://links.lww.com/JS9/A323) through backward selection. Operations involving the rectum and colon were performed in 25.7% (HR=10.67, 95% CI: 7.48-15.23) and 13.6% (HR=5.92, 95% CI: 4.15-8.44), respectively, imposing the greatest impact on the risk for reoperation after 30 days in the same surgical area. After surgery with the use of mesh, 13.7% of patients underwent reoperation (HR=3.01, 95% CI: 2.71-3.34).

In the subgroup analysis of benign versus malignant indications for initial surgery, endometriosis posed no significant impact. Intra-abdominal infection was only significant in the malign indication subgroup (Tables O, Supplemental Digital Content 2, https://links.lww.com/JS9/A323 and P, Supplemental Digital Content 2, https://links.lww.com/JS9/A323). In the laparoscopic subgroup sex was excluded for multivariable analysis through backward selection, in the open approach subgroup endometriosis and radiotherapy had no significant impact on the risk of reoperation in the same area after 30 days (Tables Q, Supplemental Digital Content 2, https://links.lww.com/JS9/A323 and R, Supplemental Digital Content 2, https://links.lww.com/JS9/A323). For the subgroup of reoperation within 30 days after initial surgery, IBD, intra-abdominal infection, radiotherapy in history, and mesh placement had no significant impact on the risk of reoperation in the univariable analysis (Table S, Supplemental Digital Content 2, https://links.lww.com/JS9/A323) and therefore were not incorporated in the multivariable analysis (Table T, Supplemental Digital Content 2, https://links.lww.com/JS9/A323).

The nomogram based on the multivariable analysis for predicting reoperation later than 30 days is seen in Figure 3. The predictive accuracy for this nomogram was good ( c-statistic=0.73) and internal validation through bootstrapping demonstrated comparable accuracy ( c-statistic=0.73). With an optimism of 0.001, the original nomogram was retained.

Figure 3:

: Nomogram to calculate the risk for reoperation later than 30 days in the same area. By drawing a vertical line from each variable to the point axis on top and summing the individual points for all variables, the total score is calculated. From the total score axis perpendicular to the bottom, the linear predictor and the 2-year and 5-year risk for reoperation are determined. GI, gastrointestinal; IBD, inflammatory bowel disease.

Discussion

Using a large national database, nomograms were constructed to predict the risk for reoperation in individual patients. The discriminative value of the prediction model for the risk of reoperation overall was considered moderate, whereas the prediction models for reoperation in the same surgical area were considered good. The risk factors with the highest impact on reoperations in all the models were mesh placement at initial surgery and operations involving the colon or rectum. Furthermore, an IBD diagnosis, younger age, malignancy, open surgical approach, and female sex increased the risk for reoperation.

Epidemiological findings of this cohort demonstrated that approximately one in seven patients will undergo abdominal or pelvic reoperation within 5 years after initial abdominal surgery. In multivariable analysis, the rate of reoperation overall was one in five after laparoscopic surgery compared with almost one in three after open surgery. The rate of reoperation in the same surgical area was 30% lower after laparoscopic surgery compared with open procedures.

Our study addresses an important knowledge gap in predicting the risk of abdominal reoperation in the general surgical population. Previous research on predicting the risk of reoperations are mainly based on short-term reoperations for complications of the initial operation. However, the literature shows that the majority of reoperations are unplanned, and half of the reoperations are unrelated to the initial operation. Also in our cohort, only one in five of reoperations could be identified as a possibly planned reoperation. These possibly planned reoperations were included in our study because we aimed to predict the overall incidence of reoperation for the individual patient. Moreover, it is difficult to ascertain if reoperation is planned or not based on the available administrative codes. Our nomograms provide an overall prediction for the risk of reoperation, the estimation of the risk for reoperation might be further tailored based on foreseeable and planned reoperation.

In a recent survey among Dutch surgeons, only one in seven surgeons acknowledged the increased risk of adhesion-related complications in IBD patients. In our cohort, reoperation risk was highest for patients with IBD. As many as three out of 10 patients with IBD underwent reoperation within 5 years and one out of four patients had a reoperation in the same surgical area. This correlates with previous literature on IBD patients, reporting reoperation in almost 20% of patients within 30 months and 25% within 5 years after the first resection.

In a previous single-center cohort of general surgery, some risk factors for reoperation were confirmed, including female sex, younger age, and an open approach. In that study, a higher rate of reoperation was recorded (27%), possibly due to the relatively higher number of extensive operations performed in a tertiary referral setting, the low number of laparoscopies, and the inclusion of patients with several previous operations.

In females, the higher reoperation risk might be partly attributable to fertility-related operations. Notably, uterus-sparing gynecological operations had a higher impact on the reoperation risk than procedures with hysterectomy. The increased risk of reoperation following oncological surgery is explained by future operations for local recurrence or metastases and procedures involving (reversal of) the ileostomy or colostomy. For younger patients, the increased risk for reoperation might be attributable to the fact that younger patients are more often deemed fit for surgery should a new condition be diagnosed for which surgery is indicated, whereas in older and frail patients surgery for relative indications might be more frequently avoided.

A major strength of this study is the building of the nomogram based on the national database (Scottish Medical Linkage Database, managed by the NHS), with validated data and low migration numbers allowing a population-based study in a broad surgical cohort. The NHS database consists of all Scottish patients undergoing the first abdominal surgery during the study period, without the possibility of opt-out.

The broad population on which the model was fitted also comes with some limitations, as some surgical indications and procedures might come with specific inherent risks that are not fully captured by multivariable analysis. However, we deliberately performed our analyses on a broad surgical cohort, because the risk of reoperation and subsequent adhesiolysis is relevant to the entire abdominal surgical population and our aim was to develop a model which is suitable for the majority of patients. The epidemiology of reoperations for a number of specific conditions such as IBD or malignancy have been described previously.

Another limitation is the lack of an external population for validation of the model. However, this cohort consists of nationwide unselected patients representative of the daily practice of surgery departments in a high-income country with high data density due to centralized reporting. Internal cross-validation using bootstrapping was performed, which demonstrated good internal validation with no need for correction of all original prediction models.

Excluding patients with previous abdominal surgery potentially limits the generalizability of the model. Patients undergoing reoperation are part of daily clinical practice, as more than half of abdominal operation performed in current practice are reoperations. The reasons for including only patients undergoing their first operation are both methodological and clinical. Methodologically, the risk of reoperation cannot be attributed to characteristics relating to the most recent operation if patients undergoing reoperation are included in the model. Clinically, patients undergoing their first operation seem most relevant as these patients are often unaware of the relatively high risk of future reoperation. Second, utilizing adhesion prevention strategies is conceptually most efficacious when applied directly at the first incidence of peritoneal trauma. A specific limitation of excluding patients with prior surgical history is that more patients with malignancy at a later age and a history of previous surgery at a younger age might have been excluded. However, the number of older patients and patients with malignancy was still high. The effect of age and malignancy was also consistent throughout the subgroup analyses. Therefore, we consider the model appropriate also for elderly and oncological patients.

For our assessments, we had to rely on the OPCS and ICD-10 codes available for each readmission. This type of data is not granular enough to score variables such as surgical experience, and prescribed medication or to differentiate accurately between elective and emergency surgery. Moreover, ideally, a model would be fitted on the outcome 'reoperation requiring adhesiolysis.' In clinical practice, the OPCS-10 and ICD-10 codes for adhesiolysis are often used only if adhesiolysis was the primary indication for surgery (e.g. in case of adhesive small bowel obstruction). Furthermore, adhesiolysis is often poorly documented even in operative reports. Also in the SCAR update database, only a very small proportion of reoperations were coded as an adhesiolysis procedure. For this reason, nomograms were built for reoperation in the same surgical area in which the need for adhesiolysis is reportedly high even following laparoscopic surgery. The corresponding nomogram had a good predictive ability.

Our prediction model enables the identification of patients at increased risk of reoperations in support of clinical decision-making and informed consent. Although some risk factors are intuitively related to a higher risk of reoperation, surveys among surgeons, gynecologists, and general practitioners have demonstrated that the incidence of reoperation and the impact of risk factors for adhesion formation are often underestimated and poorly mentioned in the informed consent procedure. If the adhesion-related risk is mentioned, it is often in patients with an increased risk of small bowel obstruction. The high incidence of abdominal reoperations indicates that these risks should also be discussed. In case of a planned reoperation, the use of adhesion barriers might be discussed. In these patients with an expected reoperation, adhesion barriers have been demonstrated to reduce operative time and potentially the risk of iatrogenic injury. Accurate and relevant patient information is essential in the informed consent and shared decision-making process. Many efforts have been made in the past decades to improve patient information regarding surgical procedures and the development of decision aids in particular. Most patients are now well informed about the success rate and short-term complications of surgery. Information about long-term complications related to adhesions, such as reoperation risk but also small bowel obstruction, and chronic pain is often inadequate.

Strategies to minimize the extent of adhesion formation include minimally invasive surgery and the use of adhesion barriers. Laparoscopy has been shown to reduce the extent and incidence of adhesion formation to the previous incision site to 40% and any adhesions to 60%, while after open surgery the incidence is up to 80 and 90%, respectively. Despite the decrease of adhesions and adhesion-related complications, the burden after laparoscopy remains high. Adhesion barriers could further reduce adhesion formation and have been demonstrated to reduce operative time in two-stage procedures. Nevertheless, the search for an optimal barrier continues because of some important practical limitations of currently available barriers. Recent surveys in the UK and The Netherlands have demonstrated that the use of adhesion barriers is rare.

Conclusions

The constructed prediction model provides a prognosis of the individual risk for reoperation. Overall, in our cohort, one in seven patients had a reoperation within 5 years after abdominal surgery. The highest impact on the risk of reoperation is provided by the placement of mesh at initial surgery followed by the type of surgical procedure, with the highest risk after initial colorectal operations. Furthermore, previous radiotherapy, an IBD diagnosis, surgical area, malignancy as an indication for initial surgery, open approach, younger age, and female sex increased the risk for reoperation in all prediction models.

Sources of funding

An unrestricted research grant was provided by Nordic Pharma for this investigator initiated research.

Author contribution

M.K.T.: methodology, formal analysis, validation, writing - original draft - review and editing, visualization, project administration. P.K.: conceptualization, visualization, data curation, writing - review and editing, funding acquisition. A.J.: visualization, data curation, formal analysis. T.D.G.: formal analysis, writing - review and editing. M.W.J.S., E.A.G., M.C.P., N.D.B., and H.v.G.: conceptualization, supervision, writing - review and editing. R.P.G.t.B.: conceptualization, methodology, supervision, funding acquisition, writing - review and editing.

Conflicts of interest disclosure

The authors declare that they have no financial conflict of interest with regard to the content of this report.

Research registration unique identifying number (UIN)

The study is registered on Clinicaltrials.gov number NCT05516420.

Guarantor

Masja K. Toneman and Richard P.G. Ten Broek.

Data availability statement

The data that support the findings of this study are available from the Scottish National Health Service (NHS). Restrictions apply to the availability of these data, which were used under license for this study. Data derived from the analysis are available from the authors with the permission of the Scottish NHS.

The used repository was the Safe Haven ( https://shs.epcc.ed.ac.uk/2fa/scotnsh.html) from the NHS.

Provenance and peer review

Not commissioned, externally peer-reviewed.

# data[].attributes.attachment_link.title
Predicting long-term risk of reoperations following... : International Journal of Surgery

# data[].attributes.attachment_link.description
often required, and patients have an increased risk of complications. Therefore, the aim of this study was to provide an evidence-based prediction model based on the risk of reoperation. Materials and methods: A nationwide cohort study was conducted including all patients undergoing an initial abdominal or pelvic operation between 1 June 2009 and 30 June 2011 in Scotland.

# data[].attributes.headline
Venous Thromboembolism (VTE) in Post-Prostatectomy Patients: Systematic Review and Meta-Analysis

# data[].attributes.subject
Venous Thromboembolism (VTE) in Post-Prostatectomy Patients: Systematic Review and Meta-Analysis

# data[].attributes.attachment_link.readable_text
The .gov means it's official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Affiliations

1 Department of Urology, Swansea Bay University Health Board, Swansea SA6 6NL, UK.

2 Department of Urology, Imperial College Healthcare NHS Trust, London W6 8RF, UK.

3 School of Medicine, Centre for Medical Engineering and Technology, University of Dundee, Dundee DD1 9SY, UK.

4 Urological Surgery Department, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK.

5 Department of Urology & Nephrology, Dartford, and Gravesham NHS Trust, Dartford DA2 8DA, UK.

Free PMC article

Free PMC article

Affiliations

1 Department of Urology, Swansea Bay University Health Board, Swansea SA6 6NL, UK.

2 Department of Urology, Imperial College Healthcare NHS Trust, London W6 8RF, UK.

3 School of Medicine, Centre for Medical Engineering and Technology, University of Dundee, Dundee DD1 9SY, UK.

4 Urological Surgery Department, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK.

5 Department of Urology & Nephrology, Dartford, and Gravesham NHS Trust, Dartford DA2 8DA, UK.

Abstract

Radical prostatectomy (RP) is one of the recommended treatments to achieve oncological outcomes in localized prostate cancer. However, a radical prostatectomy is a major abdominopelvic surgery. Venous thromboembolism (VTE) is a well-known complication associated with surgical procedures, including RP. There is a lack of consensus regarding VTE prophylaxis in urological procedures. The aim of this systematic review and meta-analysis was to investigate different aspects of VTE in post-radical prostatectomy patients. A comprehensive literature search was performed, and relevant data were extracted. The primary aim was to perform a systematic review and meta-analysis (wherever possible) of VTE occurrence in post-RP patients in relation to surgical approach, pelvic lymph node dissection, and type of prophylaxis (mechanical or combined prophylaxis). The secondary aim was to investigate the incidence and other risk factors of VTE in post-RP patients. A total of 16 studies were included for quantitative analysis. Statistical methods for analysis included the DerSimonian-Laird random effects. We were able to conclude that the overall incidence of VTE in post-radical prostatectomy is 1% (95% CI) and minimally invasive procedures (MIS), including laparoscopic, as well as robotic procedures for radical prostatectomy and RP without pelvic lymph node dissection (PLND), are associated with less risk of developing VTE. Additional pharmacological prophylaxis to mechanical methods may not be necessary in all cases and should be considered in high-risk patients only.

Keywords: mechanical prophylaxis; pharmacological prophylaxis; prostate cancer; radical prostatectomy; venous thromboembolism.

Conflict of interest statement

The authors declare no conflict of interest.

References

Guyatt G.H., Eikelboom J.W., Gould M.K., Garcia D.A., Crowther M., Murad M.H., Kahn S.R., Falck-Ytter Y., Francis C.W., Lansberg M.G., et al. Approach to Outcome Measurement in the Prevention of Thrombosis in Surgical and Medical Patients. Chest. 2012;141:e185S-e194S. doi: 10.1378/chest.11-2289. - DOI - PMC - PubMed

Kibel A.S., Loughlin K.R. Pathogenesis and Prophylaxis of Postoperative Thromboembolic Disease in Urological Pelvic Surgery. J. Urol. 1995;153:1763-1774. doi: 10.1016/S0022-5347(01)67302-6. - DOI - PubMed

Geerts W.H., Heit J.A., Clagett G.P., Pineo G.F., Colwell C.W., Anderson F.A., Wheeler H.B. Prevention of Venous Thromboembolism. Chest. 2001;119:132S-175S. doi: 10.1378/chest.119.1_suppl.132S. - DOI - PubMed

Geerts W.H., Pineo G.F., Heit J.A., Bergqvist D., Lassen M.R., Colwell C.W., Ray J.G. Prevention of Venous Thromboembolism. Chest. 2004;126:338S-400S. doi: 10.1378/chest.126.3_suppl.338S. - DOI - PubMed

Zhan C., Miller M.R. Excess Length of Stay, Charges, and Mortality Attributable to Medical Injuries During Hospitalization. JAMA. 2003;290:1868-1874. doi: 10.1001/jama.290.14.1868. - DOI - PubMed

Grant support

This research received no external funding.

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Venous Thromboembolism (VTE) in Post-Prostatectomy Patients: Systematic Review and Meta-Analysis - PubMed

# data[].attributes.attachment_link.description
Radical prostatectomy (RP) is one of the recommended treatments to achieve oncological outcomes in localized prostate cancer. However, a radical prostatectomy is a major abdominopelvic surgery. Venous thromboembolism (VTE) is a well-known complication associated with surgical procedures, including R ...

# data[].attributes.headline
Gefitinib and methotrexate to resolve tubal ectopic pregnancy: the GEM3 RCT

# data[].attributes.subject
Gefitinib and methotrexate to resolve tubal ectopic pregnancy: the GEM3 RCT

# data[].attributes.headline
ORthopaedic trauma hospital outcomes - Patient operative delays (ORTHOPOD) Study: The management of day-case orthopaedic trauma in the United Kingdom

# data[].attributes.subject
ORthopaedic trauma hospital outcomes - Patient operative delays (ORTHOPOD) Study: The management of day-case orthopaedic trauma in the United Kingdom

# data[].attributes.attachment_link.readable_text
The .gov means it's official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Abstract

Introduction: ORTHOPOD: Day Case Trauma is a multicentre prospective service evaluation of day-case trauma surgery across four countries. It is an epidemiological assessment of injury burden, patient pathways, theatre capacity, time to surgery and cancellation. It is the first evaluation of day-case trauma processes and system performance at nationwide scale.

Methods: Data was prospectively recorded through a collaborative approach. Arm one captured weekly caseload burden and operating theatre capacity. Arm two detailed patient and injury demographics, and time to surgery for specific injury groups. Patients scheduled for surgery between 22/08/22 and 16/10/22 and operated on before 31/10/22, were included. For this analysis, hand and spine injuries were excluded.

Results: Data was obtained from 86 Data Access Groups (70 in England, 2 in Wales, 10 in Scotland and 4 in Northern Ireland). After exclusions, 709 weeks worth of data representing 23,138 operative cases were analysed. Day-case trauma patients (DCTP) accounted for 29.1% of overall trauma burden and utilised 25.7% of general trauma list capacity. They were predominantly adults aged 18 to 59 (56.7%) with upper limb Injuries (65.7%). Across the four nations, the median number of day-case trauma lists (DCTL) available per week was 0 (IQR 1). 6 of 84 (7.1%) hospitals had at least five DCTLs per week. Rates of cancellation (13.2% day-case; 11.9% inpatient) and escalation to elective operating lists (9.1% day-case; 3.4% inpatient) were higher in DCTPs. For equivalent injuries, DCTPs waited longer for surgery. Distal radius and ankle fractures had median times to surgery within national recommendations: 3 days and 6 days respectively. Outpatient route to surgery was varied. Dominant pathways (>50% patients listed at that episode) in England and Wales were uncommon but the most frequently seen was listing patients in the emergency department, 16 of 80 hospitals (20%).

Conclusion: There is significant mismatch in DCTP management and resource availability. There is also considerable variation in DCTP route to surgery. Suitable DCTL patients are often managed as inpatients. Improving day-case trauma services reduces the burden on general trauma lists and this study demonstrates there is considerable scope for service and pathway development and improved patient experience.

Keywords: Ambulatory; Cancellations; Day-case trauma; Delays; Fracture; Time to surgery; Trauma.

Conflict of interest statement

Declaration of Competing Interests Mr William Eardley serves as the Vice-chair on the British Orthopaedic Association (BOA) Trauma Committee. Mr Alex Trompeter is a member of the BOA Trauma Committee and is the lead for the BOA Standards for Trauma and Orthopaedics (BOAST) guidelines.

Similar articles

'Golden Patient': A quality improvement project aiming to improve trauma theatre efficiency in the Royal Gwent Hospital.

Key T, Reid G, Vannet N, Lloyd J, Burckett-St Laurent D. Key T, et al. BMJ Open Qual. 2019 Feb 18;8(1):e000515. doi: 10.1136/bmjoq-2018-000515. eCollection 2019. BMJ Open Qual. 2019. PMID: 30997419 Free PMC article.

Management implications for the perioperative surgical home related to inpatient case cancellations and add-on case scheduling on the day of surgery.

Epstein RH, Dexter F. Epstein RH, et al. Anesth Analg. 2015 Jul;121(1):206-218. doi: 10.1213/ANE.0000000000000789. Anesth Analg. 2015. PMID: 26086516

The Impact of Sterile Instrument Set Wrapping Defects on Trauma and Orthopaedic Surgery Theatre Lists.

Anazor F, Sibanda V, Altaf K, Downer L, Relwani J. Anazor F, et al. Cureus. 2022 Oct 3;14(10):e29861. doi: 10.7759/cureus.29861. eCollection 2022 Oct. Cureus. 2022. PMID: 36337817 Free PMC article.

Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) acute day hospital versus admission; (2) vocational rehabilitation; (3) day hospital versus outpatient care.

Marshall M, Crowther R, Almaraz-Serrano A, Creed F, Sledge W, Kluiter H, Roberts C, Hill E, Wiersma D, Bond GR, Huxley P, Tyrer P. Marshall M, et al. Health Technol Assess. 2001;5(21):1-75. doi: 10.3310/hta5210. Health Technol Assess. 2001. PMID: 11532238 Review.

Evidence Brief: Comparative Effectiveness of Appointment Recall Reminder Procedures for Follow-up Appointments [Internet].

Peterson K, McCleery E, Anderson J, Waldrip K, Helfand M. Peterson K, et al. Washington (DC): Department of Veterans Affairs (US); 2015 Jul. Washington (DC): Department of Veterans Affairs (US); 2015 Jul. PMID: 27606388 Free Books & Documents. Review.

# data[].attributes.attachment_link.keywords[]
affs=["ashford and st peter's hospitals."]

# data[].attributes.attachment_link.keywords[]
affs=["ashford and st peter's hospitals."]

# data[].attributes.attachment_link.keywords[]
affs=["ashford and st peter's hospitals."]

# data[].attributes.attachment_link.keywords[]
affs=["ashford and st peter's hospitals."]

# data[].attributes.attachment_link.keywords[]
affs=["ashford and st peter's hospitals."]

# data[].attributes.attachment_link.keywords[]
affs=['dumfries and galloway royal infirmary.']

# data[].attributes.attachment_link.keywords[]
affs=['dumfries and galloway royal infirmary.']

# data[].attributes.attachment_link.keywords[]
affs=['dumfries and galloway royal infirmary.']

# data[].attributes.attachment_link.keywords[]
affs=['dumfries and galloway royal infirmary.']

# data[].attributes.attachment_link.keywords[]
affs=['harrogate and district nhs foundation trust.']

# data[].attributes.attachment_link.keywords[]
affs=['harrogate and district nhs foundation trust.']

# data[].attributes.attachment_link.keywords[]
affs=['harrogate and district nhs foundation trust.']

# data[].attributes.attachment_link.keywords[]
affs=['harrogate and district nhs foundation trust.']

# data[].attributes.attachment_link.keywords[]
affs=['maidstone & tunbridge wells nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['maidstone & tunbridge wells nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['maidstone & tunbridge wells nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['maidstone & tunbridge wells nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['maidstone & tunbridge wells nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['southport and ormskirk nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['southport and ormskirk nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['southport and ormskirk nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['southport and ormskirk nhs trust.']

# data[].attributes.attachment_link.keywords[]
affs=['warrington & halton nhs teaching hospitals.']

# data[].attributes.attachment_link.keywords[]
affs=['warrington & halton nhs teaching hospitals.']

# data[].attributes.attachment_link.keywords[]
affs=['warrington & halton nhs teaching hospitals.']

# data[].attributes.attachment_link.keywords[]
affs=['warrington & halton nhs teaching hospitals.']

# data[].attributes.attachment_link.keywords[]
affs=['warrington & halton nhs teaching hospitals.']

# data[].attributes.attachment_link.keywords[]
affs=['warrington & halton nhs teaching hospitals.']

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
ORthopaedic trauma hospital outcomes - Patient operative delays (ORTHOPOD) Study: The management of day-case orthopaedic trauma in the United Kingdom - PubMed

# data[].attributes.attachment_link.description
There is significant mismatch in DCTP management and resource availability. There is also considerable variation in DCTP route to surgery. Suitable DCTL patients are often managed as inpatients. Improving day-case trauma services reduces the burden on general trauma lists and this study demonstrates ...

# data[].attributes.headline
In-house anaesthetic database development: data driven care to improve patient care

# data[].attributes.subject
In-house anaesthetic database development: data driven care to improve patient care

# data[].attributes.headline
Immune Thrombocytopenia: A Rare Adverse Event of Vancomycin Therapy

# data[].attributes.subject
Immune Thrombocytopenia: A Rare Adverse Event of Vancomycin Therapy

# data[].attributes.attachment_link.title
Immune Thrombocytopenia: A Rare Adverse Event of Vancomycin Therapy

# data[].attributes.attachment_link.description
Vancomycin, a glycopeptide antibiotic, is widely used for Gram-positive cocci or bacilli bacteria-induced serious infections. Although considered safe and effective, it still causes adverse events. Vancomycin-induced immune thrombocytopenia is a rarely reported adverse event, manifesting from asympt…

# data[].attributes.headline
Conference Abstract -  British Association of Perinatal Medicine and Neonatal Society                                                       13 Neonatal prolonged jaundice screening – change of practice during Covid pandemic 

# data[].attributes.subject
Conference Abstract -  British Association of Perinatal Medicine and Neonatal Society                                                       13 Neonatal prolonged jaundice screening – change of practice during Covid pandemic 

# data[].attributes.attachment_link.readable_text
Introduction Persistent neonatal jaundice can occur in 15-20% of newborn babies. It was believed that Pregnanediol secreted in human milk inhibits conjugation of bilirubin however, a study based on mass-spectrometry in 1980s did not provide such evidence. A rapid decrease in jaundice when breast feeding is stopped suggests some inhibitor in human milk that remains unknown. The prolonged jaundice screening is aimed at minority of cases that have underlying pathology.

Background Until May 2020, babies were screened by SHO but in the first wave of Covid-19 pandemic, junior doctors were redeployed to adult wards. Hence babies were directly referred to phlebotomist if they are deemed well by the Health Visitor or to A&E if they were unwell.

Methods The phlebotomists attended a teaching session on prolonged jaundice, and they started to collect vital information including parental report of stool colour, weight gain and adequacy of feeding. Screening was done within 48 hours and Consultant was notified who sent 'normal screening' letter or arranged follow-up as necessary.

Results Before Covid, 363 babies were seen over three years. Average haemoglobin and bilirubin were 140g/L and 144mmol/L respectively. Two babies had high ALT which normalised on repeat test, and none had conjugated hyperbilirubinemia.

In one year during Covid, 121 babies were seen. Average haemoglobin and bilirubin were similar (144g/L and 156mmol/L respectively). One baby had elevated ALT and three had conjugated hyperbilirubinemia that normalised subsequently. None needed referral to Liver Unit.

There was no significant difference in timing of the prolonged jaundice screen (21.9 days Vs 24.6 days) between the two groups. An arbitrary level of total bilirubin of >200 mmol/L and haemoglobin <120g/L was used to identify babies with potential haemolysis and no babies needed investigations for haemolysis in either group.

We have observed that with adequate safety measures including wellness screening at the point of referral, vital questions asked by phlebotomists and a structure to deal with and communicate the results, it is possible to run a safe prolonged jaundice screening without the need for medical review in secondary care.

In the three years before Covid, two cases of congenital heart disease (VSD/ASD) where picked up which would have been picked up at 6 weeks by GP (or earlier through A&E if unwell). Pathological causes of prolonged jaundice can still be safely picked up by this improvised pathway and the select few cases can be seen in consultant clinic as necessary.

References

Rodie ME, Barclay A, Harry C, Simpson J. NICE recommendation for the formal assessment of babies with prolonged jaundice: too much for well infants? ADC Volume 96.

Sampath S, Puttha R, Thomson APJ. Investigating prolonged jaundice in healthy breastfed infants- time to change current practice? ADC Volume 97.

# data[].attributes.attachment_link.title
13 Neonatal prolonged jaundice screening - change of practice during Covid pandemic

# data[].attributes.attachment_link.description
Introduction Persistent neonatal jaundice can occur in 15-20% of newborn babies. It was believed that Pregnanediol secreted in human milk inhibits conjugation of bilirubin however, a study based on mass-spectrometry in 1980s did not provide such evidence. A rapid decrease in jaundice when breast feeding is stopped suggests some inhibitor in human milk that remains unknown.

# data[].attributes.headline
Predicting long-term risk of reoperations following abdominal and pelvic surgery: a nationwide retrospective cohort study

# data[].attributes.subject
Predicting long-term risk of reoperations following abdominal and pelvic surgery: a nationwide retrospective cohort study

# data[].attributes.attachment_link.title
Predicting long-term risk of reoperations following... : International Journal of Surgery

# data[].attributes.attachment_link.description
often required, and patients have an increased risk of complications. Therefore, the aim of this study was to provide an evidence-based prediction model based on the risk of reoperation. Materials and methods: A nationwide cohort study was conducted including all patients undergoing an initial ab…

# data[].attributes.headline
Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN): Protocol for a Cross-Sectional Study

# data[].attributes.subject
Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN): Protocol for a Cross-Sectional Study

# data[].attributes.attachment_link.readable_text
Protocol

1 St Mary's Hospital, London, United Kingdom

2 Darent Valley Hospital, London, United Kingdom

3 University College London Medical School, London, United Kingdom

4 Tunbridge Wells Hospital, Kent, United Kingdom

5 Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands

6 St Georges University Hospital National Health Service Trust, London, United Kingdom

7 University of Birmingham Medical School, Birmingham, United Kingdom

8 Barts and The London School of Medicine and Dentistry, London, United Kingdom

9 South West London Elective Orthopaedic Centre, London, United Kingdom

10 University Hospital Coventry & Warwickshire, Coventry, United Kingdom

11 Imperial College London, London, United Kingdom

12 Institute of Health Sciences Education, Queen Mary University of London, London, United Kingdom

13 Barts Health National Health Service Trust, Royal London Hospital, London, United Kingdom

14 Maxillofacial Unit, Queen Alexandra Hospital, Portsmouth, United Kingdom

15 Department of Otolaryngology, Head and Neck Surgery, Cambridge University Hospitals National Health Service Foundation, Cambridge, United Kingdom

16 Department of Vascular and General Surgery, Croydon University Hospital, London, United Kingdom

17 Division of Surgery and Interventional Sciences, University College London, London, United Kingdom

*these authors contributed equally

Corresponding Author:

Maria W Georgi, BSc (Hons), MBBS

University College London Medical School

Goodge Street

London, WC1E 6BT

United Kingdom

Phone: 44 07578636123

Email: maria.georgi@icloud.com

Background: The unequal distribution of academic and professional outcomes between different minority groups is a pervasive issue in many fields, including surgery. The implications of differential attainment remain significant, not only for the individuals affected but also for the wider health care system. An inclusive health care system is crucial in meeting the needs of an increasingly diverse patient population, thereby leading to better outcomes. One barrier to diversifying the workforce is the differential attainment in educational outcomes between Black and Minority Ethnic (BME) and White medical students and doctors in the United Kingdom. BME trainees are known to have lower performance rates in medical examinations, including undergraduate and postgraduate exams, Annual Review of Competence Progression, as well as training and consultant job applications. Studies have shown that BME candidates have a higher likelihood of failing both parts of the Membership of the Royal Colleges of Surgeons exams and are 10% less likely to be considered suitable for core surgical training. Several contributing factors have been identified; however, there has been limited evidence investigating surgical training experiences and their relationship to differential attainment. To understand the nature of differential attainment in surgery and to develop effective strategies to address it, it is essential to examine the underlying causes and contributing factors. The Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN) study aims to describe and compare the factors and outcomes of attainment between different ethnicities of doctors and medical students.

Objective: The primary aim will be to compare the effect of experiences and perceptions of surgical education of students and doctors of different ethnicities.

Methods: This protocol describes a nationwide cross-sectional study of medical students and nonconsultant grade doctors in the United Kingdom. Participants will complete a web-based questionnaire collecting data on experiences and perceptions of surgical placements as well as self-reported academic attainment data. A comprehensive data collection strategy will be used to collect a representative sample of the population. A set of surrogate markers relevant to surgical training will be used to establish a primary outcome to determine variations in attainment. Regression analyses will be used to identify potential causes for the variation in attainment.

Results: Data collected between February 2022 and September 2022 yielded 1603 respondents. Data analysis is yet to be competed. The protocol was approved by the University College London Research Ethics Committee on September 16, 2021 (ethics approval reference 19071/004). The findings will be disseminated through peer-reviewed publications and conference presentations.

Conclusions: Drawing upon the conclusions of this study, we aim to make recommendations on educational policy reforms. Additionally, the creation of a large, comprehensive data set can be used for further research.

International Registered Report Identifier (IRRID): DERR1-10.2196/40545

JMIR Res Protoc 2023;12:e40545

doi:10.2196/40545

Keywords

Overview

Diversity and inclusion in the health care workforce is fundamentally important to the delivery of health care. There is strong evidence to suggest that an inclusive workforce is able to better meet the needs of a diverse patient population and leads to better patient outcomes [,]. According to the latest available data from National Health Service Digital, as of September 2021, the share of Black and Minority Ethnic (BME) staff in the National Health Service workforce in England was 24.2%, which is higher than the proportion of BME people in the general population (18%) [].

One of the current barriers to a diverse workforce is differential attainment. This is defined as "an unexplained variation in results in assessment, training, and recruitment outcomes seen in candidates based on factors other than academic ability when compared to their peers" [] and is presently observed across several important demographic characteristics, including gender, age, socioeconomic status, and ethnicity. It is well recognized that Asian and BME trainees are more likely to perform poorly in undergraduate and postgraduate medical examinations [,], Annual Review of Competence Progression, and applications for training and consultant posts [,]. A BME candidate is independently more likely to fail both part A and Part B of the Membership of the Royal Colleges of Surgeons (MRCS) examinations and 10% less likely to be deemed appointable for core surgical training [,]. Additionally, only 20% of leadership roles across the surgical colleges are held by BME surgeons [] despite BME staff making up 46% of the medical workforce []. Furthermore, BME surgeons are disproportionately more likely to be referred to the General Medical Council (22% BME vs 17% White) [].

The current understanding of causes of differential attainment is derived from thematic analyses on the barriers and issues facing BME doctors. There are several recognized factors, including curriculum and examination biases; relationships between BME trainees and trainers; a lack of support and mentorship; differences in social and cultural capital; and feelings of workplace exclusion due to microaggressions, harassment, and discrimination [-]. The Royal College of Surgeons of England's Kennedy Report specifically attributes these factors as potential barriers to the progression of equality and diversity in surgery []. This is significant as surgical training has a unique reliance on the "apprenticeship" between the trainee and the trainer, leading to potentially unique differences in the relative effect of the aforementioned factors associated with differential attainment in surgery.

Rationale for This Study

The evidence base for determining differential attainment is generated by smaller scale, qualitative studies, which have demonstrated that the experience of BME students and trainees is a factor contributing to differential attainment. However, smaller-scale studies may only capture a limited insight of the experiences of BME trainees and provide limited appreciation of the heterogeneous mix of different trainees of different ethnicities with a variety of experiences under the BME umbrella. Additionally, there is little published evidence that focuses on assessing the unique elements of the "surgical" experiences of surgical trainees, junior doctors, and medical students. This observational, multicenter study aims to compare both the experiences of surgical training between different ethnicities and the level of attainment reached. This study will ultimately aim to evaluate the relationship between educational and training experiences in surgery and attainment and analyze the role of ethnicity in this relationship.

Aims and Objectives

The ATTAIN (Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors) study aims to answer the following questions:

Are the experiences and perceptions of surgical education different between BME and non-BME medical students and junior doctors? If so, how and where are these differences seen?

In what ways are measures of attainment in surgery linked to experiences and perceptions of surgical education?

Primary Objective

The primary objective of this study is as follows:

To compare the effect of experiences and perceptions of surgical education of students and doctors of different ethnicities.

Secondary Objectives

The secondary objectives of this study are the following:

To measure potential differences in both the experiences and perceptions of surgical education of students and doctors of different ethnicities on attainment.

To identify potential factors associated with potential differences in educational experience and attainment between the aforementioned cohorts as areas of further study.

This study will consist of a 15-minute questionnaire (), which will be administered over a 28- to 32-week period. This will be distributed to every medical school and Higher Education England region.

Our population of interest consists of all medical students and nonconsultant grade doctors, including doctors in training and nontraining roles in foundation year, core or specialty trainee, as well as fellowship or staff and associate specialist (SAS) grade equivalents, with any experience of surgical training in the United Kingdom. This will be defined as any substantial period of time (being more than a total of 4 weeks) when the primary place of work or learning was (or is) in a surgical department or specialty, including but not limited to medical school rotations, assistantships, and clinical roles.

Inclusion Criteria

The following will be included in the study:

Medical students at UK medical schools, identified by the Medical Schools Council, who have self-identified as having experience of surgical training as defined above.

Anyone who has worked as a nonconsultant grade doctor (including doctors in training and nontraining roles in foundation year, core or specialty trainee, as well as fellowship or staff and SAS grade equivalents) in the United Kingdom, regardless of the country of graduation with experience of surgical training as defined above, either during medical school (if graduated in the United Kingdom) or when working as a doctor in the United Kingdom.

Exclusion Criteria

The following are excluded from the study:

Doctors or medical students who have not had either a surgical placement during medical school or experience of surgical training in the United Kingdom as defined above.

Doctors or medical students who have not either attended medical school in the United Kingdom or worked in the United Kingdom in a clinical role as a doctor.

Consultant doctors who have completed their surgical training, attained their certificate of completion of training, and are employed as a temporary or permanent consultant.

Survey Development

The survey was developed using the guidance set out in "Developing questionnaires for educational research: AMEE Guide No. 87" []. An initial literature review was conducted based on the General Medical Council's "Evaluating the impact of interventions aimed at addressing variation in progression associated with protected characteristics known as Differential Attainment" []. Expert opinion was sought from academic surgeons and medical educationalists (Katherine Woolf, PAB, SF, EI, and SV) to increase content validity. Questions were integrated from previously validated questionnaires, such as the Everyday Discrimination Scale [] and Maslach Burnout Inventory [], to increase the construct validity of our survey. A further focus group was conducted to ensure the conceptualization of our constructs matched how respondents thought of them, to increase the face validity of our questionnaire. A pilot questionnaire (N=78) was conducted to ensure reliability and to determine construct validity. This is a first of its kind cross-sectional survey; therefore, we will be using the preliminary survey with results as a comparator to assess reliability of the study. In addition, questions were based on literature and evidence-based theories that underwent peer review from established experts in this field. Our questionnaire will collect demographic data, including questions on protected characteristics such as self-defined ethnicity, socioeconomic status, gender, and grade. Data on academic attainment will consist of questions detailing a participant's achievements, including medical school decile, prizes, publications, Annual Review of Competence Progression outcomes, MRCS examination results, and specialty training application outcomes. Surgical experiences will consist of questions around the working relationships participants have with colleagues, experiences of discrimination due to ethnicity, and feelings of burnout.

Patient and Public Involvement Statement

This study will involve input of medical students and doctors of different grades. An initial survey was distributed at a national medical conference, which yielded information on topics of interest. The preliminary questionnaire was piloted among medical students and junior doctors, who gave qualitative feedback on the design of the study. The finalized questionnaire was distributed to collaborators who gave additional feedback.

Data Collection

Eligible participants will be invited to participate via web-based and in-person recruitment, including but not limited to medical school societies, medical school mailing lists, organizations focused on medical education, social media, surgical colleges, Higher Education England deaneries, and independent professional surgical bodies.

Additionally, snowball sampling will be incorporated, as eligible participants will be invited to collaborate as regional leads prior to the study period, with one collaborator per medical school or deanery. The collaborators will ensure that their medical school or training deanery is engaged with the study; they will be responsible for dissemination of the questionnaire and are recruited specifically to ensure participants are representative of their local population to prevent bias. Eligible regional leads will be acknowledged as collaborative authors under the "ATTAIN Study Group" in future publications. Participants will also be asked to share the questionnaire with other eligible colleagues.

Data Protection, Consent, and Confidentiality

The questionnaire will be hosted and stored in Jisc [], which is compliant with regulations including General Data Protection Regulation and good clinical practice guidelines (ICH E6). The research team will have access to data determined by the study lead. Audit logs are also available to provide an overview of data access and modifications. Participants will receive a participant information sheet before starting the questionnaire. Participants will give consent for publication on completion of the questionnaire; consent can be rescinded up until completion of the questionnaire for any or no reason. On completion and submission of the questionnaire, consent cannot be withdrawn, as no identifiable data are collected. If the questionnaire is not completed, data will not be collected or stored. The only personal data collected from participants is ethnicity, participants' names or email addresses will not be collected. Any data collected will only be accessed by the members of the research team at any time. Upon the completion of each questionnaire, all documentation will be stored on a secure server that will be only accessible to the chief investigator, study leads, and statistics team.

Data Analysis

Statistical Analysis

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [] guidelines for cross sectional studies will be followed. Participants will be stratified by level of training prior to analysis, and results will be presented separately. Methods of data imputation will not be used. Descriptive statistics will be presented by ethnicity. Demographic characteristics and questionnaire responses will be described by the following statistics: mean (SD), median (IQR), and frequency with proportion. All hypotheses will be tested at a 5% significance level. Differences in participant characteristics and questionnaire responses between ethnicities will be assessed using parametric and nonparametric tests, including chi-square tests, ANOVA, and Kruskal-Wallis H tests, which will be followed by multiple appropriate post hoc pairwise comparisons with Bonferroni correction. An explanatory model will be created by hierarchical multiple linear regression, with the dependent variable attainment and the following covariates: ethnicity, perceptions of surgical training, surgical experience, sex, socioeconomic status, and age. A correlation matrix will test for the presence of multicollinearity. Another possible confounding variable will be geographical location; the data will be stratified by region and examined for such an effect for those regions with a sufficient number of respondents. SPSS (version 28; IBM Corp) [] will be used for analysis. Post hoc analyses may be undertaken in the future as part of follow-up studies.

Sample Size Calculation

A priori sample size calculation was performed for a 2-tailed test of 2 independent proportions using G*Power (version 3.1.9.7; Heinrich-Heine-Universität Düsseldorf) [], based on a comparison of MRCS A pass rates between White and BME candidates. Our predicted effect size was estimated based on historical data sourced by Scrimgeour et al [] from the Intercollegiate MRCS database held by the Royal College of Surgeons of England. With α and β error probability set to .05 and .2 respectively, a minimum of 318 participants per group will be required. Broadly stratifying by level of training (eg, medical student, foundation or core trainee, and registrar or SAS grade) and dividing into BME versus non-BME, this means that 1908 participants will be required (318 × 6 = 1908).

Ethics Approval

The protocol was approved by the University College London Research Ethics Committee on September 16, 2021 (19071/004). Participants gave informed consent for their anonymized responses to be used for research purposes, including for analysis, presentation, and publication of data. There will be no compensation type for participation in the study.

Data collected between February 2022 and September 2022 yielded 1603 respondents. Data analysis is yet to be competed. The findings will be disseminated through peer-reviewed publications and conference presentations.

Overview

Impact

Understanding the combined effect of individual experiences of surgical training is important in breaking barriers and promoting change within the medical workforce, leading to a more diverse and inclusive profession. To our knowledge, this is the first study to evaluate the relationship between educational and training experiences in surgery and attainment and analyze the role of ethnicity in this relationship. Although both the presence of [-] and possible causative factors for differential attainment based on gender, ethnicity, and socioeconomic status have been demonstrated [-], a comprehensive, high-powered data set linking experience and attainment is not currently present.

Expected Impact

The ATTAIN study's findings will add value to the current body of work in differential attainment by providing further insight and context to the interaction between different causative factors. We also hope to highlight areas of excellence and areas of improvement in surgical education, directing suggestions for evidence-based changes to undergraduate and postgraduate surgical education. Our findings offer policy makers evidence-informed recommendations to improve undergraduate and postgraduate surgical education, which will guide the creation and expansion of resources that can efficiently mitigate differential attainment. As society moves to tackle systemic inequalities, we hope our study will demonstrate a commitment to achieve this within medicine and surgery.

We also hope to remind the workforce of the principles of respect that are pivotal to our duties as health care professionals. Mental well-being and burnout are key performance indicators and should be protected to drive excellence in an individual's career progression.

Limitations

One of the potential limitations of this study is the lack of prior validated questionnaires on differential attainment. It could be argued that the topic of "differential attainment" is so large that a single questionnaire would not be an appropriate method able to collect valid or reliable data. We have tried to improve the quality and rigor of our questionnaire by using a well-established methodology for questionnaire construction and incorporating elements from previously validated questionnaires that are valid for our research question. However, bias cannot be eliminated from the study. Sampling bias may occur if recruitment is limited to streams disproportionately used by one group (eg, overusing social media may attract more medical students and junior trainees). This will be minimized by using multiple communication channels, including professional bodies and trainee-led organizations. Additionally, recall bias is unavoidable in sections of the questionnaire where past achievements are recounted.

We also recognize that our research question is heavily focused on ethnicity; however, there are several different factors that are known to be independently associated with differential attainment, including gender and socioeconomic status.

Although these factors may be controlled for in the study, it may be difficult to completely account for nonlinear intersectional relationships between factors. Future research should be considered to explore the relationships between these different factors in more detail.

Conclusions

We envisage that the results of the study will provide us with an advancement in knowledge on factors that correlate to attainment and provide us with greater depth in understanding the link between attainment in surgery and experiences of surgical training. Following the results, we aim to create national guidance for independent surgical bodies to incorporate into the current strategies used to tackle the inequalities and injustices in health care.

Acknowledgments

We would like to thank and acknowledge Professor Katherine Woolf for her input into the design of the questionnaire.

This research received no specific grant from any funding agency in the public, commercial, or nonprofit sectors.

Data Availability

The data sets generated during and analyzed during this study are available from the corresponding author on reasonable request.

Authors' Contributions

IO and SB conceived the study and have contributed equally as first authors. All authors have made significant contributions to the design of the questionnaire and the protocol paper and fulfill the ICMJE (Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals) criteria for authorship.

Conflicts of Interest

None declared.

Multimedia Appendix 1

The ATTAIN (Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors" study survey.
PDF File (Adobe PDF File), 376 KB

‎

BME: Black and Minority Ethnic

MRCS: Membership of the Royal Colleges of Surgeons

SAS: staff and associate specialist

STROBE: Strengthening the Reporting of Observational Studies in Epidemiology

Edited by A Mavragani; submitted 02.07.22; peer-reviewed by S Azadnajafabad; comments to author 05.04.23; revised version received 18.04.23; accepted 03.05.23; published 16.06.23

©Samar Babiker, Innocent Ogunmwonyi, Maria W Georgi, Lawrence Tan, Sharmi Haque, William Mullins, Prisca Singh, Nadya Ang, Howell Fu, Krunal Patel, Jevan Khera, Monty Fricker, Simon Fleming, Lolade Giwa-Brown, Peter A Brennan, Ekpemi Irune, Stella Vig, Arjun Nathan. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 16.06.2023.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on https://www.researchprotocols.org, as well as this copyright and license information must be included.

Background: The unequal distribution of academic and professional outcomes between different minority groups is a pervasive issue in many fields, including surgery. The implications of differential attainment remain significant, not only for the individuals affected but also for the wider health care system. An inclusive health care system is crucial in meeting the needs of an increasingly diverse patient population, thereby leading to better outcomes. One barrier to diversifying the workforce is the differential attainment in educational outcomes between Black and Minority Ethnic (BME) and White medical students and doctors in the United Kingdom. BME trainees are known to have lower performance rates in medical examinations, including undergraduate and postgraduate exams, Annual Review of Competence Progression, as well as training and consultant job applications. Studies have shown that BME candidates have a higher likelihood of failing both parts of the Membership of the Royal Colleges of Surgeons exams and are 10% less likely to be considered suitable for core surgical training. Several contributing factors have been identified; however, there has been limited evidence investigating surgical training experiences and their relationship to differential attainment. To understand the nature of differential attainment in surgery and to develop effective strategies to address it, it is essential to examine the underlying causes and contributing factors. The Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN) study aims to describe and compare the factors and outcomes of attainment between different ethnicities of doctors and medical students.

Objective: The primary aim will be to compare the effect of experiences and perceptions of surgical education of students and doctors of different ethnicities.

Methods: This protocol describes a nationwide cross-sectional study of medical students and nonconsultant grade doctors in the United Kingdom. Participants will complete a web-based questionnaire collecting data on experiences and perceptions of surgical placements as well as self-reported academic attainment data. A comprehensive data collection strategy will be used to collect a representative sample of the population. A set of surrogate markers relevant to surgical training will be used to establish a primary outcome to determine variations in attainment. Regression analyses will be used to identify potential causes for the variation in attainment.

Results: Data collected between February 2022 and September 2022 yielded 1603 respondents. Data analysis is yet to be competed. The protocol was approved by the University College London Research Ethics Committee on September 16, 2021 (ethics approval reference 19071/004). The findings will be disseminated through peer-reviewed publications and conference presentations.

Conclusions: Drawing upon the conclusions of this study, we aim to make recommendations on educational policy reforms. Additionally, the creation of a large, comprehensive data set can be used for further research.

International Registered Report Identifier (IRRID): DERR1-10.2196/40545

JMIR Res Protoc 2023;12:e40545

doi:10.2196/40545

Keywords

Overview

Diversity and inclusion in the health care workforce is fundamentally important to the delivery of health care. There is strong evidence to suggest that an inclusive workforce is able to better meet the needs of a diverse patient population and leads to better patient outcomes [,]. According to the latest available data from National Health Service Digital, as of September 2021, the share of Black and Minority Ethnic (BME) staff in the National Health Service workforce in England was 24.2%, which is higher than the proportion of BME people in the general population (18%) [].

One of the current barriers to a diverse workforce is differential attainment. This is defined as "an unexplained variation in results in assessment, training, and recruitment outcomes seen in candidates based on factors other than academic ability when compared to their peers" [] and is presently observed across several important demographic characteristics, including gender, age, socioeconomic status, and ethnicity. It is well recognized that Asian and BME trainees are more likely to perform poorly in undergraduate and postgraduate medical examinations [,], Annual Review of Competence Progression, and applications for training and consultant posts [,]. A BME candidate is independently more likely to fail both part A and Part B of the Membership of the Royal Colleges of Surgeons (MRCS) examinations and 10% less likely to be deemed appointable for core surgical training [,]. Additionally, only 20% of leadership roles across the surgical colleges are held by BME surgeons [] despite BME staff making up 46% of the medical workforce []. Furthermore, BME surgeons are disproportionately more likely to be referred to the General Medical Council (22% BME vs 17% White) [].

The current understanding of causes of differential attainment is derived from thematic analyses on the barriers and issues facing BME doctors. There are several recognized factors, including curriculum and examination biases; relationships between BME trainees and trainers; a lack of support and mentorship; differences in social and cultural capital; and feelings of workplace exclusion due to microaggressions, harassment, and discrimination [-]. The Royal College of Surgeons of England's Kennedy Report specifically attributes these factors as potential barriers to the progression of equality and diversity in surgery []. This is significant as surgical training has a unique reliance on the "apprenticeship" between the trainee and the trainer, leading to potentially unique differences in the relative effect of the aforementioned factors associated with differential attainment in surgery.

Rationale for This Study

The evidence base for determining differential attainment is generated by smaller scale, qualitative studies, which have demonstrated that the experience of BME students and trainees is a factor contributing to differential attainment. However, smaller-scale studies may only capture a limited insight of the experiences of BME trainees and provide limited appreciation of the heterogeneous mix of different trainees of different ethnicities with a variety of experiences under the BME umbrella. Additionally, there is little published evidence that focuses on assessing the unique elements of the "surgical" experiences of surgical trainees, junior doctors, and medical students. This observational, multicenter study aims to compare both the experiences of surgical training between different ethnicities and the level of attainment reached. This study will ultimately aim to evaluate the relationship between educational and training experiences in surgery and attainment and analyze the role of ethnicity in this relationship.

Aims and Objectives

The ATTAIN (Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors) study aims to answer the following questions:

Are the experiences and perceptions of surgical education different between BME and non-BME medical students and junior doctors? If so, how and where are these differences seen?

In what ways are measures of attainment in surgery linked to experiences and perceptions of surgical education?

Primary Objective

The primary objective of this study is as follows:

To compare the effect of experiences and perceptions of surgical education of students and doctors of different ethnicities.

Secondary Objectives

The secondary objectives of this study are the following:

To measure potential differences in both the experiences and perceptions of surgical education of students and doctors of different ethnicities on attainment.

To identify potential factors associated with potential differences in educational experience and attainment between the aforementioned cohorts as areas of further study.

This study will consist of a 15-minute questionnaire (), which will be administered over a 28- to 32-week period. This will be distributed to every medical school and Higher Education England region.

Our population of interest consists of all medical students and nonconsultant grade doctors, including doctors in training and nontraining roles in foundation year, core or specialty trainee, as well as fellowship or staff and associate specialist (SAS) grade equivalents, with any experience of surgical training in the United Kingdom. This will be defined as any substantial period of time (being more than a total of 4 weeks) when the primary place of work or learning was (or is) in a surgical department or specialty, including but not limited to medical school rotations, assistantships, and clinical roles.

Inclusion Criteria

The following will be included in the study:

Medical students at UK medical schools, identified by the Medical Schools Council, who have self-identified as having experience of surgical training as defined above.

Anyone who has worked as a nonconsultant grade doctor (including doctors in training and nontraining roles in foundation year, core or specialty trainee, as well as fellowship or staff and SAS grade equivalents) in the United Kingdom, regardless of the country of graduation with experience of surgical training as defined above, either during medical school (if graduated in the United Kingdom) or when working as a doctor in the United Kingdom.

Exclusion Criteria

The following are excluded from the study:

Doctors or medical students who have not had either a surgical placement during medical school or experience of surgical training in the United Kingdom as defined above.

Doctors or medical students who have not either attended medical school in the United Kingdom or worked in the United Kingdom in a clinical role as a doctor.

Consultant doctors who have completed their surgical training, attained their certificate of completion of training, and are employed as a temporary or permanent consultant.

Survey Development

The survey was developed using the guidance set out in "Developing questionnaires for educational research: AMEE Guide No. 87" []. An initial literature review was conducted based on the General Medical Council's "Evaluating the impact of interventions aimed at addressing variation in progression associated with protected characteristics known as Differential Attainment" []. Expert opinion was sought from academic surgeons and medical educationalists (Katherine Woolf, PAB, SF, EI, and SV) to increase content validity. Questions were integrated from previously validated questionnaires, such as the Everyday Discrimination Scale [] and Maslach Burnout Inventory [], to increase the construct validity of our survey. A further focus group was conducted to ensure the conceptualization of our constructs matched how respondents thought of them, to increase the face validity of our questionnaire. A pilot questionnaire (N=78) was conducted to ensure reliability and to determine construct validity. This is a first of its kind cross-sectional survey; therefore, we will be using the preliminary survey with results as a comparator to assess reliability of the study. In addition, questions were based on literature and evidence-based theories that underwent peer review from established experts in this field. Our questionnaire will collect demographic data, including questions on protected characteristics such as self-defined ethnicity, socioeconomic status, gender, and grade. Data on academic attainment will consist of questions detailing a participant's achievements, including medical school decile, prizes, publications, Annual Review of Competence Progression outcomes, MRCS examination results, and specialty training application outcomes. Surgical experiences will consist of questions around the working relationships participants have with colleagues, experiences of discrimination due to ethnicity, and feelings of burnout.

Patient and Public Involvement Statement

This study will involve input of medical students and doctors of different grades. An initial survey was distributed at a national medical conference, which yielded information on topics of interest. The preliminary questionnaire was piloted among medical students and junior doctors, who gave qualitative feedback on the design of the study. The finalized questionnaire was distributed to collaborators who gave additional feedback.

Data Collection

Eligible participants will be invited to participate via web-based and in-person recruitment, including but not limited to medical school societies, medical school mailing lists, organizations focused on medical education, social media, surgical colleges, Higher Education England deaneries, and independent professional surgical bodies.

Additionally, snowball sampling will be incorporated, as eligible participants will be invited to collaborate as regional leads prior to the study period, with one collaborator per medical school or deanery. The collaborators will ensure that their medical school or training deanery is engaged with the study; they will be responsible for dissemination of the questionnaire and are recruited specifically to ensure participants are representative of their local population to prevent bias. Eligible regional leads will be acknowledged as collaborative authors under the "ATTAIN Study Group" in future publications. Participants will also be asked to share the questionnaire with other eligible colleagues.

Data Protection, Consent, and Confidentiality

The questionnaire will be hosted and stored in Jisc [], which is compliant with regulations including General Data Protection Regulation and good clinical practice guidelines (ICH E6). The research team will have access to data determined by the study lead. Audit logs are also available to provide an overview of data access and modifications. Participants will receive a participant information sheet before starting the questionnaire. Participants will give consent for publication on completion of the questionnaire; consent can be rescinded up until completion of the questionnaire for any or no reason. On completion and submission of the questionnaire, consent cannot be withdrawn, as no identifiable data are collected. If the questionnaire is not completed, data will not be collected or stored. The only personal data collected from participants is ethnicity, participants' names or email addresses will not be collected. Any data collected will only be accessed by the members of the research team at any time. Upon the completion of each questionnaire, all documentation will be stored on a secure server that will be only accessible to the chief investigator, study leads, and statistics team.

Data Analysis

Statistical Analysis

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [] guidelines for cross sectional studies will be followed. Participants will be stratified by level of training prior to analysis, and results will be presented separately. Methods of data imputation will not be used. Descriptive statistics will be presented by ethnicity. Demographic characteristics and questionnaire responses will be described by the following statistics: mean (SD), median (IQR), and frequency with proportion. All hypotheses will be tested at a 5% significance level. Differences in participant characteristics and questionnaire responses between ethnicities will be assessed using parametric and nonparametric tests, including chi-square tests, ANOVA, and Kruskal-Wallis H tests, which will be followed by multiple appropriate post hoc pairwise comparisons with Bonferroni correction. An explanatory model will be created by hierarchical multiple linear regression, with the dependent variable attainment and the following covariates: ethnicity, perceptions of surgical training, surgical experience, sex, socioeconomic status, and age. A correlation matrix will test for the presence of multicollinearity. Another possible confounding variable will be geographical location; the data will be stratified by region and examined for such an effect for those regions with a sufficient number of respondents. SPSS (version 28; IBM Corp) [] will be used for analysis. Post hoc analyses may be undertaken in the future as part of follow-up studies.

Sample Size Calculation

A priori sample size calculation was performed for a 2-tailed test of 2 independent proportions using G*Power (version 3.1.9.7; Heinrich-Heine-Universität Düsseldorf) [], based on a comparison of MRCS A pass rates between White and BME candidates. Our predicted effect size was estimated based on historical data sourced by Scrimgeour et al [] from the Intercollegiate MRCS database held by the Royal College of Surgeons of England. With α and β error probability set to .05 and .2 respectively, a minimum of 318 participants per group will be required. Broadly stratifying by level of training (eg, medical student, foundation or core trainee, and registrar or SAS grade) and dividing into BME versus non-BME, this means that 1908 participants will be required (318 × 6 = 1908).

Ethics Approval

The protocol was approved by the University College London Research Ethics Committee on September 16, 2021 (19071/004). Participants gave informed consent for their anonymized responses to be used for research purposes, including for analysis, presentation, and publication of data. There will be no compensation type for participation in the study.

Data collected between February 2022 and September 2022 yielded 1603 respondents. Data analysis is yet to be competed. The findings will be disseminated through peer-reviewed publications and conference presentations.

Overview

Impact

Understanding the combined effect of individual experiences of surgical training is important in breaking barriers and promoting change within the medical workforce, leading to a more diverse and inclusive profession. To our knowledge, this is the first study to evaluate the relationship between educational and training experiences in surgery and attainment and analyze the role of ethnicity in this relationship. Although both the presence of [-] and possible causative factors for differential attainment based on gender, ethnicity, and socioeconomic status have been demonstrated [-], a comprehensive, high-powered data set linking experience and attainment is not currently present.

Expected Impact

The ATTAIN study's findings will add value to the current body of work in differential attainment by providing further insight and context to the interaction between different causative factors. We also hope to highlight areas of excellence and areas of improvement in surgical education, directing suggestions for evidence-based changes to undergraduate and postgraduate surgical education. Our findings offer policy makers evidence-informed recommendations to improve undergraduate and postgraduate surgical education, which will guide the creation and expansion of resources that can efficiently mitigate differential attainment. As society moves to tackle systemic inequalities, we hope our study will demonstrate a commitment to achieve this within medicine and surgery.

We also hope to remind the workforce of the principles of respect that are pivotal to our duties as health care professionals. Mental well-being and burnout are key performance indicators and should be protected to drive excellence in an individual's career progression.

Limitations

One of the potential limitations of this study is the lack of prior validated questionnaires on differential attainment. It could be argued that the topic of "differential attainment" is so large that a single questionnaire would not be an appropriate method able to collect valid or reliable data. We have tried to improve the quality and rigor of our questionnaire by using a well-established methodology for questionnaire construction and incorporating elements from previously validated questionnaires that are valid for our research question. However, bias cannot be eliminated from the study. Sampling bias may occur if recruitment is limited to streams disproportionately used by one group (eg, overusing social media may attract more medical students and junior trainees). This will be minimized by using multiple communication channels, including professional bodies and trainee-led organizations. Additionally, recall bias is unavoidable in sections of the questionnaire where past achievements are recounted.

We also recognize that our research question is heavily focused on ethnicity; however, there are several different factors that are known to be independently associated with differential attainment, including gender and socioeconomic status.

Although these factors may be controlled for in the study, it may be difficult to completely account for nonlinear intersectional relationships between factors. Future research should be considered to explore the relationships between these different factors in more detail.

Conclusions

We envisage that the results of the study will provide us with an advancement in knowledge on factors that correlate to attainment and provide us with greater depth in understanding the link between attainment in surgery and experiences of surgical training. Following the results, we aim to create national guidance for independent surgical bodies to incorporate into the current strategies used to tackle the inequalities and injustices in health care.

# data[].attributes.attachment_link.title
Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN): Protocol for a Cross-Sectional Study

# data[].attributes.attachment_link.description
Background: The unequal distribution of academic and professional outcomes between different minority groups is a pervasive issue in many fields, including surgery. The implications of differential attainment remain significant, not only for the individuals affected but also for the wider health care system.

# data[].attributes.headline
Post-Fracture Care Program: Pharmacological Treatment of Osteoporosis in Older Adults with Fragility Fractures

# data[].attributes.subject
Post-Fracture Care Program: Pharmacological Treatment of Osteoporosis in Older Adults with Fragility Fractures

# data[].attributes.attachment_link.readable_text
Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

Papers of particular interest, published recently, have been highlighted as: * Of importance ** Of major importance

Society NAM. Management of osteoporosis in postmenopausal women: the 2021 position statement of the North American Menopause Society. Menopause. 2021;28:973-97.

Article Google Scholar

UK consensus guideline on the management of patients at low, high, and very high risk of osteoporotic fracture. Cyrus Cooper,1 Kassim Javaid,2 Mary Elliott,3 David Stephens,4 Nuttan Tanna. www.Guidelines.co.uk 2020 [ https://www.guidelines.co.uk/musculoskeletal-and-joints-/osteoporotic-fracture-guideline/455546.article] accessed on 9 th October 2022.

* El Miedany Y, Abu-Zaid MH, El Gaafary M, et al. Egyptian consensus on treat-to-target approach for osteoporosis: a clinical practice guideline from the Egyptian Academy of bone health and metabolic bone diseases. Egypt Rheumatol Rehabil. 2021;48:5. https://doi.org/10.1186/s43166-020-00056-9. A recent study for healthcare professionals involved in bone health management, which provides a comprehensive and updated approach to the assessment and treatment of osteoporosis.

Article Google Scholar

* Ayub N, Faraj M, Ghatan S, JAA R, Napoli N, Oei L. The treatment gap in osteoporosis. J Clin Med. 2021;10(13):3002. A recent study highlighting that osteoporosis treatment gap could be narrowed by improved awareness of both the patient and doctor on the risks of not receiving the treatment and the risks and benefits of osteoporotic treatment.

El Miedany Y. Recent developments towards closing the gap in osteoporosis management. Egypt Rheumatol Rehabil. 2021;48:4. https://doi.org/10.1186/s43166-020-00048-9.

Article Google Scholar

Kenwright J, Gardner T. Mechanical influences on tibial fracture healing. Clin Orthop. 1998;355(Suppl):179-90.

Article Google Scholar

Howenstein A, Wally M, Pierrie S, et al. Preventing fragility fractures: a 3-month critical window of opportunity. Geriatric Orthop Surg Rehabil. 2021:12.

International Osteoporosis Foundation. Capture of the fracture: identifying patients. https://www.capturethefracture.org/identifying-patients. Accessed 7th October 2022.

Centre for Metabolic Bone Diseases, University of Sheffield, UK. Fracture Risk Assessment Tool (FRAX). https://www.sheffield.ac.uk/FRAX/tool.aspx?country=19. Accessed 7th October 2022.

Beaudoin C, Jean S, Moore L, Gamache P, Bessette L. Ste-Marie LG (2018) Number, location, and time since prior fracture as predictors of future fracture in the elderly from the general population. J Bone Miner Res. 2019;33(11):1956-66.

Article Google Scholar

* Camacho PM, Petak SM, Binkley N, Diab DL, Eldeiry LS, Farooki A, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis: 2020 update. Endocr Pract. 2020;26(5):564-70. Recent guidelines which provided a practical tool for the diagnosis, evaluation, and treatment of postmenopausal osteoporosis.

* Shoback D, Rosen CJ, Black DM, Cheung AM, Murad MH, Eastell R. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105(3):587. Meta-analysis and primary clinical trials assessing the efficacy of romosozumab, a monoclonal antibody targeting sclerostin, for the prevention of fractures.

Article Google Scholar

Ontario Osteoporosis Strategy (2017) Provincial performance data for osteoporosis management. https://www.osteostrategy.on.ca/wp-content/uploads/Final-OP-Provincial-Performance-Status-Report-Apr-2017-1.pdf . Accessed 7th October 2022.

van der Poest CE, Patka P, Vandormael K, et al. The effect of alendronate on bone mass after distal forearm fracture. J Bone Miner Res. 2000;15:586-93.

Google Scholar

Douglas B. Muchmore, Raloxifene: a selective estrogen receptor modulator (SERM) with multiple target system effects. The Oncologist. 2000;5(5):388-92.

Article Google Scholar

Shin YH, Gong HS. Recent update in the diagnosis and treatment of bone frailty in patients with a distal radius fracture. J Hand Surg Asian Pac. 2016;21:307-12.

Article Google Scholar

AAOS updates clinical practice guideline for management of hip fractures in older adults. https://www.aaos.org/aaos-home/newsroom/press-releases/aaos-updates-clinical-practice-guideline-for-management-of-hip-fractures-in-older-adults/ accessed on 9 th October 2022.

Jachna, Carolyna; Patel, Abu T.B. Current opinion in orthopaedics: 2004;15(1):2-7.

Download references

Author information

Authors and Affiliations

Institute of Medical Sciences, Canterbury Christ Church University, Canterbury, UK

Yasser El Miedany

King's College, London, UK

Mathias Toth

Darent Valley Hospital, Kent, UK

Mathias Toth

Rheumatology, Physical Medicine and Rehabilitation, Alexandria University, Alexandria, Egypt

Walaa Elwakil

Rheumatology and Rehabilitation, Ain Shams University, Cairo, Egypt

Sally Saber

Contributions

All authors shared in the review of the literature, writing, and reviewing the manuscript.

Corresponding author

Correspondence to Yasser El Miedany.

Ethics declarations

Conflict of Interest

All authors have no financial or non-financial interests that are directly or indirectly related to the work submitted for publication to disclose.

Yasser El Miedany, Mathias Toth, Walaa Elwakil, and Sally Saber declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Mini-abstract

This review discusses recent literature regarding the clinical and pharmacological management of osteoporotic fractures, provides insight into new patterns of post-fracture care, and analyzes controversies in the current pharmacological treatment of osteoporosis in older adults with fragility fractures.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Reprints and Permissions

About this article

Cite this article

El Miedany, Y., Toth, M., Elwakil, W. et al. Post-Fracture Care Program: Pharmacological Treatment of Osteoporosis in Older Adults with Fragility Fractures. Curr Osteoporos Rep (2023). https://doi.org/10.1007/s11914-023-00791-w
Download citation

Get shareable link

Keywords

Osteoporosis

Guidelines

Fragility fractures

Low trauma fractures

Fracture hip

Fracture vertebrae

FRAX

Algorithm

Bone-Care

Bisphosphonates

Denosumab

Romosozumab

Egyptian Academy of bone health

# data[].attributes.attachment_link.title
Post-Fracture Care Program: Pharmacological Treatment of Osteoporosis in Older Adults with Fragility Fractures - Current Osteoporosis Reports

# data[].attributes.attachment_link.description
Purpose of Review To present and discuss the recently published scientific evidence on the approach, mode of action, and timing of osteoporosis therapy initiation after fragility fractures. Recent Findings A comprehensive management approach is required to reduce mortality and morbidity associated with fragility fractures.

# data[].attributes.headline
Conference Abstract - 206 Quality improvement in communication, through parent’s experience survey at neonatal intensive care unit

# data[].attributes.subject
Conference Abstract - 206 Quality improvement in communication, through parent’s experience survey at neonatal intensive care unit

# data[].attributes.attachment_link.title
206 Quality improvement in communication, through parent’s experience survey at neonatal intensive care unit

# data[].attributes.attachment_link.description
Aims Communication between parents/carers and healthcare providers in a setting of neonatal intensive care unit is crucial to reduce their emotional stress, help in decision making, engaging them in active care, while building trust and confidence in the health care services provided. To implement a…

# data[].attributes.headline
A rare case of silent Gonadotroph Adenoma presenting with secondary infertility, oligomenorrhea in a female patient with a history of polycystic ovarian syndrome

# data[].attributes.subject
A rare case of silent Gonadotroph Adenoma presenting with secondary infertility, oligomenorrhea in a female patient with a history of polycystic ovarian syndrome

# data[].attributes.attachment_link.title
A rare case of silent Gonadotroph Adenoma presenting with secondary infertility, oligomenorrhea in a female patient with a history of polycystic ovarian syndrome | SFEBES2022 | Society for Endocrinology BES 2022 | Endocrine Abstracts

# data[].attributes.attachment_link.description
Background: Gonadotroph adenomas are usually clinically non-functioning and hypersecretion of FSH or LH is unusual, and no distinct hormone-dependent clinical phenotype is present. Positive immunostaining for nuclear transcription factor SF1 is usually sufficient to diagnose gonadotroph adenoma.

# data[].attributes.headline
Conference Abstract - 2022-RA-641-ESGO A framework for managing inappropriate referral to the gynaecology rapid access clinic

# data[].attributes.subject
Conference Abstract - 2022-RA-641-ESGO A framework for managing inappropriate referral to the gynaecology rapid access clinic

# data[].attributes.attachment_link.provider_name
International Journal of Gynecologic Cancer

# data[].attributes.attachment_link.readable_text
Introduction/Background The UK National Institute for Health and Care of Excellence(NICE) has published guidance for suspected cancer referrals to help Primary Care doctors refer patients for further investigations. The threshold cancer probability for referral is set at 3%. Patients are then seen in rapid access clinics(RAC) in Secondary Care. Unfortunately, many referrals are inappropriate and this creates a burden in secondary care. These referrals also cause unnecessary anxiety to the patients. To improve the efficacy and effectiveness of the RAC, we identify inappropriate referrals and manage these patients in an alternative pathway. We provide timely feedback and education for staff working in Primary Care. Standardised letters have been developed for each type of inappropriate referral, which are sent to both the patient and the referring doctor.

Methodology A retrospective analysis of all suspected cancer referral forms sent to our unit between May 1st 2021 and April 31st 2022 was performed.

Results A total number of 958 suspected cancer referrals were made to our unit within the period of 12 months. These were triaged by a senior gynaecologist and 28% were deemed inappropriate. Of these inappropriate referrals, 15% were for suspicion of endometrial cancer, 7% were for ovarian cancer and 6% were for cervical, vulval and vaginal cancers grouped together.Breakthrough bleeding on Hormone Replacement Therapy (HRT) was the most common inappropriate referral (n=81). Other common reasons included: obviously benign lesions of the vulva, vagina and cervix, intermenstrual bleeding, postcoital bleeding, non-suspicious ovarian cysts, endometrial thickening, and isolated elevation of CA125. We have identified Primary Care doctors that are outliers and provided targeted education and training.

Conclusion We have identified common reasons for inappropriate referral and created an alternative pathway for these patients. Targeted education has been provided for Primary Care doctors. These measures have enabled the RAC to function more effectively.

# data[].attributes.attachment_link.title
2022-RA-641-ESGO A framework for managing inappropriate referral to the gynaecology rapid access clinic

# data[].attributes.attachment_link.description
Introduction/Background The UK National Institute for Health and Care of Excellence(NICE) has published guidance for suspected cancer referrals to help Primary Care doctors refer patients for further investigations. The threshold cancer probability for referral is set at 3%. Patients are then seen in rapid access clinics(RAC) in Secondary Care.

# data[].attributes.attachment_link.readable_text
Philip Canning Farrant was born in Bristol. He was a medical student at Bristol when he met Rosemary. They married and had four children, one of whom (the author of this obituary) is a doctor. Five of their 14 grandchildren are doctors.

After his house jobs, Philip worked as a pathologist in the Royal Army ...

# data[].attributes.attachment_link.description
Philip Canning Farrant was born in Bristol. He was a medical student at Bristol when he met Rosemary. They married and had four children, one of whom (the author of this obituary) is a doctor. Five of their 14 grandchildren are doctors. After his house jobs, Philip worked as a pathologist in the Royal Army ...

# data[].attributes.headline
How to make the most out of your dermatology placement

# data[].attributes.subject
How to make the most out of your dermatology placement

# data[].attributes.attachment_link.readable_text
Anisha Bandyopadhyay , foundation year 1 doctor 1,

Khawar Hussain , specialist registrar in dermatology 2

1Darent Valley Hospital, Dartford and Gravesham NHS Trust, Dartford, Kent, UK

2Chelsea and Westminster Hospital NHS Foundation Trust

Correspondence to: anisha.bandyopadhyay{at}nhs.net

Dermatology is the study of skin, hair, and nails-the skin being the largest organ of the human body. With more than 2000 conditions included in the specialty of dermatology, unsurprisingly dermatological diseases are the most common presentations in general practice.1 Dermatology overlaps with most medical and surgical specialties because skin, hair, and nails can provide helpful clues to diagnoses in paediatrics, ophthalmology, plastic surgery, and ear, nose, and throat, as well as in psychiatry, given the massive psychological impact skin conditions can have on mental health. Medical students need to be competent in basic dermatological skills regardless of their future specialty.

Undergraduate training provides limited exposure to dermatology,2 with the average placement for just one week.3 If you are fortunate to have a dermatology placement during medical school, you should optimise your time and prepare for diverse learning environments such as wards, surgical theatres, and clinics, both generalised and specialised.

This article aims to guide students on what to expect and how to prepare for, and make the most out of, a dermatology placement.

Before placement

Time and experience are needed to develop a good knowledge of the breadth and depth of dermatology. An understanding of normal skin physiology is important to appreciate what happens when skin becomes diseased. Before a placement begins, revise the anatomy of the skin and adnexa and familiarise yourself with common conditions (box 1). This will solidify your learning and maximise your ability to participate during clinical discussions with dermatologists. Make sure you are comfortable with how to obtain a dermatological focused history, perform an examination, and communicate the findings (box 2).

RETURN TO TEXT

# data[].attributes.attachment_link.title
How to make the most out of your dermatology placement

# data[].attributes.attachment_link.description
Dermatology is the study of skin, hair, and nails-the skin being the largest organ of the human body.

# data[].attributes.headline
Understanding Patients’ Experiences and Perspectives of Tele-Prehabilitation: A Qualitative Study to Inform Service Design and Delivery

# data[].attributes.subject
Understanding Patients’ Experiences and Perspectives of Tele-Prehabilitation: A Qualitative Study to Inform Service Design and Delivery

# data[].attributes.attachment_link.readable_text
General Surgery, Darent Valley Hospital, Dartford DA2 8DA, UK

Kent and Medway Prehab, Phase B CIC, London E1 6RA, UK

Author to whom correspondence should be addressed.

1. Introduction

Unhealthy lifestyle behaviours (e.g., physical inactivity, poor nutrition, smoking, and harmful levels of alcohol consumption) are risk factors for perioperative morbidity and complications [ 1]. Modifying these risk factors in acute settings can enhance an individual's functional capacity and, therefore, improve their physical function and reduce their risk of developing postoperative complications [ 2]. In the longer term, it is important that ongoing health promotion plays a role within the cancer care continuum [ 3]. The ramifications of cancer treatment can continue to have a detrimental effect on patients' quality of life, leading to disability and reduced occupational or household productivity [ 4]. For these reasons, it is important for healthcare professionals and patients to understand that cancer is understood as both an acute illness and one with long-term ill-health consequences.

The time of cancer diagnosis may offer a window of opportunity to encourage patients to change unhealthy lifestyle behaviours when they may be more receptive to change [ 5]. Behaviour change may only be transient depending on the strength of the motivating factors. Individuals may only change behaviours in the immediate period before surgery for perioperative benefit or make sustained healthier lifestyle changes to better their long-term general health [ 6, 7]. Prehabilitation is a behaviour change intervention for patients to participate in their preoperative care [ 8, 9]. This intervention is aimed at optimising an individual's physical functionality and psychological wellbeing before surgery to maintain a normal level of function during and after their treatment [ 10]. Prehabilitation promotes and facilitates healthier lifestyle changes by modifying behavioural patterns [ 11]. Tele-prehabilitation is an innovative service in delivering prehabilitation interventions in a telecommunication format [ 12]. Our tele-prehabilitation service was adopted at the start of the COVID-19 pandemic and was expected to provide a sustainable solution to the lockdown restrictions placed during the pandemic [ 13].

Despite the advertised potential benefits of prehabilitation, not all patients offered our service choose to engage [ 14, 15]. Gaining a better understanding of the actions that underline and influence cancer patients' behaviours is an important step to developing an effective and evidence-based prehabilitation programme. Guidance from the U.K. Medical Research Council recommends that the development of interventions should be based on evidence and theory [ 16]. A service that is evidenced in behavioural change theory may result in more effective uptake, improve adherence, and greater satisfaction. The capability, opportunity, motivation, and behaviour (COM-B) model of behaviour change is a theoretical framework that has been used to design and better understand behaviour change interventions [ 17]. The COM-B model recognises that there are three components to any behaviour change, and all three components must be met for an individual to perform a particular behaviour. The COM-B model proposes that the person (1) needs to have the psychological and physical capability to perform the behaviour, (2) the physical and social opportunity to engage in it, and (3) must be motivated to engage [ 18, 19].

The COM-B model has been successfully applied to a variety of health behaviours [ 20, 21]. Few researchers have investigated patients' experiences and needs of tele-prehabilitation using the COM-B model [ 22, 23, 24]. The present study was conducted to evaluate our service by exploring our patients' capabilities, opportunities, and motivations to participating in our tele-prehabilitation service. The themes identified from these interviews were mapped to the COM-B model. The COM-B model was chosen over other health behaviour theories because it has the complexity to guide our understanding of a particular behaviour of interest (e.g., participating in prehabilitation). This allows for the identification of the sources of behaviour, and it can be used to identify the barriers and facilitators to behaviour change. Understanding the determinants of behaviour change is important to developing effective interventions. The findings from this study allow us to identify recommendations for service redesign and delivery and to widen participation and improve uptake into our tele-prehabilitation programme. The aim of this study was to qualitatively explore our patients' experiences and perspective of tele-prehabilitation, which enabled them to engage in tele-prehabilitation, using the COM-B model of behaviour change.

2. Materials and Methods

2.1. Study Design

We conducted a descriptive qualitative study using individual, semistructured interviews with our past participants. A qualitative research method was chosen as it best captured our patients' personal accounts of their care. We applied the COM-B model to explore our patients' experiences and perspectives of tele-prehabilitation to enable us to better understand their behaviours for participating. Individual interviews were chosen over focus groups for two reasons: (1) not all patients would feel comfortable discussing weight management and diet in front of others and (2) rapport can be built in one-to-one interviews encouraging individuals to discuss more sensitive topics. Quantitative data on patient demographics were collected to provide context and to aid the transferability of our qualitative findings.

2.2. Participants

This was a follow-up of patients that had enrolled and completed a structured tele-prehabilitation programme from May 2020 to June 2021. This study formed part of our service evaluation into our tele-prehabilitation programme. Eligible patients were: (1) adults (≥18 years) with a new diagnosis of cancer, (2) able to converse in English, (3) had participated in our tele-prehabilitation programme, and (4) were based in the community (i.e., had been discharged from the hospital following surgery). The exclusion criteria included declining to participate in tele-prehabilitation and failure to complete the programme. Patients were recruited from across the southeast region of England from multiple oncological disciplines. Potential interview candidates were identified and invited to participated by a prehabilitation instructor and a consultant in perioperative care.

The sample included 22 patients who were recruited using purposive sampling. Purposive sampling ensures perspectives from a variety of demographics and can produce patterns across the different groups to be identified. A sample size of 22 patients was deemed sufficient to support the data and provide a variety of patient experiences. Furthermore, we determined the sample size when the concept of information power was achieved. Information power is based on the principle that the more information the sample holds; the fewer the participants are needed [ 25, 26]. Thematic saturation is reached when no new themes are generated from the analysis. This was achieved after 22 interviews; therefore, recruitment was ceased.

2.3. Ethical Considerations

We consulted the NHS Research Ethics Committee, which stated that no formal approval was required for this study as it was considered a service evaluation. Data were based on the assessment of service delivery, and we were looking to evaluate a community tele-prehabilitation programme that required participants to self-refer. We were evaluating the standard of our service and whether it was meeting the needs of the individuals who chose to participate.

All patients received information about the service evaluation, and they were informed that they could withdraw at any time. Patients provided informed consent to participate in tele-prehabilitation and for their data to be used in the assessment of our service design and delivery. The study was conducted according to the ethical statements of the Declaration of Helsinki.

2.4. Prehabilitation

Our prehabilitation service is community-based and delivered through telecommunication methods (termed tele-prehabilitation) [ 12]. This format has enabled us to provide equitable access across the county. We receive referrals across the southeast region of England from nine acute National Health Service (NHS) Trusts. We provide our patients a multimodal intervention comprising of four key components: (1) a personalised exercise programme, (2) education on nutrition and healthy eating, (3) support and advice on smoking cessation and alcohol reduction, and (4) counselling (including cognitive behavioural therapy). The approach was developed by a core team of professionals, including an anaesthetist, a general practitioner (GP), exercise physiologists, counsellors, public health and wellbeing leads, and public health support staff, with feedback from a patient steering group.

2.5. Data Collection

We conducted 30 min semistructured interviews with patients who had completed tele-prehabilitation within 3 to 12 months. Interviews were conducted over the phone or via videoconference call according to patient preference with a member of the research team. The interviewer introduced the service evaluation and confirmed patient consent to participate. The interview questions were developed with input from our multidisciplinary team. These questions involved gathering information on their experiences and perceptions of prehabilitation. An interview guide was used to direct the interview toward specific topics ( Table 1). A semistructured interview guide steered discussions to cover the three components of the COM-B model. It consisted of open-ended questions to build an understanding of the capability, opportunity, and motivation components needed to facilitate a behaviour change (i.e., engage with tele-prehabilitation and adhere to our intervention recommendations). The interviewer used prompts and probing as appropriate to elicit more in-depth responses to the questions.

2.6. Data Analysis

The interviews were recorded and transcribed verbatim by colleagues from both the public health and research teams, and all data were de-identified. The study was conducted in accordance with the principles of the Declaration of Helsinki. Interview transcriptions were analysed to identify themes and conceptual categories. A deductive approach was taken to explore themes that aligned with the COM-B model.

The Braun and Clarke method for thematic analysis was applied for data analysis [ 27].The transcribed data were read multiple times to develop familiarity. Data segments that were relevant to the aim of the study were coded. Codes were grouped together to identify patterns and generate themes. Themes were reviewed and defined according to the categories of the COM-B model's determinants of health behaviour change: capability, opportunity, and motivation. Analysis was manually performed using Microsoft Word (Microsoft Inc., Redmond, WA, USA).

3. Results

3.1. Patient Characteristics

We invited 22 patients to take part in the interviews, and all agreed to be interviewed. The male-to-female patient ratio was even. The median age of our patient was 66 years (range 42 to 83 years). Most the patients self-identified as White British and had a colorectal cancer diagnosis. Patients beyond the county were able to participate in our programme. Patient demographics and characteristics are outlined in Table 2.

3.2. Overview of Themes

Patients provided key insights based on their experiences and perspectives that impacted their capabilities, opportunities, and motivations to participate in tele-prehabilitation ( Table 3). The initial coding framework was organised into three categories according to the components of the COM-B model: patients' (1) capabilities, (2) opportunities, and (3) motivations to participate in our service.

3.2.1. Component 1. Patients' Capabilities to Participate

Theme 1.1. Information and Knowledge

As prehabilitation is relatively new, most of our patients did not have the abilities to participate because they were unaware of the programme before their cancer diagnosis. Patients often did not know what support was locally available to them. Many only heard about the service from other healthcare professionals (e.g., their oncologist, surgeon, or cancer nurse specialist) or word of mouth from other cancer patients promoting our programme when seeking for support after their diagnosis.

They described the interactions with members of the prehabilitation team as key facilitators in their ability to participate. A few patients felt unsupported from their hospital care and sought support from our team. This was particularly welcome during the period when COVID-19 lockdown restrictions were in place and patients were advised to socially distance. The regular interactions served as an opportunity to build a rapport with their prehabilitation professional, lessening feelings of social isolation. Patients spoke positively about their initial encounter with a member of the prehabilitation team. They felt well-informed about the programme. Information was provided in pieces and in a way that was easy to understand and absorb.

3.2.2. Component 2. Patients' Opportunities to Participate

Theme 2.1. Convenience of Tele-Prehabilitation

A prominent theme highlighted during the interviews was the convenience of tele-prehabilitation. Patients appreciated that tele-prehabilitation provided an alternative solution during the COVID-19 lockdown restrictions. For some patients, the remote delivery of a home-based programme provided a degree of flexibility and convenience to enable them to incorporate exercise into their daily routines and around their work or personal commitments. In addition, they agreed that some individuals may not have access to hospital transport (e.g., prohibited by the cost of public transport or hospital parking) or had time constraints.

Theme 2.2. Widening Accessibility

The patients appreciated that the tele-prehabilitation programme has the potential to widen accessibility. Some patients mentioned that the provision of telehealth allowed them to access the service when, typically, it would geographically fall outside of their catchment area. Furthermore, a few patients would have been unable to travel to in-centre appointments because of their physical limitations. Their physical symptoms (e.g., pain, poor mobility, or diarrhoea) would have restricted them from participating in the in-centre supervised sessions.

Moreover, a few patients with psychological issues (e.g., anxiety or overthinking) would have found it difficult to attend prehabilitation sessions in a hospital setting. They mentioned that hospital visits and clinical interactions with hospital staff heightened their levels of anxiety and created stress as they were associated with receiving bad news and it would have been a barrier for them to attend in-centre prehabilitation.

3.2.3. Component 3. Patients' Motivations to Participate

Theme 3.1. Health Outcomes

A prominent theme was the emotional response to receiving a cancer diagnosis. Patients were motivated to modify their lifestyle to optimise their health as a result of this new diagnosis. In acute settings, all the patients believed that participation in our service would enable them to withstand the adverse consequences of their cancer treatment, leading to better health outcomes and quicker recovery. A few patients felt concerned about their health given the diagnosis and were motivated to change to beat their disease. Some perceived prehabilitation to be a core component of their cancer treatment. Others reported general long-term health-related reasons as a motivation to adopt a healthier lifestyle, including reducing the risk of chronic diseases (e.g., cardiovascular disease and diabetes) and improving their quality of life.

" You've got to keep your body physically fit... So, if you do have to have aggressive treatment or surgery, then you're more likely to recover from it."

(Woman, 66 years, did not disclose diagnosis)

Theme 3.3. Patient-Professional Relationship

Patients said the availability of support from the prehabilitation team helped to track their progress and maintain engagement. Patients had regular one-to-one interactions with a member of the prehabilitation team, enabling them to build trust and rapport. The weekly or biweekly phone calls served as an opportunity to set goals, and encourage and reinforce healthy behaviours. The positive interactions between the patient and their prehabilitation professional facilitated healthier behaviour changes.

The prehabilitation team emphasised the use of monitoring, plans and goals. Many patients often monitored their exercises and diet and set their own goals. They were motivated to achieve their goals to return to their normal routines after finishing their cancer treatment.

Theme 3.4. Positive Mindset

Many patients had a positive mindset toward their health outcomes and disease. They perceived this positive mindset as a motivation to engage with our intervention programme and to cope with their disease and recovery.

" The advice that I had from (prehabilitation professional), and the counselling I got, certainly put me in a more positive mental attitude, a positive emotional attitude, but also helped me physically to be in the right place as well."

(Man, 62 years, colorectal cancer)

4. Discussion

In this study, we sought to understand the experiences and perspectives of our tele-prehabilitation programme amongst a diverse group of patients living with cancer as part of our service evaluation. Understanding these is an important element of a patient-centred approach as they will influence their decision to engage with our service. The diagnosis of cancer is a life-changing event that offers a teachable moment and an opportunity for behaviour change [ 28]. These behaviour changes may only be transient in the absence of a support programme. It is important that our tele-prehabilitation service is modelled on theories of behavioural change to enhance uptake. Here, we provide several key recommendations for service redesign and delivery based on our findings.

Our study provides the insight that prehabilitation can promote an element of self-efficacy. Self-efficacy is an important concept: it refers to an individual's belief to whether they can perform a challenging task under specific circumstances [ 29]. At the start of the intervention, our exercise physiologists collaborated with each patient to establish personalised goals. Achieving these goals produced feelings of success and empowerment in the patients. In turn, this developed their confidence to believe they had the physical and psychological capabilities to continue making positive behaviour changes. A study looking at oesophageal cancer patients found a correlation between self-efficacy and better health outcomes and improved quality of life [ 30]. Prehabilitation must promote self-efficacy for this reason. We recommend the following aspects to consider when designing a prehabilitation service: (1) the plans need to be personalised, (2) patients should be taught the necessary skills to self-manage their health, and (3) the goal should be appropriate and attainable according to each patient.

A prominent theme extracted from the analysis was the convenience and accessibility of our tele-prehabilitation service. This approach to delivering prehabilitation can address some of the recruitment issues highlighted in previous studies [ 14, 15]. Before COVID-19, our patients had to rely on travelling to the hospital for scheduled prehabilitation appointments. The studies examining the feasibility of in-centre prehabilitation showed that the commonest barriers to engagement are occupational or household commitments and patient unwillingness, or inability, to travel to the hospital. Patients welcomed the flexibility of our tele-prehabilitation service adaptation in this study. Patients did not need to travel, enabling those with a lack of access to hospital transport or those living outside of the region to participate. Patients were able to engage in our intervention in the safety and comfort of their own home, which may have facilitated engagement for some patients with physical limitations or those suffering with hospital anxiety. The inflexibility of in-centre prehabilitation, due to the fixed timing and locations, may limit recruitment and service uptake. Studies examining the adherence of exercise training interventions during chemotherapy amongst breast cancer patients concluded that convenience is a positive predictor for adherence [ 31, 32]. Furthermore, a review looking at the cost-effectiveness of telemedicine showed that this method of delivering healthcare has the potential to reduce costs [ 33]. Tele-prehabilitation can provide cost-saving benefits to patients (e.g., costs for fuel or hospital parking, childcare, and gym memberships). The financial cost of attending in-centre prehabilitation may be a barrier for engagement for some patients. For these reasons, tele-prehabilitation can play a role in widening participation and provide the opportunity for patients who may have previously declined to take part in prehabilitation to engage.

A disadvantage of tele-prehabilitation is the missed opportunity for peer support. Our tele-prehabilitation patients often sought support and advice from other cancer patients through online patient forums. Patients felt in-centre prehabilitation would provide opportunities to meet other patients, enabling them to share their experiences and to give or receive advice. Oesophageal cancer patients found peer support was important to minimising feelings of isolation and providing coping advice that could not be provided by friends or family [ 34, 35]. Bringing patients together to discuss shared experiences can create a sense of shared identity and social belonging [ 36, 37]. Peer support programmes can provide both educational and emotional benefits [ 38]. It is imperative that we incorporate these findings to improve the quality of our service to produce better patient outcomes and experiences for future participants. We envisage that the redesign of our service will include a combination of remote delivery for the convenience and in-centre sessions to allow patients to come together to share their own lived-in experiences. In addition, we anticipate that there will be a cohort of patients that will prefer to meet other patients remotely; therefore, we have created an online peer support forum for patients to discuss their own experiences.

Our patients identified several motivations for engaging in prehabilitation, including cancer outcomes, support from friends and family, and the rapport developed with their prehabilitation professional. A recurring theme motivating patients to participate in prehabilitation was their ability to change the course of their recovery. Patients believed prehabilitation would enable them to withstand the consequences of their treatment and recover quicker. All our patients reported a favourable attitude toward participating in prehabilitation to change their health behaviours for immediate perioperative benefit. Our finding is in keeping with that of a study that explored patients' attitudes toward behaviour change interventions. Their cohort of patients were more motivated to change for perioperative benefit than for long-term health gains [ 7, 39]. Prehabilitation can be a teachable moment to positively influence patients to change their unhealthy lifestyle behaviours [ 28]. We recommend that prehabilitation is introduced at the start of the patients' cancer diagnoses; patients are more likely to be motivated to participate, and in turn, this can maximise their health outcomes.

The application of the COM-B model provided a starting point to better understand the barriers and facilitators to participating in tele-prehabilitation. It highlights three distinct explanatory components and the potential influences on behaviour change. We found that our patients' experiences with tele-prehabilitation were mostly positive, which in turn impacted their capabilities, opportunities, and motivations to participate. We provided several recommendations for service improvement from this study. Furthermore, we recommend incorporating prehabilitation within Public Health England's strategy for people with newly diagnosed cancer and cancer survivors [ 40]. The established integrated care systems may help contribute toward the United Kingdom's Cancer Prevention Strategy.

Limitations

We aimed to recruit a sample who we deemed would be most representative of the patients that would participate in our programme with our purposive sampling strategy. However, this nonprobability sampling had the potential to introduce selection bias. The age range of our study population was wide; our interviewees ranged from 42 to 83 years old. This was reflected in our study population, who were older by default, because the incidence rates for all cancers combined are highest amongst the older population [ 41]. In 2016-2018, more than one-third of new cancer cases were diagnosed in people aged 75 year and over in the United Kingdom. The highest incidence rates were observed in those aged between 85 and 89 years old.

The patients self-selected to participate in the programme, which suggests that they may have already had an element of self-efficacy and motivation to participate in behaviour change interventions. Patients' responses were dependent on their personal recall of their own experiences, which may not be representative of our population or generalisable to other settings. The nature of the questions may have influenced the answers provided. We had a small sample size. A consideration in future studies may be to interview patients who declined to engage with our service. Understanding their experiences and perceptions for nonparticipation would add value to our service evaluation and provide a broader perspective for intervention development. Furthermore, there was an element of observer bias.

5. Conclusions

Our findings provided insight into the factors important for designing behaviour change intervention services. Patients' positive experiences with tele-prehabilitation impacted their capabilities, opportunities, and motivations to participate. Understanding behaviour change theories and applying them in practice has the potential to yield effective interventions.

Wu F, Laza-Cagigas R, Rampal T. Understanding Patients' Experiences and Perspectives of Tele-Prehabilitation: A Qualitative Study to Inform Service Design and Delivery. Clinics and Practice. 2022; 12(4):640-652. https://doi.org/10.3390/clinpract12040067

Chicago/Turabian Style

Wu, Fiona, Roberto Laza-Cagigas, and Tarannum Rampal. 2022. "Understanding Patients' Experiences and Perspectives of Tele-Prehabilitation: A Qualitative Study to Inform Service Design and Delivery" Clinics and Practice 12, no. 4: 640-652. https://doi.org/10.3390/clinpract12040067

# data[].attributes.attachment_link.title
Understanding Patients' Experiences and Perspectives of Tele-Prehabilitation: A Qualitative Study to Inform Service Design and Delivery

# data[].attributes.attachment_link.description
Background: Tele-prehabilitation is a behaviour change intervention that facilities the modification of unhealthy lifestyle behaviours. Understanding patients' experiences of tele-prehabilitation provides important insights into service improvement. In this study, we aimed to describe our patients' perceptions of tele-prehabilitation and capture their capabilities, opportunities, and motivations to participate.

# data[].attributes.headline
Rare paediatric cardiopulmonary presentation of Behcet’s disease

# data[].attributes.subject
Rare paediatric cardiopulmonary presentation of Behcet’s disease

# data[].attributes.attachment_link.readable_text
Abstract

This case discusses a 10-year-old boy who presented in significant respiratory distress with cardiac tamponade with associated gross ascites and hepatomegaly, requiring urgent transfer for pericardiocentesis. On further investigation, he was found to have multiple pulmonary emboli and evidence of panserositis. An underlying rheumatological cause was suspected in the absence of any evidence of infection or malignancy, and blood tests were positive for anti-double stranded DNA, anticardiolipin and antiglycoprotein antibodies as well as HLA B51. In his medical history, he has previously had mouth ulcers, chronic anaemia of undetermined cause and erythema multiforme. These symptoms, along with clinical presentation, mean a diagnosis of Behcet's disease and associated antiphospholipid syndrome was felt to be most likely. Anticoagulation therapy was commenced for treatment of the emboli, and colchicine was started for management of Behcet's disease. The patient was discharged clinically well from the hospital and continues under specialist rheumatological and haematological follow-up.

pericardial disease

paediatric intensive care

vasculitis

cardiovascular medicine

rheumatology

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center's RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Read the full text or download the PDF:

# data[].attributes.attachment_link.title
Rare paediatric cardiopulmonary presentation of Behcet's disease

# data[].attributes.attachment_link.description
This case discusses a 10-year-old boy who presented in significant respiratory distress with cardiac tamponade with associated gross ascites and hepatomegaly, requiring urgent transfer for pericardiocentesis. On further investigation, he was found to have multiple pulmonary emboli and evidence of panserositis.

# data[].attributes.headline
The Emotional Impact of Novel Coronavirus on Healthcare Workers: A Cross-Sectional Study

# data[].attributes.subject
The Emotional Impact of Novel Coronavirus on Healthcare Workers: A Cross-Sectional Study

# data[].attributes.headline
An Updated Analysis of Clinical Outcome Measures Across Patients From the UK Medical Cannabis Registry

# data[].attributes.subject
An Updated Analysis of Clinical Outcome Measures Across Patients From the UK Medical Cannabis Registry

# data[].attributes.attachment_link.description
If the address matches an existing account you will receive an email with instructions to reset your password.

# data[].attributes.headline
Conference Abstract - POS0734 - Analysis of improvement in giant cell arteritis: defining thresholds for GCA-response

# data[].attributes.subject
Conference Abstract - POS0734 - Analysis of improvement in giant cell arteritis: defining thresholds for GCA-response

# data[].attributes.headline
Conference Abstract - POS0215 - Classic versus atypical Polymyalgia Rheumatica: two sides of the same coin of misclassification?

# data[].attributes.subject
Conference Abstract - POS0215 - Classic versus atypical Polymyalgia Rheumatica: two sides of the same coin of misclassification?

# data[].attributes.headline
Conference Abstract - POS0494 - Development and validation of a questionnaire for pre-romosozumab therapy screening

# data[].attributes.subject
Conference Abstract - POS0494 - Development and validation of a questionnaire for pre-romosozumab therapy screening