Publications by authors named "Thomas M Drake"

48 Publications

Prospective validation of the 4C prognostic models for adults hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol.

Thorax 2021 Nov 22. Epub 2021 Nov 22.

Respiratory Department, Imperial College, London, UK.

Purpose: To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19.

Methods: Prospective observational cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups.

Results: 76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, -0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions.

Conclusion: Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making.

Trial Registration Number: ISRCTN66726260.
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http://dx.doi.org/10.1136/thoraxjnl-2021-217629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610617PMC
November 2021

Remote diagnosis of surgical-site infection using a mobile digital intervention: a randomised controlled trial in emergency surgery patients.

NPJ Digit Med 2021 Nov 18;4(1):160. Epub 2021 Nov 18.

Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh, UK.

Surgical site infections (SSI) cause substantial morbidity and pose a burden to acute healthcare services after surgery. We aimed to investigate whether a smartphone-delivered wound assessment tool can expedite diagnosis and treatment of SSI after emergency abdominal surgery. This single-blinded randomised control trial (NCT02704897) enroled adult emergency abdominal surgery patients in two tertiary care hospitals. Patients were randomised (1:1) to routine postoperative care or additional access to a smartphone-delivered wound assessment tool for 30-days postoperatively. Patient-reported SSI symptoms and wound photographs were requested on postoperative days 3, 7, and 15. The primary outcome was time-to-diagnosis of SSI (Centers for Disease Control definition). 492 patients were randomised (smartphone intervention: 223; routine care: 269). There was no significant difference in the 30-day SSI rate between trial arms: 21 (9.4%) in smartphone vs 20 (7.4%, p = 0.513) in routine care. Among the smartphone group, 32.3% (n = 72) did not utilise the tool. There was no significant difference in time-to-diagnosis of SSI for patients receiving the intervention (-2.5 days, 95% CI: -6.6-1.6, p = 0.225). However, patients in the smartphone group had 3.7-times higher odds of diagnosis within 7 postoperative days (95% CI: 1.02-13.51, p = 0.043). The smartphone group had significantly reduced community care attendance (OR: 0.57, 95% CI: 0.34-0.94, p = 0.030), similar hospital attendance (OR: 0.76, 95% CI: 0.28-1.96, p = 0.577), and significantly better experiences in accessing care (OR: 2.02, 95% CI: 1.17-3.53, p = 0.013). Smartphone-delivered wound follow-up is feasible following emergency abdominal surgery. This can facilitate triage to the appropriate level of assessment required, allowing earlier postoperative diagnosis of SSI.
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http://dx.doi.org/10.1038/s41746-021-00526-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602321PMC
November 2021

Acute kidney injury in patients hospitalised with COVID-19 from the ISARIC WHO CCP-UK Study: a prospective, multicentre cohort study.

Nephrol Dial Transplant 2021 Oct 18. Epub 2021 Oct 18.

Roslin Institute, University of Edinburgh, Edinburgh, UK.

Background: Acute kidney injury (AKI) is common in COVID-19. This study investigated adults hospitalised with COVID-19 and hypothesised that risk factors for AKI would include co-morbidities and non-white race.

Methods: A prospective multicentre cohort study was performed using patients admitted to 254 UK hospitals with COVID-19 between January 17th 2020 and December 5th 2020.

Results: Of 85,687 patients, 2,198 (2.6%) received acute kidney replacement therapy (KRT). Of 41,294 patients with biochemistry data, 13,000 (31.5%) had biochemical AKI: 8,562 stage 1 (65.9%), 2,609 stage 2 (20.1%) and 1,829 stage 3 (14.1%). The main risk factors for KRT were chronic kidney disease (CKD: Adjusted odds ratio (aOR) 3.41: 95% confidence interval 3.06-3.81), male sex (aOR 2.43: 2.18-2.71) and black race (aOR 2.17: 1.79-2.63). The main risk factors for biochemical AKI were admission respiratory rate >30 breaths per minute (aOR 1.68: 1.56-1.81), CKD (aOR 1.66: 1.57-1.76) and black race (aOR 1.44: 1.28-1.61). There was a gradated rise in the risk of 28-day mortality by increasing severity of AKI: stage 1 aOR 1.58 (1.49-1.67); stage 2 aOR 2.41 (2.20-2.64); stage 3 aOR 3.50 (3.14-3.91); KRT aOR 3.06 (2.75-3.39). AKI rates peaked in April 2020 and the subsequent fall in rates could not be explained by the use of dexamethasone or remdesivir.

Conclusions: AKI is common in adults hospitalised with COVID-19 and it is associated with a heightened risk of mortality. Although the rates of AKI have fallen from the early months of the pandemic, high-risk patients should have their kidney function and fluid status monitored closely.
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http://dx.doi.org/10.1093/ndt/gfab303DOI Listing
October 2021

Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility.

Hepatology 2021 Oct 15. Epub 2021 Oct 15.

Centre for Medical Informatics, Usher Institute, University of Edinburgh.

Background & Aims: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.

Approach & Results: We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases,506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P < 5 * 10 ), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.

Conclusions: This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
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http://dx.doi.org/10.1002/hep.32199DOI Listing
October 2021

Genome-Wide Association Study of NAFLD Using Electronic Health Records.

Hepatol Commun 2021 Sep 17. Epub 2021 Sep 17.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edingburgh, Scotland.

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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http://dx.doi.org/10.1002/hep4.1805DOI Listing
September 2021

The long-term sequelae of COVID-19: an international consensus on research priorities for patients with pre-existing and new-onset airways disease.

Lancet Respir Med 2021 Dec 17;9(12):1467-1478. Epub 2021 Aug 17.

Population Health Science Institute, NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle, UK. Electronic address:

Persistent ill health after acute COVID-19-referred to as long COVID, the post-acute COVID-19 syndrome, or the post-COVID-19 condition-has emerged as a major concern. We undertook an international consensus exercise to identify research priorities with the aim of understanding the long-term effects of acute COVID-19, with a focus on people with pre-existing airways disease and the occurrence of new-onset airways disease and associated symptoms. 202 international experts were invited to submit a minimum of three research ideas. After a two-phase internal review process, a final list of 98 research topics was scored by 48 experts. Patients with pre-existing or post-COVID-19 airways disease contributed to the exercise by weighting selected criteria. The highest-ranked research idea focused on investigation of the relationship between prognostic scores at hospital admission and morbidity at 3 months and 12 months after hospital discharge in patients with and without pre-existing airways disease. High priority was also assigned to comparisons of the prevalence and severity of post-COVID-19 fatigue, sarcopenia, anxiety, depression, and risk of future cardiovascular complications in patients with and without pre-existing airways disease. Our approach has enabled development of a set of priorities that could inform future research studies and funding decisions. This prioritisation process could also be adapted to other, non-respiratory aspects of long COVID.
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http://dx.doi.org/10.1016/S2213-2600(21)00286-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372501PMC
December 2021

Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol.

Lancet Reg Health Eur 2021 Sep 6;8:100186. Epub 2021 Aug 6.

Head of Data, ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.

Background: This study sought to establish the long-term effects of Covid-19 following hospitalisation.

Methods: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L).

Findings: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age.

Interpretation: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females.

Funding: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation.
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http://dx.doi.org/10.1016/j.lanepe.2021.100186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343377PMC
September 2021

Incidence and risk factors for persistent symptoms in adults previously hospitalized for COVID-19.

Clin Exp Allergy 2021 09 12;51(9):1107-1120. Epub 2021 Aug 12.

Inflammation, Repair and Development Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK.

Background: The long-term sequalae of COVID-19 remain poorly characterized. We assessed persistent symptoms in previously hospitalized patients with COVID-19 and assessed potential risk factors.

Methods: Data were collected from patients discharged from 4 hospitals in Moscow, Russia between 8 April and 10 July 2020. Participants were interviewed via telephone using an ISARIC Long-term Follow-up Study questionnaire.

Results: 2,649 of 4755 (56%) discharged patients were successfully evaluated, at median 218 (IQR 200, 236) days post-discharge. COVID-19 diagnosis was clinical in 1291 and molecular in 1358. Most cases were mild, but 902 (34%) required supplemental oxygen and 68 (2.6%) needed ventilatory support. Median age was 56 years (IQR 46, 66) and 1,353 (51.1%) were women. Persistent symptoms were reported by 1247 (47.1%) participants, with fatigue (21.2%), shortness of breath (14.5%) and forgetfulness (9.1%) the most common symptoms and chronic fatigue (25%) and respiratory (17.2%) the most common symptom categories. Female sex was associated with any persistent symptom category OR 1.83 (95% CI 1.55 to 2.17) with association being strongest for dermatological (3.26, 2.36 to 4.57) symptoms. Asthma and chronic pulmonary disease were not associated with persistent symptoms overall, but asthma was associated with neurological (1.95, 1.25 to 2.98) and mood and behavioural changes (2.02, 1.24 to 3.18), and chronic pulmonary disease was associated with chronic fatigue (1.68, 1.21 to 2.32).

Conclusions: Almost half of adults admitted to hospital due to COVID-19 reported persistent symptoms 6 to 8 months after discharge. Fatigue and respiratory symptoms were most common, and female sex was associated with persistent symptoms.
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http://dx.doi.org/10.1111/cea.13997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444748PMC
September 2021

Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study.

Lancet 2021 07;398(10296):223-237

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

Background: COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK.

Methods: We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities.

Findings: Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were the most frequent. Cardiovascular (12·3%, 8973 of 73 197), neurological (4·3%, 3115 of 73 197), and gastrointestinal or liver (0·8%, 7901 of 73 197) complications were also reported.

Interpretation: Complications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause a substantial strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19.

Funding: National Institute for Health Research and the UK Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(21)00799-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285118PMC
July 2021

Effect of Hepatocellular Carcinoma Surveillance Programmes on Overall Survival in a Mixed Cirrhotic UK Population: A Prospective, Longitudinal Cohort Study.

J Clin Med 2021 Jun 24;10(13). Epub 2021 Jun 24.

Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.

Introduction: Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are no trial data on whether surveillance improves clinical outcomes in a UK cirrhosis population of mixed aetiology. Our aim was to determine the impact of, and adherence to, surveillance on overall survival.

Methods: We prospectively collected data on consecutive patients diagnosed with HCC between January 2009 and December 2015 at two large UK centres. We assessed outcomes depending on whether they had been entered into an HCC surveillance programme, and if they had adhered to that.

Results: Out of 985 patients diagnosed with HCC in this study, 40.0% had been enrolled in a surveillance programme. Of these, 76.6% were adherent with surveillance and 24.4% were not. Adherence to surveillance was significantly associated with improved overall survival, even when accounting for lead-time bias using different approaches (HR for 270 days lead-time adjustment 0.64, 0.53 to 0.76, < 0.001).

Conclusions: When adjusted for lead-time bias, HCC surveillance is associated with improved overall survival; however, the beneficial effect of surveillance on survival was lower than reported in studies that did not account fully for lead-time bias.
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http://dx.doi.org/10.3390/jcm10132770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269358PMC
June 2021

Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study.

Lancet Microbe 2021 Aug 2;2(8):e354-e365. Epub 2021 Jun 2.

Medical Research Council-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK.

Background: Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19.

Methods: The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded.

Findings: We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59-84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. and were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and most common in secondary respiratory infections. Bloodstream infections were most frequently caused by and . Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives.

Interpretation: In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist.

Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.
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http://dx.doi.org/10.1016/S2666-5247(21)00090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172149PMC
August 2021

Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK.

Lancet Respir Med 2021 07 14;9(7):773-785. Epub 2021 May 14.

Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK; Department of Respiratory Medicine, Alder Hey Children's Hospital, Liverpool, UK.

Background: Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital.

Methods: In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260.

Findings: Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8-32·7) in March 9 to April 26, 2020, to 16·4% (15·0-17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65-0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94-0·95) of the reduction in in-hospital mortality.

Interpretation: The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain.

Funding: National Institute for Health Research and the Medical Research Council.
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http://dx.doi.org/10.1016/S2213-2600(21)00175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121531PMC
July 2021

Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study.

Lancet Rheumatol 2021 Jul 7;3(7):e498-e506. Epub 2021 May 7.

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

Background: Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease.

Methods: This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations.

Results: Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0·95, 95% CI 0·84-1·07; p=0·35), critical care admission (1·01, 0·87-1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80-1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96-1·32; p=0·14), requirement for oxygen (1·00, 0·89-1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92-1·26; p=0·33).

Interpretation: NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity.

Funding: National Institute for Health Research and Medical Research Council.
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http://dx.doi.org/10.1016/S2665-9913(21)00104-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104907PMC
July 2021

What is the recovery rate and risk of long-term consequences following a diagnosis of COVID-19? A harmonised, global longitudinal observational study protocol.

BMJ Open 2021 03 10;11(3):e043887. Epub 2021 Mar 10.

London School of Hygiene & Tropical Medicine, London, UK.

Introduction: Very little is known about possible clinical sequelae that may persist after resolution of acute COVID-19. A recent longitudinal cohort from Italy including 143 patients followed up after hospitalisation with COVID-19 reported that 87% had at least one ongoing symptom at 60-day follow-up. Early indications suggest that patients with COVID-19 may need even more psychological support than typical intensive care unit patients. The assessment of risk factors for longer term consequences requires a longitudinal study linked to data on pre-existing conditions and care received during the acute phase of illness. The primary aim of this study is to characterise physical and psychosocial sequelae in patients post-COVID-19 hospital discharge.

Methods And Analysis: This is an international open-access prospective, observational multisite study. This protocol is linked with the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) and the WHO's Clinical Characterisation Protocol, which includes patients with suspected or confirmed COVID-19 during hospitalisation. This protocol will follow-up a subset of patients with confirmed COVID-19 using standardised surveys to measure longer term physical and psychosocial sequelae. The data will be linked with the acute phase data. Statistical analyses will be undertaken to characterise groups most likely to be affected by sequelae of COVID-19. The open-access follow-up survey can be used as a data collection tool by other follow-up studies, to facilitate data harmonisation and to identify subsets of patients for further in-depth follow-up. The outcomes of this study will inform strategies to prevent long-term consequences; inform clinical management, interventional studies, rehabilitation and public health management to reduce overall morbidity; and improve long-term outcomes of COVID-19.

Ethics And Dissemination: The protocol and survey are open access to enable low-resourced sites to join the study to facilitate global standardised, longitudinal data collection. Ethical approval has been given by sites in Colombia, Ghana, Italy, Norway, Russia, the UK and South Africa. New sites are welcome to join this collaborative study at any time. Sites interested in adopting the protocol as it is or in an adapted version are responsible for ensuring that local sponsorship and ethical approvals in place as appropriate. The tools are available on the ISARIC website (www.isaric.org). PROTOCOL REGISTRATION NUMBER: osf.io/c5rw3/ PROTOCOL VERSION: 3 August 2020 EUROQOL ID: 37035.
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http://dx.doi.org/10.1136/bmjopen-2020-043887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948153PMC
March 2021

Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK.

Lancet Respir Med 2021 07 4;9(7):699-711. Epub 2021 Mar 4.

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

Background: Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use.

Methods: We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age (<16 years, 16-49 years, and ≥50 years). In-hospital mortality was measured by use of multilevel Cox proportional hazards, adjusting for demographics, comorbidities, and medications (inhaled corticosteroids, short-acting β-agonists [SABAs], and long-acting β-agonists [LABAs]). Patients with asthma who were taking an inhaled corticosteroid plus LABA plus another maintenance asthma medication were considered to have severe asthma.

Findings: 75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16-49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16-49 years: adjusted odds ratio [OR] 1·20 [95% CI 1·05-1·37]; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 [1·08-1·27]; p<0·0001), and patients aged 50 years and older with chronic pulmonary disease (with or without asthma) were significantly less likely than those without a respiratory condition to receive critical care (adjusted OR 0·66 [0·60-0·72] for those without asthma and 0·74 [0·62-0·87] for those with asthma; p<0·0001 for both). In patients aged 16-49 years, only those with severe asthma had a significant increase in mortality compared to those with no asthma (adjusted hazard ratio [HR] 1·17 [95% CI 0·73-1·86] for those on no asthma therapy, 0·99 [0·61-1·58] for those on SABAs only, 0·94 [0·62-1·43] for those on inhaled corticosteroids only, 1·02 [0·67-1·54] for those on inhaled corticosteroids plus LABAs, and 1·96 [1·25-3·08] for those with severe asthma). Among patients aged 50 years and older, those with chronic pulmonary disease had a significantly increased mortality risk, regardless of inhaled corticosteroid use, compared to patients without an underlying respiratory condition (adjusted HR 1·16 [95% CI 1·12-1·22] for those not on inhaled corticosteroids, and 1·10 [1·04-1·16] for those on inhaled corticosteroids; p<0·0001). Patients aged 50 years and older with severe asthma also had an increased mortality risk compared to those not on asthma therapy (adjusted HR 1·24 [95% CI 1·04-1·49]). In patients aged 50 years and older, inhaled corticosteroid use within 2 weeks of hospital admission was associated with decreased mortality in those with asthma, compared to those without an underlying respiratory condition (adjusted HR 0·86 [95% CI 0·80-0·92]).

Interpretation: Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease.

Funding: National Institute for Health Research, Medical Research Council, NIHR Health Protection Research Units in Emerging and Zoonotic Infections at the University of Liverpool and in Respiratory Infections at Imperial College London in partnership with Public Health England.
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http://dx.doi.org/10.1016/S2213-2600(21)00013-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241313PMC
July 2021

Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study.

Lancet Respir Med 2021 04 11;9(4):349-359. Epub 2021 Jan 11.

School of Informatics, University of Edinburgh, Edinburgh, UK.

Background: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.

Methods: We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).

Findings: 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal-external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [-0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model.

Interpretation: The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.

Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.
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http://dx.doi.org/10.1016/S2213-2600(20)30559-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832571PMC
April 2021

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Am J Respir Crit Care Med 2020 12;202(12):1656-1665

Oxford Interstitial Lung Disease Service, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18;  = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71). Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.
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http://dx.doi.org/10.1164/rccm.202007-2794OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737581PMC
December 2020

Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.

BMJ 2020 08 27;370:m3249. Epub 2020 Aug 27.

Respiratory Medicine, Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, UK

Objective: To characterise the clinical features of children and young people admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to coronavirus disease 2019 (covid-19) (MIS-C).

Design: Prospective observational cohort study with rapid data gathering and near real time analysis.

Setting: 260 hospitals in England, Wales, and Scotland between 17 January and 3 July 2020, with a minimum follow-up time of two weeks (to 17 July 2020).

Participants: 651 children and young people aged less than 19 years admitted to 138 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory confirmed SARS-CoV-2.

Main Outcome Measures: Admission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C.

Results: Median age was 4.6 (interquartile range 0.3-13.7) years, 35% (225/651) were under 12 months old, and 56% (367/650) were male. 57% (330/576) were white, 12% (67/576) South Asian, and 10% (56/576) black. 42% (276/651) had at least one recorded comorbidity. A systemic mucocutaneous-enteric cluster of symptoms was identified, which encompassed the symptoms for the WHO MIS-C criteria. 18% (116/632) of children were admitted to critical care. On multivariable analysis, this was associated with age under 1 month (odds ratio 3.21, 95% confidence interval 1.36 to 7.66; P=0.008), age 10-14 years (3.23, 1.55 to 6.99; P=0.002), and black ethnicity (2.82, 1.41 to 5.57; P=0.003). Six (1%) of 627 patients died in hospital, all of whom had profound comorbidity. 11% (52/456) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Children meeting MIS-C criteria were older (median age 10.7 (8.3-14.1) 1.6 (0.2-12.9) years; P<0.001) and more likely to be of non-white ethnicity (64% (29/45) 42% (148/355); P=0.004). Children with MIS-C were five times more likely to be admitted to critical care (73% (38/52) 15% (62/404); P<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with fatigue (51% (24/47) 28% (86/302); P=0.004), headache (34% (16/47) 10% (26/263); P<0.001), myalgia (34% (15/44) 8% (21/270); P<0.001), sore throat (30% (14/47) (12% (34/284); P=0.003), and lymphadenopathy (20% (9/46) 3% (10/318); P<0.001) and to have a platelet count of less than 150 × 10/L (32% (16/50) 11% (38/348); P<0.001) than children who did not have MIS-C. No deaths occurred in the MIS-C group.

Conclusions: Children and young people have less severe acute covid-19 than adults. A systemic mucocutaneous-enteric symptom cluster was also identified in acute cases that shares features with MIS-C. This study provides additional evidence for refining the WHO MIS-C preliminary case definition. Children meeting the MIS-C criteria have different demographic and clinical features depending on whether they have acute SARS-CoV-2 infection (polymerase chain reaction positive) or are post-acute (antibody positive).

Study Registration: ISRCTN66726260.
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http://dx.doi.org/10.1136/bmj.m3249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488201PMC
August 2020

Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score.

BMJ 2020 09 9;370:m3339. Epub 2020 Sep 9.

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

Objective: To develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19).

Design: Prospective observational cohort study.

Setting: International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium-ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020 PARTICIPANTS: Adults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction.

Main Outcome Measure: In-hospital mortality.

Results: 35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73).

Conclusions: An easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations.

Study Registration: ISRCTN66726260.
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http://dx.doi.org/10.1136/bmj.m3339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116472PMC
September 2020

The effects of physical distancing on population mobility during the COVID-19 pandemic in the UK.

Lancet Digit Health 2020 08 12;2(8):e385-e387. Epub 2020 Jun 12.

Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, EH16 4UX, UK. Electronic address:

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http://dx.doi.org/10.1016/S2589-7500(20)30134-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292602PMC
August 2020

Left cardiac sympathetic denervation in the management of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: A meta-regression.

Congenit Heart Dis 2019 Nov 16;14(6):1102-1112. Epub 2019 Oct 16.

Southwest Sydney Clinical School, Liverpool Hospital, Sydney, Australia.

Background: Left cardiac sympathetic denervation (LCSD) has been proposed as useful therapy for long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), in addition to anti-arrhythmic agents and implantable cardioverter defibrillators. This study aimed to assess the current evidence for LCSD and compare the open vs the video-assisted thoracoscopic surgery (VATS) approaches.

Methods: MEDLINE, Embase and Cochrane library databases were searched up to December 2018 for studies reporting the long-term outcomes of LCSD in LQTS, CPVT patients. The incidence of cardiac events (CEs) before and after surgery, the change in QTc interval, and surgical complications were pooled to estimate the efficacy of LCSD. Meta-regression was used to estimate the effects of surgical approach (open vs VATS) on outcomes following LCSD.

Results: Twenty-seven papers met our inclusion criteria (647 patients). VATS was used in 408 patients (63.1%), open surgery in 239 (36.9%). Mean follow-up was 32.3 ± 32.5 months. Postsurgery, 398/585 patients (68.0%) were free of CEs and QTc decreased from 522 ± 61.6 ms to 494 ± 52.3 ms. Meta-regression showed no differences between the two approaches in the incidence of CEs and surgical complications. VATS was associated with a smaller reduction in QTc (β-coefficient -20.04, 95% CI -36.82 to -3.27, P = .019).

Conclusions: LCSD was associated with a reduction in the incidence of CEs in LQTS, CPVT patients and in the duration of QTc. Open surgery was associated with a greater reduction in QTc. Due to the limitations that hindered our study, a randomized trial is warranted to fully establish LCSD safety and efficacy.
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http://dx.doi.org/10.1111/chd.12855DOI Listing
November 2019

Can a smartphone-delivered tool facilitate the assessment of surgical site infection and result in earlier treatment? Tracking wound infection with smartphone technology (TWIST): protocol for a randomised controlled trial in emergency surgery patients.

BMJ Open 2019 10 3;9(10):e029620. Epub 2019 Oct 3.

Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh, UK.

Introduction: National data suggest that surgical site infection (SSI) complicates 2%-10% of general surgery cases, although the patient-reported incidence is much higher. SSIs cause significant patient morbidity and represent a significant burden on acute healthcare services, in a cohort predominantly suitable for outpatient management. Over three-quarters of UK adults now own smartphones, which could be harnessed to improve access to care. We aim to investigate if a smartphone-delivered wound assessment tool results in earlier treatment.

Methods And Analysis: This is a randomised controlled trial aiming to recruit 500 patients across National Health Service (NHS) hospitals. All emergency abdominal surgery patients over the age of 16 who own smartphones will be considered eligible, with the exclusion of those with significant visual impairment. Participants will be randomised in a 1:1 ratio between standard postoperative care and the intervention - use of the smartphone tool in addition to standard postoperative care. The main outcome measure will be time-to-diagnosis of SSI with secondary outcome measures considering use of emergency department and general practitioner services and patient experience. Follow-up will be conducted by clinicians blinded to group allocation. Analysis of time-to-diagnosis will be by comparison of means using an independent two sample t-test.

Ethics And Dissemination: This is the first randomised controlled trial on the use of a smartphone-delivered wound assessment tool to facilitate the assessment of SSI and the impact on time-to-diagnosis. The intervention is being used in addition to standard postoperative care. The study design and protocol were reviewed and approved by Southeast Scotland Research and Ethics Committee (REC Ref: 16/SS/0072 24/05/2016). Study findings will be presented at academic conferences, published in peer-reviewed journals and are expected in 2020. A written lay summary will be available to study participants on request.

Trial Registration Number: NCT02704897; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-029620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797297PMC
October 2019

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study.

JAMA Oncol 2019 12;5(12):1749-1768

Department of Family and Community Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data.

Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning.

Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence.

Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs).

Conclusions And Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.
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http://dx.doi.org/10.1001/jamaoncol.2019.2996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777271PMC
December 2019

Malnutrition, nutritional interventions and clinical outcomes of patients with acute small bowel obstruction: results from a national, multicentre, prospective audit.

BMJ Open 2019 07 27;9(7):e029235. Epub 2019 Jul 27.

Colorectal Surgery, Addenbrooke's Hospital, Cambridge, Cambridgeshire, UK.

Objective: The aim of this study was to assess the nutritional status of patients presenting with small bowel obstruction (SBO), along with associated nutritional interventions and clinical outcomes.

Design: Prospective cohort study.

Setting: 131 UK hospitals with acute surgical services.

Participants: 2069 adult patients with a diagnosis of SBO were included in this study. The mean age was 67.0 years and 54.7% were female.

Primary And Secondary Outcome Measures: Primary outcome was in-hospital mortality. Secondary outcomes recorded included: major complications (composite of in-hospital mortality, reoperation, unplanned intensive care admission and 30-day readmission), complications arising from surgery (anastomotic leak, wound dehiscence), infection (pneumonia, surgical site infection, intra-abdominal infection, urinary tract infection, venous catheter infection), cardiac complications, venous thromboembolism and delirium.

Results: Postoperative adhesions were the most common cause of SBO (49.1%). Early surgery (<24 hours postadmission) took place in 30.0% of patients, 22.0% underwent delayed operation and 47.9% were managed non-operatively. Malnutrition as stratified by Nutritional Risk Index was common, with 35.7% at moderate risk and 5.7% at severe risk of malnutrition. Dietitian review occurred in just 36.4% and 55.9% of the moderate and severe risk groups. In the low risk group, 30.3% received nutritional intervention compared with 40.7% in moderate risk group and 62.7% in severe risk group. In comparison to the low risk group, patients who were at severe or moderate risk of malnutrition had 4.2 and 2.4 times higher unadjusted risk of in-hospital mortality, respectively. Propensity-matched analysis found no difference in outcomes based on use or timing of parenteral nutrition.

Conclusions: Malnutrition on admission is associated with worse outcomes in patients with SBO, and marked variation in management of malnutrition was observed. Future trials should focus on identifying effective and cost-effective nutritional interventions in SBO.
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http://dx.doi.org/10.1136/bmjopen-2019-029235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661661PMC
July 2019

The effect of liver transplantation on patient-centred outcomes: a propensity-score matched analysis.

Transpl Int 2019 Aug 20;32(8):808-819. Epub 2019 Mar 20.

Scottish Liver Transplant Unit, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

It is unclear whether liver transplantation confers an increase in health-related quality of life (HR-QoL) across all dimensions of health. This study aimed to estimate the effect of liver transplantation on HR-QoL. Pre- and post-transplantation patients attending an outpatient clinic were invited to complete the condition-specific 'Short form of liver disease QOL' questionnaire. Mixed-effect linear regression and propensity-score matching (PSM) on pretransplantation characteristics were used to estimate the difference in overall HR-QoL associated with transplantation. Of 454/609 (74.5%) eligible patients who were included in the analysis, 102 (22.5%) patients fall under pretransplantation category, and 352 (77.5%) were under post-transplantation category. Overall HR-QoL post-transplantation significantly increased in patients without hepatocellular carcinoma (HCC) (β = 16.84, 95% CI: 13.33 to 20.35, P < 0.001), but not with HCC (β = 1.25, 95% CI: -5.09 to 7.60, P = 0.704). Donation after circulatory death (DCD) organ recipients had a significantly lower HR-QoL (β = -4.61, 95% CI: -8.95 to -0.24, P = 0.043). Following PSM, transplantation was associated with a significant increase in overall HR-QoL (average treatment effect: 6.3, 95% CI: 2.1-10.9). There is a significant improvement in HR-QoL attributable to transplantation in this cohort. Post-transplantation HR-QoL was affected by several factors, including HCC status and DCD transplantation, which has important implications for counselling prior to liver transplantation.
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http://dx.doi.org/10.1111/tri.13416DOI Listing
August 2019

Cancer epigenetics in solid organ tumours: A primer for surgical oncologists.

Eur J Surg Oncol 2019 05 5;45(5):736-746. Epub 2019 Feb 5.

Department of Clinical Surgery, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK; Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway. Electronic address:

Cancer is initiated through both genetic and epigenetic alterations. The end-effect of such changes to the DNA machinery is a set of uncontrolled mechanisms of cell division, invasion and, eventually, metastasis. Epigenetic changes are now increasingly appreciated as an essential driver to the cancer phenotype. The epigenetic regulation of cancer is complex and not yet fully understood, but application of epigenetics to clinical practice and in cancer research has the potential to improve cancer care. Epigenetics changes do not cause changes in the DNA base-pairs (and, hence, does not alter the genetic code per se) but rather occur through methylation of DNA, by histone modifications, and, through changes to chromatin structure to alter genetic expression. Epigenetic regulators are characterized as writers, readers or erasers by their mechanisms of action. The human epigenome is influenced from cradle to grave, with internal and external life-time exposure influencing the epigenetic marks that may act as modifiers or drivers of carcinogenesis. Preventive and public health strategies may follow from better understanding of the life-time influence of the epigenome. Epigenetics may be used to define risk, to investigate mechanisms of carcinogenesis, to identify biomarkers, and to identify novel therapeutic options. Epigenetic alterations are found across many solid cancers and are increasingly making clinical impact to cancer management. Novel epigenetic drugs may be used for a more tailored and specific response to treatment of cancers. We present a primer on epigenetics for surgical oncologists with examples from colorectal cancer, breast cancer, pancreatic cancer and hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.ejso.2019.02.005DOI Listing
May 2019

Atrial Fibrillation After Gastrointestinal Surgery: Incidence and Associated Risk Factors.

J Surg Res 2019 06 5;238:23-28. Epub 2019 Feb 5.

Clinical Research Fellow, Department of General Surgery, Sheffield Teaching Hospitals, Sheffield, UK. Electronic address:

Background: Atrial fibrillation (AF) is a common dysrhythmia that can occur after major physiological stress including surgery (postoperative AF). There are few data on postoperative AF after abdominal surgery. We set out to define the incidence of de novo postoperative AF after abdominal surgery and associated risk factors.

Methods: The Patient History Integrated Data store administrative database was interrogated for patients aged ≥65 y undergoing abdominal surgery from April 2012 to April 2014. Patients with pre-existing AF were excluded. The primary outcome was diagnosis of AF.

Results: Two thousand nine hundred and sixty-seven cases were included of whom 187 developed postoperative AF within 90 d (6.3%). The rate of postoperative AF varied by operation and was highest in small bowel resection (17.2%) and lowest in biliary surgery (4.8%). Median time to detection of postoperative AF was 32 d. Patients who developed postoperative AF were significantly older than those who did not develop AF (median age 75.3 y versus 72.4 y, P < 0.01). Logistic regression modeling found increasing age (odds ratio [OR] 1.03 [confidence interval {CI} 1.01-1.06], hypertension OR 1.73 [CI 1.19-2.51]), congestive cardiac failure (OR 3.04 [CI 1.88-4.92], and vascular disease OR 2.29 [CI 1.39-3.37]) were predictive of the development of postoperative AF within 30 d. The area under the curve for this model was 0.733.

Conclusions: Postoperative AF affects a significant number of patients after abdominal surgery. Demographics such as history of cardiovascular disease might aid prediction of postoperative AF. Postoperative AF is mostly identified after discharge, suggesting the need for postoperative screening.
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http://dx.doi.org/10.1016/j.jss.2019.01.017DOI Listing
June 2019

Systematic Review and Meta-analysis of Nonsteroidal Anti-inflammatory Drugs to Improve GI Recovery After Colorectal Surgery.

Dis Colon Rectum 2019 02;62(2):248-256

Section of Translational Anaesthesia and Surgery, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, United Kingdom.

Background: The management of delayed GI recovery after surgery is an unmet challenge. Uncertainty over its pathophysiology has limited previous research, but recent evidence identifies intestinal inflammation and activation of µ-opioid receptors as key mechanisms. Nonsteroidal anti-inflammatory drugs are recommended by enhanced recovery protocols for their opioid-sparing and anti-inflammatory properties.

Objectives: The purpose of this study was to explore the safety and efficacy of nonsteroidal anti-inflammatory drugs to improve GI recovery and to identify opportunities for future research.

Data Sources: MEDLINE, Embase, and the Cochrane Library were systematically searched from inception up to January 2018.

Study Selection: Randomized controlled trials assessing the effect of nonsteroidal anti-inflammatory drugs on GI recovery after elective colorectal surgery were eligible.

Main Outcome Measures: Postoperative GI recovery, including first passage of flatus, stool, and oral tolerance, were measured.

Results: Six randomized controlled trials involving 563 participants were identified. All of the participants received patient-controlled morphine and either nonsteroidal anti-inflammatory drug (nonselective: n = 4; cyclooxygenase-2 selective: n = 1; either: n = 1) or placebo. Patients receiving the active drug had faster return of flatus (mean difference: -17.73 h (95% CI, -21.26 to -14.19 h); p < 0.001), stool (-9.52 h (95% CI, -14.74 to -4.79 h); p < 0.001), and oral tolerance (-12.00 h (95% CI, -18.01 to -5.99 h); p < 0.001). Morphine consumption was reduced in the active groups of 4 studies (average reduction, 12.9-30.0 mg), and 1 study demonstrated significantly reduced measures of systemic inflammation. Nonsteroidal anti-inflammatory drugs were not associated with adverse events, but 1 study was temporarily suspended for safety.

Limitations: The data presented are relatively outdated but represent the best available evidence.

Conclusions: Nonsteroidal anti-inflammatory drugs may represent an effective and accessible intervention to improve GI recovery, but hesitancy over their use after colorectal surgery persists. Additional preclinical research to characterize their mechanisms of action, followed by well-designed clinical studies to test safety and patient-reported efficacy, should be considered.
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http://dx.doi.org/10.1097/DCR.0000000000001281DOI Listing
February 2019
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