National Institute For Health Research Biomedical Research Centre Research Articles

Performance of antigen lateral flow devices in the UK during the alpha, delta, and omicron waves of the SARS-CoV-2 pandemic: a diagnostic and observational study

Antigen lateral flow devices (LFDs) have been widely used to control SARS-CoV-2. We aimed to improve understanding of LFD performance with changes in variant infections, vaccination, viral load, and LFD use, and in the detection of infectious individuals. In this diagnostic study, paired LFD and RT-PCR test results were prospectively collected from asymptomatic and symptomatic participants in the UK between Nov 4, 2020, and March 21, 2022, to support the National Health Service (NHS) England's Test and Trace programme. The LFDs evaluated were the Innova SARS-CoV-2 Antigen Rapid Qualitative Test, the Orient Gene Rapid Covid-19 (Antigen) Self-Test, and the Acon Flowflex SARS-CoV-2 Antigen Rapid Test (Self-Testing). Test results were collected across various community testing settings, including predeployment testing sites, routine testing centres, homes, schools, universities, workplaces, targeted community testing, and from health-care workers. We used multivariable logistic regression to analyse LFD sensitivity and specificity using RT-PCR as a reference standard, adjusting for viral load, LFD manufacturer, test setting, age, sex, test assistance, symptom status, vaccination status, and SARS-CoV-2 variant. National contact tracing data from NHS Test and Trace (Jan 1, 2021, to Jan 11, 2022) were used to estimate the proportion of transmitting index patients (with ≥1 RT-PCR-positive or LFD-positive contact) potentially detectable by LFDs (specifically Innova, as the most widely used LFD) with time, accounting for index viral load, variant, and symptom status. We assessed 75 382 pairs of LFD and RT-PCR tests. Of these, 4131 (5·5%) were RT-PCR-positive. LFD sensitivity versus RT-PCR was 63·2% (95% CI 61·7-64·6) and specificity was 99·71% (95% CI 99·66-99·74). Increased viral load was independently associated with being LFD positive (adjusted odds ratio [aOR] 2·85 [95% CI 2·66-3·06] per 1 log10 copies per mL increase; p<0·0001). There was no evidence that LFD sensitivity differed for delta (B.1.617.2) infections versus alpha (B.1.1.7) or pre-alpha (B.1.177) infections (aOR 1·00 [0·69-1·45]; p=0·99), whereas omicron (BA.1 or BA.2) infections appeared more likely to be LFD positive (aOR 1·63 [1·02-2·59]; p=0·042). Sensitivity was higher in symptomatic participants (68·7% [95% CI 66·9-70·4]) than in asymptomatic participants (52·8% [50·1-55·4]). Among 347 374 unique index patients with probable onward transmission, 78·3% (95% CI 75·3-81·2) were estimated to have been detectable with LFDs (Innova), and this proportion was mostly stable with time and for successive variants. Overall, the estimated proportion of infectious index patients detectable by the Innova LFD was lower in asymptomatic patients (57·6% [53·6-61·9]) versus symptomatic patients (79·7% [76·7-82·5]). LFDs remained able to detect most SARS-CoV-2 infections throughout vaccine roll-out and across different viral variants. LFDs can potentially detect most infections that transmit to others and reduce the risk of transmission. However, performance is lower in asymptomatic individuals than in symptomatic individuals. UK Health Security Agency, the UK Government Department of Health and Social Care, National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, and the University of Oxford NIHR Biomedical Research Centre.

The global burden of perinatal common mental health disorders and substance use among migrant women: a systematic review and meta-analysis

There are one billion migrants globally, of whom 82 million are forced migrants. Pregnant migrants face pre-migration stressors such as conflict, transit stressors including poverty, and post-migration stressors including navigating the immigration system; these stressors can make them vulnerable to mental illness. We aimed to assess the global prevalence of and risk factors for perinatal mental health disorders or substance use among women who are migrants. In this systematic review and meta-analysis, we searched OVID MEDLINE, Embase, PsycINFO, CENTRAL, Global Health, Scopus, and Web of Science for studies published from database inception until July 8, 2022. Cohort, cross-sectional, and interventional studies with prevalence data for any mental illness in pregnancy or the postnatal period (ie, up to a year after delivery) or substance use in pregnancy were included. The primary outcome was the prevalence of perinatal common mental health disorders among women who are migrants, globally. Data for study quality and risk factors were also extracted. A random-effects meta-analysis was used to calculate pooled prevalence estimates, when appropriate. Sensitivity analyses were conducted according to study quality, sample representativeness, and method of outcome assessment. Risk factor data were synthesised narratively. This study is registered with PROSPERO, CRD42021226291. 18 650 studies were retrieved, of which 135 studies comprising data from 621 995 participants met the inclusion criteria. 123 (91%) of 135 studies were conducted in high-income host countries. Five (4%) of 135 studies were interventional, 40 (30%) were cohort, and 90 (66%) were cross-sectional. The most common regions of origin of participants were South America, the Middle East, and north Africa. Only 26 studies presented disaggregated data for forced migrants or economic migrants. The pooled prevalence of perinatal depressive disorders was 24·2% (range 0·5-95·5%; I2 98·8%; τ2 0·01) among all women who are migrants, 32·5% (1·5-81·6; 98·7%; 0·01) among forced migrants, and 13·7% (4·7-35·1; 91·5%; 0·01) among economic migrants (p<0·001). The pooled prevalence of perinatal anxiety disorders was 19·6% (range 1·2-53·1; I2 96·8%; τ2 0·01) among all migrants. The pooled prevalence of perinatal post-traumatic stress disorder (PTSD) among all migrant women was 8·9% (range 3·2-33·3; I2 97·4%; τ2 0·18). The pooled prevalence of perinatal PTSD among forced migrants was 17·1% (range 6·5-44·3; I2 96·6%; τ2 0·32). Key risk factors for perinatal depression were being a recently arrived immigrant (ie, approximately within the past year), having poor social support, and having a poor relationship with one's partner. One in four women who are migrants and who are pregnant or post partum experience perinatal depression, one in five perinatal anxiety, and one in 11 perinatal PTSD. The burden of perinatal mental illness appears higher among women who are forced migrants compared with women who are economic migrants. To our knowledge, we have provided the first pooled estimate of perinatal depression and PTSD among women who are forced migrants. Interpreting the prevalence estimate should be observed with caution due to the very wide range found within the included studies. Additionally, 66% of studies were cross-sectional representing low quality evidence. These findings highlight the need for community-based routine perinatal mental health screening for migrant communities, and access to interventions that are culturally sensitive, particularly for forced migrants who might experience a higher burden of disease than economic migrants. UK National Institute for Health Research (NIHR); March of Dimes European Preterm Birth Research Centre, Imperial College; Imperial College NIHR Biomedical Research Centre; and Nuffield Department of Population Health, University of Oxford.

MP09-17 PREDICTING INCIDENCE VERSUS MORTALITY FOR CANCERS ASSOCIATED WITH OVERDIAGNOSIS: AN OVERLOOKED ISSUE FOR POLYGENIC RISK SCORES AND CANCER SCREENING

You have accessJournal of UrologyCME1 May 2022MP09-17 PREDICTING INCIDENCE VERSUS MORTALITY FOR CANCERS ASSOCIATED WITH OVERDIAGNOSIS: AN OVERLOOKED ISSUE FOR POLYGENIC RISK SCORES AND CANCER SCREENING Andrew Vickers, Amit Sud, Jonine Bernstein, and Richard Houlston Andrew VickersAndrew Vickers More articles by this author , Amit SudAmit Sud More articles by this author , Jonine BernsteinJonine Bernstein More articles by this author , and Richard HoulstonRichard Houlston More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002531.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Population-based cancer screening programs, including prostate-specific antigen (PSA) screening for prostate cancer, are generally directed at all healthy individuals in a given age stratum. It has recently been proposed that PSA screening could be risk-stratified using polygenic risk scores (PRSs) based on panels of single-nucleotide polymorphisms (SNPs): those with high PRS would be screened whereas those with low PRS would be exempted. However, prostate cancer PRSs were generated using the endpoint of cancer incidence rather than cancer-specific mortality, and it has been demonstrated that the PRSs do not differentially predict lethal vs. indolent disease. As such, use of PRSs to risk-stratify screening will not address overdiagnosis, the major problem associated with PSA screening. METHODS: We developed a simple net benefit formulation to comparing different screening strategies, given as: deaths prevented – number screened / NWS – number diagnosed / (NWD -1), where NWS and NWD are the number of individuals we would be willing to, respectively, screen and diagnose, to prevent one death. We applied the formula to empirical data on PSA screening and varied NWS and NWD to assess the effects on our findings. RESULTS: Risk-stratifying PSA screening using a PRS that does not differentially discriminate between incident and lethal cancer did not improve screening outcomes in our model. Net benefit was 4 per 1000 for screening all eligible men. For a PRS with a C-index of 0.75 (higher than is typically found) but which did not discriminate between incidence and mortality, net benefit was 3.80, 3.36 and 1.78 for restricting screening to those with the highest 50%, 25% and 10% PRS. Net benefit was far lower for a concordance index of 0.65, closer to what is often reported. Results were robust for different choices of NWS and NWD. In contrast, risk stratifying screening based on PSA, which does predict mortality better than incidence, was associated with a net benefit up to 5.64, higher than that for screening all men. CONCLUSIONS: Using PSA levels to determine which men should continue screening will improve screening outcomes; using PRS to risk-stratify screening will do more harm than good. If PRS-based cancer screening is to be effective, research needs to focus on identifying PRSs associated with cancer mortality. Source of Funding: This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center [P30 CA008748], a SPORE grant in Prostate Cancer to Dr. H. Scher [P50-CA92629], the Sidney Kimmel Center for Prostate and Urologic Cancers. R.H. acknowledges grant support from Cancer Research UK (C1298/A8362) and the Wellcome Trust (214388). A.S. is in receipt of a National Institute for Health Research (NIHR) Academic Clinical Lectureship and funding from the Royal Marsden Biomedical Research Centre. This is a summary of independent research supported by the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e143 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Vickers More articles by this author Amit Sud More articles by this author Jonine Bernstein More articles by this author Richard Houlston More articles by this author Expand All Advertisement PDF DownloadLoading ...

Healthcare workers’ views on mandatory SARS-CoV-2 vaccination in the UK: A cross-sectional, mixed-methods analysis from the UK-REACH study

SummaryBackgroundSeveral countries now have mandatory SARS-CoV-2 vaccination for healthcare workers (HCWs) or the general population. HCWs’ views on this are largely unknown. Using data from the nationwide UK-REACH study we aimed to understand UK HCW's views on improving SARS-CoV-2 vaccination coverage, including mandatory vaccination.MethodsBetween 21st April and 26th June 2021, we administered an online questionnaire via email to 17 891 UK HCWs recruited as part of a longitudinal cohort from across the UK who had previously responded to a baseline questionnaire (primarily recruited through email) as part of the United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) nationwide prospective cohort study. We categorised responses to a free-text question “What should society do if people do not get vaccinated against COVID-19?” using qualitative content analysis. We collapsed categories into a binary variable: favours mandatory vaccination or not, using logistic regression to calculate its demographic predictors, and its occupational, health, and attitudinal predictors adjusted for demographics.FindingsOf 5633 questionnaire respondents, 3235 answered the free text question. Median age of free text responders was 47 years (IQR 36–56) and 2705 (74.3%) were female. 18% (n = 578) favoured mandatory vaccination (201 [6%] participants for HCWs and others working with vulnerable populations; 377 [12%] for the general population), but the most frequent suggestion was education (32%, n = 1047). Older HCWs (OR 1.84; 95% CI 1.44–2.34 [≥55 years vs 16 years to <40 years]), HCWs vaccinated against influenza (OR 1.49; 95% CI 1.11–2.01 [2 vaccines vs none]), and with more positive vaccination attitudes generally (OR 1.10; 95% CI 1.06–1.15) were more likely to favour mandatory vaccination, whereas female HCWs (OR= 0.79, 95% CI 0.63–0.96, vs male HCWs) and Black HCWs (OR=0.46, 95% CI 0.25–0.85, vs white HCWs) were less likely to.InterpretationOnly one in six of the HCWs in this large, diverse, UK-wide sample favoured mandatory vaccination. Building trust, educating, and supporting HCWs who are hesitant about vaccination may be more acceptable, effective, and equitable.FundingMRC-UK Research and Innovation grant (MR/V027549/1) and the Department of Health and Social Care (DHSC) via the National Institute for Health Research (NIHR). Core funding was also provided by NIHR Biomedical Research Centres.

Thoracoscopic surgical ablation versus catheter ablation as first-line treatment for long-standing persistent atrial fibrillation: the CASA-AF RCT

Background Standalone thoracoscopic surgical ablation may be more effective than catheter ablation in patients with long-standing persistent atrial fibrillation. Objectives To determine whether or not surgical ablation is clinically superior to catheter ablation as the first-line treatment strategy in long-standing persistent atrial fibrillation. Design This was a prospective, multicentre, randomised control trial. Setting Four NHS tertiary centres in England. Participants Adults with long-standing persistent atrial fibrillation, who had European Heart Rhythm Association symptom scores &gt; 2 and who were naive to previous catheter ablation or thoracic/cardiac surgery. Interventions Minimally invasive thoracoscopic surgical ablation and conventional catheter ablation (control intervention). Main outcome measures The primary outcome was freedom from atrial fibrillation/tachycardia ≥ 30 seconds after a single procedure without antiarrhythmic drugs (class 1C/3) at 1 year, excluding a 3-month blanking period. The secondary outcomes include the intervention-related major complication rate; clinical success (≥ 75% reduction in arrhythmia burden); and changes in symptoms, quality of life and cost-effectiveness. Methods Patients (n = 120) were randomised to surgical ablation (n = 60) or catheter ablation (n = 60). An implanted loop recorder provided continuous cardiac monitoring following ablation. Follow-up visits were at 3, 6, 9 and 12 months. Loop recorder data were reviewed monthly by a physiologist who was blinded to the randomisation outcome. Results The study treatment was received by 55 patients in the surgical ablation arm and 60 patients in the catheter ablation arm; five patients withdrew from surgical ablation before treatment. Data from randomised and treated patients were analysed as per intention to treat. Patients had a mean age of 62.3 (standard deviation 9.6) years, were predominantly male (74%), had a mean left atrial diameter of 44.6 mm (standard deviation 6 mm) and were in continuous atrial fibrillation for 22 months (range 16–31 months). At 12 months, 26% of patients in the surgical ablation arm (14/54) and 28% of patients in the catheter ablation arm (17/60) were free from atrial arrhythmias after a single procedure without antiarrhythmic drugs (odds ratio 1.13, 95% confidence interval 0.46 to 2.83; p = 0.84). An arrhythmia burden reduction of ≥ 75% was seen in 36 out of 54 (67%) patients in the surgical ablation arm, compared with 46 out of 60 (77%) patients in the catheter ablation arm (odds ratio 1.64, 95% confidence interval 0.67 to 4.08; p = 0.3). Procedure-related serious complications within 30 days of the intervention occurred in 15% (8/55) of patients in the surgical ablation arm (including one death) compared with 10% (6/60) of patients in the catheter ablation arm (p = 0.46). Surgical ablation was associated with significantly higher costs (£23,221 vs. £18,186; p = 0.02) and fewer quality-adjusted life-years than catheter ablation (0.76 vs. 0.83; p = 0.02). Limitations This study was conducted in four highly specialised cardiology centres that have substantial experience in both treatment modalities; therefore, the results may not be widely generalisable. The study was not powered to detect small differences in efficacy. Conclusions We found no evidence to suggest that standalone thoracoscopic surgical ablation outcomes were superior to catheter ablation outcomes in achieving freedom from atrial arrhythmia after a single procedure without antiarrhythmic drugs. Moreover, surgical ablation is associated with a longer hospital stay, smaller improvements in quality of life and higher health-care costs than catheter ablation (standard care therapy). Future work Evaluation of the impact of ablation treatments on sinus rhythm maintenance and quality of life with extended follow-up to 3 years. Model-based economic analysis to estimate long-term benefits, harms and costs of surgical and catheter ablation compared with antiarrhythmic drug therapy in long-standing persistent atrial fibrillation patients. Trial registration Current Controlled Trials ISRCTN18250790 and ClinicalTrials.gov NCT02755688. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This study was supported by the UK Clinical Research Collaboration-registered King’s Clinical Trials Unit at King’s Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London and the NIHR Evaluation, Trials and Studies Coordinating Centre. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 18. See the NIHR Journals Library website for further project information.

Long limb compared with standard limb Roux-en-Y gastric bypass for type 2 diabetes and obesity: the LONG LIMB RCT

Background Roux-en-Y gastric bypass is recognised as a standard of care in the treatment of diabetes mellitus and obesity. However, the optimal length of the Roux-en-Y gastric bypass limbs remains controversial, with substantial variation in practice. Specifically, a longer biliopancreatic limb length of 150 cm (‘long limb’) has been hypothesised to be better for the treatment of diabetes mellitus because it increases the postprandial secretion of gut hormones, such as glucagon-like peptide 1, and increases insulin sensitivity, compared with the Roux-en-Y gastric bypass utilising a standard biliopancreatic limb length of 50 cm (‘standard limb’). Objective To evaluate the mechanisms, clinical efficacy and safety of long limb versus the standard limb Roux-en-Y gastric bypass in patients undergoing metabolic surgery for obesity and diabetes mellitus. Design A double-blind, mechanistic randomised controlled trial was conducted to evaluate the mechanisms, clinical efficacy and safety of the two interventions. Setting Imperial College London, King’s College London and their associated NHS trusts. Participants Patients with obesity and type 2 diabetes mellitus who were eligible for metabolic surgery. Interventions Participants were randomly assigned (1 : 1) to 150-cm (long limb) or 50-cm (standard limb) biliopancreatic limb Roux-en-Y gastric bypass with a fixed alimentary limb of 100 cm. The participants underwent meal tolerance tests to measure glucose excursions, glucagon-like peptide 1 and insulin secretion, and hyperinsulinaemic–euglycaemic clamps with stable isotopes to measure insulin sensitivity preoperatively, at 2 weeks after the surgery and at matched 20% total body weight loss. Clinical follow-up continued up to 1 year. Main outcome measures Primary – postprandial peak of active glucagon-like peptide 1 concentration at 2 weeks after intervention. Secondary – fasting and postprandial glucose and insulin concentrations, insulin sensitivity, glycaemic control and weight loss at 12 months after surgery, and safety of participants. Results Of the 53 participants randomised, 48 completed the trial. There were statistically significant decreases in fasting and postprandial glucose concentrations, increases in insulin, glucagon-like peptide 1 secretion and insulin sensitivity, and reductions in the levels of glycated haemoglobin (i.e. HbA1c) and weight in both long and standard limb groups. However, there were no significant differences between trial groups in any of these parameters. Limitations The main limitations of this trial include the relatively short follow-up of 12 months and elongation of the biliopancreatic limb to a fixed length of 150 cm. Conclusion Patients undergoing both types of Roux-en-Y gastric bypass benefited metabolically from the surgery. The results have not demonstrated that elongation of the biliopancreatic limb of the Roux-en-Y gastric bypass from 50 to 150 cm results in superior metabolic outcomes in terms of glucose excursions, insulin and incretin hormone secretion, and insulin sensitivity, when assessed at up to 12 months after surgery. Future work Continued longitudinal follow-up of the long and standard limb cohorts will be necessary to evaluate any differential effects of the two surgical procedures on patients’ metabolic trajectories. Trial registration Current Controlled Trials ISRCTN15283219. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 3. See the NIHR Journals Library website for further project information. The section in the report on endocrinology and investigative medicine is funded by grants from the Medical Research Council, the Biotechnology and Biological Sciences Research Council, NIHR, an Integrative Mammalian Biology Capacity Building Award and a FP7-HEALTH-2009-241592 EuroCHIP grant. This section is also supported by the NIHR Biomedical Research Centre Funding Scheme.

Inhaled Budesonide in the Treatment of Early COVID-19 Illness: A Randomised Controlled Trial

Background: Multiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. Methods: We conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. Results: 146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. Conclusion: Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.Trial Registration: ClinicalTrials.gov number, NCT04416399Funding: Oxford NIHR Biomedical Research Centre and AstraZenecaDeclaration of Interests: Dr. Ramakrishnan reports grants and non-financial support from Oxford Respiratory NIHR BRC, during the conduct of the study; non-financial support from AstraZeneca, personal fees from Australian Government Research Training Program, outside the submitted work; . Dr. Nicolau has nothing to disclose. Mrs Langford has nothing to disclose. Mr. Mahdi has nothing to disclose. Mrs Helen Jeffers reports personal fees from AstraZeneca, outside the submitted work; . Miss Mwasuku has nothing to disclose. Mrs Krassowska has nothing to disclose. Dr Fox has nothing to disclose. Dr Binnian has nothing to disclose. Dr Glover has nothing to disclose. Dr Bright has nothing to disclose. Dr. Butler reports grants from National Institute for Health Research (NIHR), Roche Molecular Diagnostics, Janssen Pharmaceuticals, and various public funding bodies for research related to diagnostics and infections. He has revcied personal fees from Pfizer INC, Roche Diagnostics, and Janssen Pharmaceuticals, outside the submitted work. Dr. Cane has nothing to disclose. Mr. Halner has nothing to disclose. Dr. Matthews has nothing to disclose. Dr. Donnelly reports grants from AstraZeneca, from Boehringer-Ingelheim, outside the submitted work; . Dr. Simpson has nothing to disclose. Dr Baker has nothing to disclose. Dr. Fadai has nothing to disclose. Dr. Peterson reports personal fees from AstraZeneca, outside the submitted work; . Mr. Bengtsson reports personal fees from AstraZeneca, outside the submitted work; Dr. Barnes reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Teva, personal fees from Covis, during the conduct of the study; Dr. Russell reports grants from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi UK, personal fees from Glaxo-SmithKline, during the conduct of the study; . Dr. Bafadhel reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi, GSK, other from Albus Health, ProAxsis, outside the submitted work; .Ethics Approval Statement: The trial was sponsored by the University of Oxford, and was approved by the Fulham London Research Ethics Committee (20/HRA/2531) and the National Health Research Authority.The ethical approval number is 20/HRA/2531.

Pharmacologic Interventions for Kawasaki Disease in Children: A Network Meta-Analysis of 56 Randomized Controlled Trials

Background: Although the current consensus recommends a standard treatment of high-dose intravenous immunoglobulin with high-dose aspirin to manage Kawasaki disease (KD), the use of different adjunctive therapies remains controversial. The aim of current network meta-analysis (NMA) was to compare the efficacy and tolerability of different existing interventions for the initial stage and the refractory stage of KD. Methods: The current NMA of randomized controlled trials (RCTs) was conducted under the frequentist model. Findings: Total fifty-six RCTs with 6,486 participants were included. The NMA demonstrated that the medium intravenous immunoglobulin (IVIG) + aspirin + infliximab [mean difference=−1.76 days (95% confidence intervals (95%CIs): −3.65 to 0.13 days) compared to high IVIG + aspirin] had the shortest fever duration; likewise, the medium IVIG + aspirin + infliximab [odds ratio (OR)=0.50, 95%CIs: 0.18 to 1.37 compared to high IVIG + aspirin] had the least CAL incidence in the initial-stage KD. The high IVIG + pulse steroid therapy (OR=0.04, 95%CIs: 0.00 to 0.43 compared to the high IVIG only) had the best fever subsided rate; likewise, the high IVIG + ciclosporin [OR=0.05 (95%CIs: 0.00 to 1.21) compared to the high IVIG only] had the least CAL incidence in the refractory-stage KD. Interpretation: The current NMA demonstrates that the addition of infliximab plus current standard therapy might be the best treatment for acute KD. Conversely, ciclosporin plus IVIG serves as the best choice for lower the CAL incidence in refractory KD. Further controlled trials are warranted to confirm these findings. Funding Statement: The authors of this work did not receive any grant supports. Brendon Stubbs is supported by a Clinical Lectureship (ICA-CL-2017-03-001) jointly funded by Health Education England (HEE) and the National Institute for Health Research (NIHR). Brendon Stubbs is part funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Brendon Stubbs is also supported by the Maudsley Charity, King’s College London and the NIHR South London Collaboration for Leadership in Applied Health Research and Care (CLAHRC) funding. This paper presents independent research. The views expressed in this publication are those of the authors and not necessarily those of the acknowledged institutions. Declaration of Interests: The authors report no financial interests or potential conflicts of interest.

National Institute for Health Research Health Informatics Collaborative: development of a pipeline to collate electronic clinical data for viral hepatitis research

ObjectiveThe National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) is a programme of infrastructure development across NIHR Biomedical Research Centres. The aim of the NIHR HIC is to...

CCopeY: A Mixed-Methods Co-Produced Study on the Mental Health Status and Coping Strategies of Young People During COVID-19 Lockdown in the UK

Background: Young people’s mental health during COVID-19 pandemic has been identified as a priority. However, studies to date are largely simple surveys and lacking any meaningful involvement from patients and the public in their design, planning and delivery. The study aim was to examine the mental health status and coping strategies of young people (aged 16-24) during and after COVID-19 lockdown using co-production methodology. Methods: We utilised a sequential co-produced mixed methods design. Participants were aged 16-24 and lived in the UK. The primary outcome was mental health status, measured using Patient Health Questionnaire (PHQ-9), anxiety coronavirus impact sub-scale (CIS) and reported self-harm. Predictors included sociodemographic variables, coping strategies (Brief COPE), sleep (Sleep Condition Indicator), personality traits (Ten-Item Personality Inventory) and optimism (Life-Orientation Test - Revised). Semi-structured interviews were also conducted with a purposive sample of survey participants. The study was registered with COVID MINDS. Results: Seven-hundred and ninety-six participants (mean age 19.6 [SD 2.7]) took part in the first survey in April 2020. Survey data showed 26.6% had poor mental health and 10% had self-harmed since lockdown. Young people identifying as Black/Black British ethnicity in our study had the highest increased odds of experiencing poor mental health. Logistic regression showed behavioural disengagement, self-blame and substance misuse coping strategies, negative affect, sleep problems and reduced conscientiousness were all significantly associated with poor mental health. Eighteen participants were followed up and interviewed. There were three main interlinking themes: (1) pre-existing and developed helpful coping strategies employed during lockdown, (2) mental health difficulties worsened during lockdown and (3) the need for mental health and non-mental health support during and after lockdown. Interpretation: To our knowledge this is the first sequential co-produced mixed methods study to examine mental health status and coping strategies of young people during COVID-19 lockdown. On average, young people’s mental health has significantly worsened since lockdown, and dysfunctional coping strategies are associated with this. However, young people have found innovative and adaptive ways to cope, including distraction and having a good routine. Going forward, appropriate and effective mental health support adapted to lockdown conditions is needed to help young people during and after lockdown.Trial Registration: The study was registered with COVID MINDS.Funding Statement: NIHR Patient Safety Translational Research Centre programme grant (Ref: PSTRC-2016-004) and Institute of Global Health Innovation. We are also grateful for support from the National Institute for Health Research (NIHR) under the Applied Research Collaboration (ARC) programme for North West London. and the Imperial NIHR Biomedical Research Centre. Declaration of Interests: PA received funding from Dr Foster Ltd (a wholly owned subsidiary of Telstra Health). AB received funding from Dr Foster Ltd and Medtronic. All other authors declare no competing interests.Ethics Approval Statement: This study was approved by the Imperial Research Ethics committee (ICREC ref: 20IC914) on 20/04/2020.

Markers of achievement for assessing and monitoring gender equity in a UK National Institute for Health Research Biomedical Research Centre: A two-factor model.

BackgroundThe underrepresentation of women in academic medicine at senior level and in leadership positions is well documented. Biomedical Research Centres (BRC), partnerships between leading National Health Service (NHS) organisations and universities, conduct world class translational research funded by the National Institute for Health Research (NIHR) in the UK. Since 2011 BRCs are required to demonstrate significant progress in gender equity (GE) to be eligible to apply for funding. However, the evidence base for monitoring GE specifically in BRC settings is underdeveloped. This is the first survey tool designed to rank and identify new GE markers specific to the NIHR BRCs.MethodsAn online survey distributed to senior leadership, clinical and non-clinical researchers, trainees, administrative and other professionals affiliated to the NIHR Oxford BRC (N = 683). Participants ranked 13 markers of GE on a five point Likert scale by importance. Data were summarised using frequencies and descriptive statistics. Interrelationships between markers and underlying latent dimensions (factors) were determined by exploratory and confirmatory factor analyses.ResultsThe response rate was 36% (243 respondents). Respondents were more frequently female (55%, n = 133), aged 41–50 years (33%, n = 81), investigators (33%, n = 81) affiliated to the BRC for 2–7 years (39.5%, n = 96). Overall participants ranked ‘BRC senior leadership roles’ and ‘organisational policies on gender equity’, to be the most important markers of GE. 58% (n = 141) and 57% (n = 139) respectively. Female participants ranked ‘organisational policies’ (64.7%, n = 86/133) and ‘recruitment and retention’ (60.9%, n = 81/133) most highly, whereas male participants ranked ‘leadership development’ (52.1%, n = 50/96) and ‘BRC senior leadership roles’ (50%, n = 48/96) as most important. Factor analyses identified two distinct latent dimensions: “organisational markers” and “individual markers” of GE in BRCs.ConclusionsA two-factor model of markers of achievement for GE with “organisational” and “individual” dimensions was identified. Implementation and sustainability of gender equity requires commitment at senior leadership and organisational policy level.

Collateral Damage: The Impact on Cancer Outcomes of the COVID-19 Pandemic

Background: Cancer diagnostics and surgery have been disrupted by the response of healthcare services to the COVID-19 pandemic. Progression of cancers during delay will impact on patient long-term survival. Methods: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of three months and six months and periods of disruption of one year and two years. Using healthcare resource costing, we contextualise attributable lives saved and life years gained from cancer surgery to equivalent volumes of COVID-19 hospitalisations. Findings: Per year, 94,912 resections for major cancers result in 80,406 long-term survivors and 1,717,051 life years gained. Per-patient delay of six months would cause attributable death of 10,555 of these individuals with loss of 205,024 life years. For cancer surgery, average life years gained (LYGs) per patient are 18·1 under standard conditions and 15·9 with a delay of six months (a loss of 2·3 LYG per patient). Taking into account units of healthcare resource (HCRU), surgery results on average per patient in 2·25 resource-adjusted life years gained (RALYGs) under standard conditions and 1·98 RALYGs following delay of six months. For 94,912 hospital COVID-19 admissions, there are 474,505 LYGs requiring of 1,097,937 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5·0 LYG and 0·43 RALYGs. Interpretation: Delay of six months in surgery for incident cancers would mitigate 43% of life years gained by hospitalisation of an equivalent volume of admissions for community acquired COVID-19. This rises to 62% when considering resource-adjusted life-years gained. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued. Funding Statement: MEJ additionally received funding from Breast Cancer Now.GL is supported by a Cancer Research UK Advanced Clinician Scientist Fellowship Award [C18081/A18180] and is Associate Director of the multi-institutional CanTest Collaborative funded by Cancer Research UK [C8640/A23385]. B.T and A.G. are supported by Cancer Research UK award C61296/A27223. R.S.H. is supported by Cancer Research UK (C1298/A8362) and Bobby Moore Fund for Cancer Research UK). A.S. is in receipt of an Academic Clinical Lectureship from National Institute for Health Research (NIHR) and Biomedical Research Centre (BRC) post-doctoral support. This is a summary of independent research supported by the NIHR BRC at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research. Declaration of Interests: The authors declare no competing interests.

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

SummaryBackgroundBefore the COVID-19 pandemic, coronaviruses caused two noteworthy outbreaks: severe acute respiratory syndrome (SARS), starting in 2002, and Middle East respiratory syndrome (MERS), starting in 2012. We aimed to assess the psychiatric and neuropsychiatric presentations of SARS, MERS, and COVID-19.MethodsIn this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases (from their inception until March 18, 2020), and medRxiv, bioRxiv, and PsyArXiv (between Jan 1, 2020, and April 10, 2020) were searched by two independent researchers for all English-language studies or preprints reporting data on the psychiatric and neuropsychiatric presentations of individuals with suspected or laboratory-confirmed coronavirus infection (SARS coronavirus, MERS coronavirus, or SARS coronavirus 2). We excluded studies limited to neurological complications without specified neuropsychiatric presentations and those investigating the indirect effects of coronavirus infections on the mental health of people who are not infected, such as those mediated through physical distancing measures such as self-isolation or quarantine. Outcomes were psychiatric signs or symptoms; symptom severity; diagnoses based on ICD-10, DSM-IV, or the Chinese Classification of Mental Disorders (third edition) or psychometric scales; quality of life; and employment. Both the systematic review and the meta-analysis stratified outcomes across illness stages (acute vs post-illness) for SARS and MERS. We used a random-effects model for the meta-analysis, and the meta-analytical effect size was prevalence for relevant outcomes, I2 statistics, and assessment of study quality.Findings1963 studies and 87 preprints were identified by the systematic search, of which 65 peer-reviewed studies and seven preprints met inclusion criteria. The number of coronavirus cases of the included studies was 3559, ranging from 1 to 997, and the mean age of participants in studies ranged from 12·2 years (SD 4·1) to 68·0 years (single case report). Studies were from China, Hong Kong, South Korea, Canada, Saudi Arabia, France, Japan, Singapore, the UK, and the USA. Follow-up time for the post-illness studies varied between 60 days and 12 years. The systematic review revealed that during the acute illness, common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5–36·0] of 129 patients), depressed mood (42 [32·6%; 24·7–40·9] of 129), anxiety (46 [35·7%; 27·6–44·2] of 129), impaired memory (44 [34·1%; 26·2–42·5] of 129), and insomnia (54 [41·9%; 22·5–50·5] of 129). Steroid-induced mania and psychosis were reported in 13 (0·7%) of 1744 patients with SARS in the acute stage in one study. In the post-illness stage, depressed mood (35 [10·5%; 95% CI 7·5–14·1] of 332 patients), insomnia (34 [12·1%; 8·6–16·3] of 280), anxiety (21 [12·3%; 7·7–17·7] of 171), irritability (28 [12·8%; 8·7–17·6] of 218), memory impairment (44 [18·9%; 14·1–24·2] of 233), fatigue (61 [19·3%; 15·1–23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9–37·3] of 181) and sleep disorder (14 [100·0%; 88·0–100·0] of 14) were frequently reported. The meta-analysis indicated that in the post-illness stage the point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7–42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1–18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1–19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1–84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1). When data for patients with COVID-19 were examined (including preprint data), there was evidence for delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis. 68 (94%) of the 72 studies were of either low or medium quality.InterpretationIf infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term.FundingWellcome Trust, UK National Institute for Health Research (NIHR), UK Medical Research Council, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.

Quantifying and Mitigating the Impact of the COVID-19 Pandemic on Outcomes in Colorectal Cancer

Background: The COVID-19 pandemic has caused disruption across cancer pathways for diagnosis and treatment. In England, 32% of colorectal cancer (CRC) is diagnosed via urgent symptomatic referral from primary care, the “2-week-wait” (2WW) pathway. Access to routine endoscopy is likely to be a critical bottleneck causing delays in CRC management due to chronic limitation in capacity, acute competition for physician time, and safety concerns. Methods: We used age-specific, stage-specific 10 year CRC survival for England 2007-2017 and 2WW CRC cases volumes. We used per-day hazard ratios of CRC survival generated from observational studies of CRC diagnosis-to-treatment interval to model the effect of different durations of per-patient delay. We utilised data from a large London observational study of faecal immunochemical testing (FIT) in symptomatic patients to model FIT-triage to mitigate delay to colonoscopy. Findings: Modest delays result in significant reduction in survival from CRC with a 4-month delay resulting across age groups in ≥20% reduction in survival in Stage 3 disease and in total over a year, 1,419 attributable deaths across the 11,266 CRC patients diagnosed via the 2WW pathway. FIT triage of >10 ug Hb/g would salvage 1,292/1,419 of the attributable deaths and reduce colonoscopy requirements by >80%. Diagnostic colonoscopy offers net survival in all age groups, providing nosocomial COVID-19 infection rates are kept low (<2·5%). Interpretation: To avoid significant numbers of avoidable deaths from CRC, normal diagnostic and surgical throughput must be maintained. An accrued backlog of cases will present to primary care following release of lockdown, supranormal endoscopy capacity will be required to manage this without undue delays. FIT-triage of symptomatic cases provides a rational approach by which to avoid patient delay and mitigate pressure on capacity in endoscopy. This would also reduce exposure to nosocomial COVID-19 infection, relevant in particular to older patient groups. Funding Statement: MEJ additionally received funding from Breast Cancer Now. B.T and A.G. are supported by Cancer Research UK award C61296/A27223. C.L. and C.T. receive support from the Movember foundation. R.S.H. is supported by Cancer Research UK (C1298/A8362) and Bobby Moore Fund for Cancer. GL is supported by a Cancer Research UK Advanced Clinician Scientist Fellowship Award [C18081/A18180] and is Associate Director of the multi-institutional CanTest Collaborative funded by Cancer Research UK [C8640/A23385]. Research UK). D.C.M is supported by Cancer Research UK (C57955/A24390. A.S. is in receipt of an Academic Clinical Lectureship from National Institute for Health Research (NIHR) and Biomedical Research Centre (BRC) post-doctoral support. This is a summary of independent research supported by the NIHR BRC at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research. Declaration of Interests: The authors declare no competing interests.

FAST-Forward Phase III Randomised Controlled Trial of 1-Week Hypofractionated Breast Radiotherapy: 5-Year Results for Efficacy and Late Normal Tissue Effects

Background: FAST-Forward aims to identify a 5-fraction (Fr) schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week which is non-inferior for local cancer control and as safe as an international standard 15Fr regimen after primary surgery for early breast cancer. Five-year results are presented. Methods: FAST-Forward (ISRCTN19906132) randomised (1:1:1) patients with invasive carcinoma of the breast (pT1-3 pN0-1 M0) after breast conservation surgery or mastectomy to 40Gy in 15Fr (3 weeks), 27Gy or 26Gy in 5Fr (1 week) to whole breast/chest wall. Primary endpoint was ipsilateral breast tumour relapse (IBTR); assuming 2% 5-year incidence for 40Gy, non-inferiority was pre-defined as < 1.6% excess for 5Fr schedules (critical hazard ratio HR=1.81). Normal tissue effects (NTE) were assessed by clinicians, patients and photographs. Findings: 4096 consenting patients (1361 40Gy, 1367 27Gy, 1368 26Gy) were recruited November 2011-June 2014 from 97 UK centres. At 71 months median follow-up, 79 IBTR events were reported (40Gy: 31, 27Gy: 27, 26Gy: 21); HRs (95%CI) versus 40Gy/15Fr were 27Gy/5Fr: 0.86 (0.51,1.44), 26Gy/5Fr: 0.67 (0.38,1.16). Five-year incidence of IBTR after 40Gy was 2.1% (1.4,3.1); estimated absolute differences versus 40Gy/15Fr were -0.3% (-1.0,0.9) for 27Gy/5Fr (p=0.0022 for non-inferiority) and -0.7% (-1.3,0.3) for 26Gy/5Fr (p=0.00019). 5-year prevalence of any clinician-assessed moderate/marked breast NTE after 40Gy: 98/986 (9.9%), 27Gy: 155/1005 (15.4%), 26Gy: 121/1020 (11.9%). Across all clinician assessments from 1-5 years, odds ratios versus 40Gy/15Fr were 1.55 (1.32,1.83, p<0.0001) for 27Gy/5Fr and 1.12 (0.94,1.34, p=0.20) for 26Gy/5Fr. Patient and photographic assessments showed higher NTE risk for 27Gy versus 40Gy but not for 26Gy. Interpretation: 5-year local tumour incidence and NTE prevalence show 26Gy/5Fr in 1 week to be an effective and safe alternative to 40Gy/15Fr in 3 weeks for patients prescribed adjuvant local radiotherapy after primary surgery for early stage breast cancer. Trial Registration: ISRCTN19906132. Funding Statement: The FAST-Forward trial is funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme - HTA (UK) (09/01/47), with programme grants from Cancer Research UK to support the work of ICRCTSU (C1491/A15955; C1491/A25351). We acknowledge NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (London, UK). Declaration of Interests: JMB reports grants from NIHR HTA and grants from Cancer Research UK during the conduct of the study, and grants and non-financial support from Novartis (previously GSK), grants and non-financial support from Astra Zeneca, grants and non-financial support from Clovis Oncology, grants and non-financial support from Janssen-Cilag, grants and non-financial support from Merck Sharpe & Dohme, grants and non-financial support from Puma Biotechnology, grants and non-financial support from Pfizer, grants and non-financial support from Roche, grants from Medivation, outside the submitted work. DAW reports travel grants from Roche Pharmaceuticals, outside the submitted work. JSH, MAS and LS report grants from NIHR HTA and grants from Cancer Research UK, during the conduct of the study. CCK reports personal fees from Roche Pharmaceutical, outside the submitted work. AA, AMB, DJB, CC, CEC, MC, AG, PH, CM, ZN, NS, IS, JRY declare no competing interests. Ethics Approval Statement: FAST-Forward was approved by the national South East Coast Kent Research Ethics Committee (11/LO/0958) and local Research and Development offices of all participating centres.

&lt;i&gt;Mycobacterium abscessus&lt;/i&gt; Genomic Clusters Span Geography and Patient Groups

Background: Mycobacterium abscessus has emerged as a significant clinical concern following reports that it is readily transmissible in healthcare settings between patients with Cystic Fibrosis (CF). Methods: We analysed consecutive M. abscessus whole-genome sequencing data from England (February-2015 to November-2019) to identify genomically similar isolates. Linkage to a national healthcare usage database was used to investigate possible contacts between patients. Multivariable regression analysis was performed to investigate factors associated with acquisition of a genomically clustered strain (within ≤25 SNPs). Findings: 2297 isolates from 906 patients underwent whole-genome sequencing as part of the routine Public Health England diagnostic service. Of 14 genomic clusters containing ≥10 patients, all but one contained patients with CF and patients without CF. Patients with CF were equally likely to have clustered isolates as those without CF. High-density phylogenetic clusters were randomly distributed over a wide geographical area. The majority of isolates with a closest genetic neighbour consistent with potential transmission had no identifiable relevant epidemiological contacts. Having a clustered isolate was independently associated with increasing age but not time spent as an hospital inpatient/outpatient. We identified two CF sibling pairs with genetically highly divergent isolates and 1 pair with closely related isolates, as well as 25 uninfected presumed household contacts with CF. Interpretation: Previously identified widely disseminated dominant clones of M. abscessus are not restricted to CF patients and occur in other chronic respiratory diseases. Our analysis does not support person-to-person transmission as an important mechanism in M. abscessus dissemination at a national level in England. Funding Statement: The research was supported by the National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance (HPRU 2012-10041) at the University of Oxford in partnership with Public Health England (PHE) and by Oxford NIHR Biomedical Research Centre. T Peto, AS Walker and DW Crook are NIHR Senior Investigators. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. The report presents independent research funded by NIHR. Declaration of Interests: SL is supported by a Medical Research Council Clinical Research Training Fellowship. DWE declares lecture fees from Gilead, outside the submitted work. TMW is a Wellcome Trust Clinical Career Development Fellow (214560/Z/18/Z). The remaining authors declare no conflicts of interest. Ethics Approval Statement: This work was carried out as a public health investigation with internal approval from Public Health England and therefore ethics committee approval was not required.

Guided self-help for depression in autistic adults: the ADEPT feasibility RCT.

Co-occurring depression frequently occurs in autism. Evidence-based psychological interventions have been successfully adapted to treat co-occurring anxiety, but there is little evidence about the usefulness of adapted cognitive-behavioural therapy for depression. To the authors' knowledge, to date there have been no randomised trials investigating the usefulness of low-intensity cognitive-behavioural therapy for depression in autism. The objectives of the study were to (1) develop a low-intensity psychological intervention for depression adapted for autism, (2) assess the feasibility and patient and therapist acceptability of the intervention, (3) estimate the rates of recruitment and retention for a full-scale randomised controlled trial and (4) identify an appropriate measure of depression to be used in a full-scale randomised controlled trial. The study comprised a randomised controlled trial (n = 70) with a nested qualitative evaluation (n = 21). Seventy eligible and consenting participants were randomly allocated to guided self-help or to treatment as usual. Adult autism services in two NHS regions. Adults with a diagnosis of autism spectrum disorder with depression, that is, a Patient Health Questionnaire-9 items score of ≥ 10. People who had attended more than six sessions of cognitive-behavioural therapy in the previous 6 months were excluded. The low-intensity intervention (guided self-help) comprised materials for nine individual sessions, based on behavioural activation adapted for autism, facilitated by therapist guides (coaches) who were graduate-level psychologists who attended training and regular supervision. Treatment as usual was standard NHS care for depression. Outcomes were measured 10, 16 and 24 weeks post randomisation using self-report and interview measures of depression, anxiety, obsessive-compulsive symptoms, social function and quality of life, and a health-care and service use questionnaire. As this was a feasibility study also designed to identify the most appropriate measure of depression, it was not possible to specify the primary outcome measure or outcome point a priori. The aims of the study were met in full. The guided self-help intervention was feasible and well received by participants and coaches. The majority of allocated participants attended the intervention in full. The most practical outcome point was determined to be 16 weeks. There were differential rates of attrition across the treatment groups: 86% of the guided self-help group remained in the study at 24 weeks, compared with 54% of treatment as usual group. The qualitative study suggested that guided self-help had enhanced credibility with participants at the point of randomisation. Inter-rater reliability of the interview measure of depression was less than adequate, limiting the conclusions that can be drawn from the prespecified sensitivity to change analyses. The intervention was feasible and well received. Although this feasibility study was not a fully powered trial, it provided some evidence that the guided self-help intervention was effective in reducing depressive symptoms. A full-scale clinical effectiveness and cost-effectiveness trial of the intervention is warranted. Improvements to the intervention materials as a result of qualitative interviews. Stakeholder consultation to consider future trial design, consider strategies to improve retention in a treatment as usual arm and select a self-report measure of depression to serve as the primary outcome measure. Current Controlled Trials ISRCTN54650760. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 68. See the NIHR Journals Library website for further project information. This study was also supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol.

Enhanced motivational interviewing for reducing weight and increasing physical activity in adults with high cardiovascular risk: the MOVE IT three-arm RCT.

Motivational interviewing (MI) enhanced with behaviour change techniques (BCTs) and deployed by health trainers targeting multiple risk factors for cardiovascular disease (CVD) may be more effective than interventions targeting a single risk factor. The clinical effectiveness and cost-effectiveness of an enhanced lifestyle motivational interviewing intervention for patients at high risk of CVD in group settings versus individual settings and usual care (UC) in reducing weight and increasing physical activity (PA) were tested. This was a three-arm, single-blind, parallel randomised controlled trial. A total of 135 general practices across all 12 South London Clinical Commissioning Groups were recruited. A total of 1742 participants aged 40-74 years with a ≥ 20.0% risk of a CVD event in the following 10 years were randomised. The intervention was designed to integrate MI and cognitive-behavioural therapy (CBT), delivered by trained healthy lifestyle facilitators in 10 sessions over 1 year, in group or individual format. The control group received UC. Simple randomisation was used with computer-generated randomisation blocks. In each block, 10 participants were randomised to the group, individual or UC arm in a 4 : 3 : 3 ratio. Researchers were blind to the allocation. The primary outcomes are change in weight (kg) from baseline and change in PA (average number of steps per day over 1 week) from baseline at the 24-month follow-up, with an interim follow-up at 12 months. An economic evaluation estimates the relative cost-effectiveness of each intervention. Secondary outcomes include changes in low-density lipoprotein cholesterol and CVD risk score. The mean age of participants was 69.75 years (standard deviation 4.11 years), 85.5% were male and 89.4% were white. At the 24-month follow-up, the group and individual intervention arms were not more effective than UC in increasing PA [mean 70.05 steps, 95% confidence interval (CI) -288 to 147.9 steps, and mean 7.24 steps, 95% CI -224.01 to 238.5 steps, respectively] or in reducing weight (mean -0.03 kg, 95% CI -0.49 to 0.44 kg, and mean -0.42 kg, 95% CI -0.93 to 0.09 kg, respectively). At the 12-month follow-up, the group and individual intervention arms were not more effective than UC in increasing PA (mean 131.1 steps, 95% CI -85.28 to 347.48 steps, and mean 210.22 steps, 95% CI -19.46 to 439.91 steps, respectively), but there were reductions in weight for the group and individual intervention arms compared with UC (mean -0.52 kg, 95% CI -0.90 to -0.13 kg, and mean -0.55 kg, 95% CI -0.95 to -0.14 kg, respectively). The group intervention arm was not more effective than the individual intervention arm in improving outcomes at either follow-up point. The group and individual interventions were not cost-effective. Enhanced MI, in group or individual formats, targeted at members of the general population with high CVD risk is not effective in reducing weight or increasing PA compared with UC. Future work should focus on ensuring objective evidence of high competency in BCTs, identifying those with modifiable factors for CVD risk and improving engagement of patients and primary care. Current Controlled Trials ISRCTN84864870. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 69. See the NIHR Journals Library website for further project information. This research was part-funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.

Platelet-rich plasma injection for adults with acute Achilles tendon rupture: the PATH-2 RCT

BackgroundAchilles tendon rupture (ATR) has a long healing period, which is challenging for patients and clinicians. Platelet-rich plasma (PRP) is an autologous concentration of platelets thought to improve tendon function recovery. Although preliminary research has indicated positive effects, there is, as yet, no evidence of clinical efficacy from adequately powered robust clinical trials.ObjectivesThe objectives were to determine the clinical efficacy of PRP in patients with acute ATR using an objective mechanical muscle–tendon function measure and patient-reported outcome measures (PROMs), and to determine which PRP components contribute to its mechanism.DesignThis was a multicentre, parallel-group, participant- and outcome assessor-blinded randomised controlled trial (RCT) comparing PRP with placebo. Two embedded substudies investigated the PRP’s quality and composition and its effects on healing tendon tissues.SettingThis trial was set in trauma and orthopaedic surgery departments in 19 NHS hospitals in England and Wales.ParticipantsAdults with acute ATR presenting within 12 days of injury to be treated non-surgically were eligible. Patients with platelet dysfunction or leg functional deficiency were excluded.InterventionsParticipants were randomised 1 : 1 to the PRP injection group or the placebo group (dry needle in the rupture gap) by central computer-based randomisation using minimisation, stratified by centre and age.Main outcome measuresThe primary outcome measure was the Limb Symmetry Index (LSI) of work during the heel-rise endurance test at 24 weeks. Secondary outcomes measures, collected at 4, 7, 13 and 24 weeks, were repetitions, maximum heel-rise height, Achilles tendon Total Rupture Score (ATRS), quality of life (as measured using the Short Form questionnaire-12 items version 2), pain and participant goal attainment. Needle biopsies of the affected tendon zone were taken under ultrasound guidance at 6 weeks from 16 participants from one centre. Whole blood was analysed for cell count. PRP was analysed for cell count, platelet activation and growth factor concentration. The primary analysis was intention to treat.ResultsA total of 230 participants were randomised: 114 to the PRP group (103 treated) and 116 to the placebo group (all treated). One participant withdrew after randomisation but before the intervention. At 24 weeks, 201 out of 230 participants (87.4%) completed the primary outcome and 216 out of 230 participants (93.9%) completed the PROMs. The treatment groups had similar participant characteristics. At 24 weeks, there was no difference in work LSI (mean difference –3.872; 95% confidence interval –10.454 to 2.710;p = 0.231), ATRS, pain or goal attainment between PRP- and placebo-injected participants. There were no differences between the groups in any PROM at any time point or in complication rates, including re-rupture and deep-vein thrombosis. There was no correlation between work LSI and platelet activation in PRP, or erythrocyte, leucocyte or platelet counts in whole blood or PRP. Biopsies showed similar cellularity and vascularity between groups.ConclusionsThis trial design and standardised PRP preparation gives the first robust RCT evidence about PRP’s role in managing ATR, which suggests that PRP offers no patient benefit. Equally robust evidence to investigate PRP application in tendon and soft tissue injuries is required. The 24-month follow-up will be completed in April 2020.Trial registrationCurrent Controlled Trials ISRCTN54992179.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. The trial was supported by the NIHR Biomedical Research Centre, Oxford, and the NIHR Fellowship programme.

Health service use by community-dwelling patients with heart failure in northwest London, 2015–18: a retrospective cohort analysis

BackgroundHeart failure management is complex and requires multidimensional care. Clinical guidelines advocate for the use of integrated care, but few studies have described overall health service use by patients with heart failure. We describe overall care usage by community-dwelling patients with heart failure in northwest London using a dataset linked across multiple health-care settings. MethodsIn this retrospective cohort analysis, we used Whole Systems Integrated Care (WSIC) data, a dataset of individual clinical events from primary care, secondary care, and other (defined as community, mental health, and social care) services in northwest London to analyse a retrospective cohort of patients with heart failure. Patients who remain in the WSIC dataset, were aged at least 18 years on Jan 1, 2015, with known age and gender, and whose diagnosis was not made after their date of death. The primary outcome was health-care usage of each of the three service categories overall as well as individual components of secondary care (eg, outpatient appointments) and other services (eg, nursing contacts). Usage patterns were identified using k-means cluster analysis using all distinct contacts for the whole study period and visualised by a heatmap. Nine health-care use variables were used to identify clusters, and differences between clusters in both clustering and non-clustering variables were analysed using Kruskal-Wallis and Pearson χ2 tests. This study was approved by the Discover Research Advisory Group. FindingsData from 39 301 patients with heart failure across 359 general practices between Jan 1, 2015, and Dec 31, 2018, were analysed. Almost all patients had some health service contact during the study period (21 226 [89·1%] of 23 828 in 2015; 24 876 [90·6%] of 27 443 in 2016; 28 663 [90·8%] of 31 554 in 2017; and 31 584 [91·1%] of 34 651 in 2018). Most commonly used services in 2018 were outpatient appointments (24 283 [70·1%] of 34 651 patients), general practitioner (GP) consultations (20 741 [59·9%] patients), unplanned accident and emergency visits (14 145 [40·8%] patients) and community services (13 762 [39·7%] patients), often for nursing. Use of cardiology-specific services ranged from 1005 (2·9%) patients for community visits to 8231 (23·8%) for outpatient visits. Five clusters of patients were identified, each with significantly different care usage patterns and distinct patient characteristics. Patterns included underuse of GP consultations, relative to the average use by the whole cohort, in patients living in more deprived areas; and increased use of other services in patients older than 75 years and those with three or more comorbidities. InterpretationHealth and social care service use was widespread but varied. Patterns of care usage suggest differences across patient groups. This might be due to variation in patients’ access to care and insufficiently integrated care at earlier stages of heart failure. The limitations of our study are that electronic health records like WSIC are not coded for research and subject to some biases; k-means testing is sensitive to the input variables and selection of k; and our findings require further validation and might not be generalisable to regions beyond the northwest London area. Further research is needed to characterise the patterns we have identified. FundingDr Foster (a Telstra Health company), the National Institute for Health Research (NIHR) Health Services Research, and the Imperial NIHR Biomedical Research Centre and the NIHR Collaboration for Leadership in Applied Health Research and Care for northwest London. The views expressed are those of the authors and not those of the NIHR.