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Development of a multicentre cohort study to understand the role of MRI and ultrasound in the diagnosis of acute haematogenous bone and joint infection in children (the PIC Bone study) : a study protocol.

AIMS: Bone and joint infections (BJI) in children are rare but can be serious. Differentiating BJI from other conditions with similar symptoms is critical. Advanced imaging (ultrasound scans (USS) and MRI) is often required to confirm the diagnosis. The differing merits of imaging type and regional variation in access to advanced imaging can lead to diagnostic uncertainty and treatment variation. The aim of this study is to evaluate the diagnostic accuracy of MRI and USS for the investigation of BJI in children, and develop and validate prediction models to aid the diagnosis of BJI in children. A nested qualitative sub-study will explore acceptability of the imaging to children, parents, and health practitioners. METHODS: A multicentre retrospective cohort of children (aged < 16 years) with suspected diagnosis of BJI will be used to estimate the diagnostic accuracy of the two imaging methods and develop the prediction models. The models will be evaluated in a second cohort of prospectively recruited children. Diagnostic test accuracy will be estimated overall, and separately for children aged under and over five years. The prediction models will be fit using logistic regression, with candidate predictors chosen based on clinical plausibility and from a review of the literature. Continuous predictors will be examined for non-linearity with confirmed BJI using fractional polynomials. Multiple imputation will be used to replace missing values. Internal validation will be carried out using bootstrapping. Model performance will be assessed with discrimination and calibration. DISCUSSION: Ethical approval for this study (registration: ISRCTN15471635) was granted (REC reference 23/WM/0027). Informed consent is being obtained from participants in the prospective cohort and the qualitative sub-study. Study findings will be published in an open access journal and presented at relevant national and international conferences. Relevant charities and associations are being engaged to promote awareness of the project.

An update on periprosthetic joint infection for UK trainees

An infection of any surgically replaced joint represents a complex medical, social, and economic problem. Infection, and the complications therein, can represent a potential significant threat to a patient's limb, life, and livelihood. We explore the role of the microbiome in normal function and implications of dysbiosis in the development of periprosthetic joint infection; and the essential role of early accurate diagnosis and collaboration between surgeons, infectious diseases specialists/microbiologists and allied health teams. The management of prosthetic joint infections should take place in a multidisciplinary team (MDT). Despite the general principles of management outlined in this review, surgical and antimicrobial management is patient-specific, considering the cultured organism and its sensitivities, and the patient's overall health, comorbidities, their function, goals and expectations.

Recovery after partial knee arthroplasty and daycare surgery

UKA is a minimally invasive procedure that allows for safe, efficient care with fewer perioperative complications, leading to higher patient satisfaction and improved cost-effectiveness. The philosophy of marginal gains has enabled day case arthroplasty to become feasible. Patients are assessed for suitability for daycase surgery, and any patients at risk of unstable conditions are excluded from the day of surgery discharge pathway. Patients are informed about the perioperative plan and given consistent advice to prepare for same day discharge. Anaesthetic of choice is GA, and premedication is intravenous. Antibiotics are administered before induction. Surgery is performed in the supine position with a thigh support and a high thigh tourniquet using Oxford microplasty instrumentation. Post-operatively, patients are allowed to eat and drink freely, receive rescue analgesia, and are mobilised fully weight bearing with crutches. Patients are provided with post-operative analgesics, laxatives and anti-emetics, have direct access to a 24-hour telephone helpline service, are admitted overnight, receive same post-operative instructions, return to UKA clinic on fifth post-operative day for physiotherapy, and are reviewed at 6 weeks. Introducing an effective outpatient arthroplasty protocol requires a multidisciplinary approach, with a consistent team message and good patient education to achieve successful same day discharge. Financial savings from a safe and effective day of surgery discharge pathway are considerable.

Autoimmunity in inflammatory bowel disease: a holobiont perspective.

Adaptive immunity towards self-antigens (autoimmunity) and intestinal commensal microbiota is a key feature of inflammatory bowel disease (IBD). Considering mucosal adaptive immunity from a holobiont perspective, where the host and its microbiome form a single physiological unit, emphasises the challenge of avoiding damaging responses to self-antigen and symbiotic microbial communities in the gut while protecting against potential pathogens. Intestinal tolerance mechanisms prevent maladaptive T and B cell responses to microbial, environmental, and self-antigens, which drive inflammation. We discuss the spectrum of antimicrobial and autoantibody responses and highlight mechanisms by which common IBD-associated adaptive immune responses contribute to disease.

Exploring nutritional supplement use for countering respiratory tract infections through an X (formerly Twitter)-based survey

Public availability of randomized clinical trial protocols: A repeated meta-research study.

OBJECTIVE: Making protocols of randomized clinical trials (RCT) publicly available is important for the trustworthiness and quality of medical research. In a previous study assessing 326 RCTs with ethical approval in 2012, only 36% had a publicly available protocol. We aimed to generate current evidence on the availability of RCT protocols and to evaluate changes over time. STUDY DESIGN AND SETTING: Using a representative sample of RCTs approved in 2016 in Switzerland, Canada, Germany, and the UK, we investigated the number of available protocols by searching PubMed, Google Scholar, trial registries, and Google. Up to June 2024, we systematically searched for (i) protocols available as peer-reviewed publications, (ii) protocols attached to trial registries and (iii) protocols shared with result publications of RCTs. We used multivariable logistic regression to examine the association of protocol availability with trial characteristics such as sample size, drug vs. non-drug interventions, multicenter vs. single center status, and RCT approval in 2016 vs. 2012. RESULTS: Of the 347 included RCTs, 228 (66%) had an available protocol. Forty-three percent (150/347) of the protocols were available as files on trial registries, 26% (91/347) as supplementary material to result publication, and 23% (81/347) as peer-reviewed publications. Protocol availability improved over time in industry trials (83.4% in 2016 vs. 34.6% in 2012). Protocol availability for non-industry trials remained low (46.4% 2016 vs. 38.1% 2012). Multicenter trials (206/256; 77.7% vs single-center trials 22/82; 26.8%) and larger sample size (>500 participants 68/77; 88.3%, 100-500 participants 131/191; 68.6%, <100 participants 29/79; 36.7%) showed higher protocol availability. CONCLUSION: The availability of protocols increased in RCTs approved in 2016 compared to RCTs from 2012. This was mainly driven by industry sponsored trials. Efforts to further improve protocol availability should be continued, especially in non-industry sponsored RCTs.

Pair wave function symmetry in UTe2 from zero-energy surface state visualization.

Although nodal spin-triplet topological superconductivity appears probable in uranium ditelluride (UTe2), its superconductive order parameter Δk remains unestablished. In theory, a distinctive identifier would be the existence of a superconductive topological surface band, which could facilitate zero-energy Andreev tunneling to an s-wave superconductor and also distinguish a chiral from a nonchiral Δk through enhanced s-wave proximity. In this study, we used s-wave superconductive scan tips and detected intense zero-energy Andreev conductance at the UTe2 (0-11) termination surface. Imaging revealed subgap quasiparticle scattering interference signatures with a-axis orientation. The observed zero-energy Andreev peak splitting with enhanced s-wave proximity signifies that Δk of UTe2 is a nonchiral state: B1u, B2u, or B3u. However, if the quasiparticle scattering along the a axis is internodal, then a nonchiral B3u state is the most consistent for UTe2.

Association between preoperative glycaemic control (HbA1c) and early outcomes following primary hip and knee arthroplasty.

AIMS: This study investigates the relationship between diabetes mellitus (DM), glycated haemoglobin (HbA1c), and postoperative outcomes among patients undergoing hip and knee arthroplasty. METHODS: We conducted a single-centre cohort study of patients who underwent primary hip or knee arthroplasty between June 2008 and December 2019 and for whom preoperative HbA1c had been recorded. Cases were categorized by preoperative HbA1c as 'diabetes' (≥ 48 mmol/mol), 'prediabetes' (≥ 42 mmol/mol and < 48 mmol/mol), 'no diabetes' (< 42 mmol/mol), or in 'remission' (preoperative HbA1c < 42 mmol/mol but having a historic HbA1c result ≥ 42 mmol/mol). Multivariable logistic regression and restricted cubic splines were used to examine the association between diabetes status, HbA1c, and early postoperative outcomes. RESULTS: Analysis of 9,454 procedures (18.4% diabetes, 23.5% prediabetes, 49.7% no diabetes, 8.4% in remission) revealed that DM was associated with a 50% greater likelihood of experiencing one or more postoperative complications (odds ratio (OR) 1.47 (95% CI 1.26 to 1.71)), a 60% greater risk of acute kidney injury or electrolyte abnormality (OR 1.57 (95% CI 1.33 to 1.87)), and more than double the risk of postoperative urinary tract infection (OR 2.25 (95% CI 1.15 to 4.52)) and deep surgical site infection (OR 2.03 (95% CI 1.05 to 3.86)) compared to individuals without diabetes. There was a substantial increase in complication risk as HbA1c entered prediabetes range with no evidence of a plateau or threshold effect, and a profound reduction in the risk of almost all recorded complications for patients in remission from previously elevated HbA1c. CONCLUSION: DM was associated with an increased risk of almost all measured early postoperative complications. Interventions to reduce elevated HbA1c, to any degree, may benefit patient outcomes, however these must be balanced with the risk of iatrogenic harm.

Effects of temporarily suspending low-dose methotrexate treatment for 2 weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions: protocol for a multicentre randomised controlled trial and nested mechanistic substudy (Vaccine Response On/Off Methotrexate (VROOM) study)

This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1136/bmjopen-2022-062599 Introduction It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions. Methods and analysis An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status. Ethics and dissemination This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers. Trial registration number ISRCTN11442263. Funding This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] DOI https://doi.org/10.1136/bmjopen-2022-062599

Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial

This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1016/S2665-9913(23)00298-9 Summary Background Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Method We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. Finding Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. Interpretation 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. Funding National Institute for Health and Care Research. Funding This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] DOI https://doi.org/10.1016/S2665-9913(23)00298-9

Core-shell microcapsules compatible with routine injection enable prime/boost immunization against malaria with a single shot.

Inadequate booster uptake threatens the success of immunization campaigns as seen with the recently rolled-out R21 malaria vaccine. The ability to administer both prime and boost immunizations with a single injection would therefore save lives and alleviate health care burdens. We present a platform for delayed delivery of the booster dose that is scalable with existing technology, easily injectable, and protective against malaria in vivo. Using chip-based microfluidics, we encapsulated the R21 malaria vaccine in polymer microcapsules that release their content weeks to months postinjection. Coinjecting microcapsules with the priming dose of the R21 vaccine elicited strong antibody responses in a mouse model and provided 85% of the protection of a standard prime/boost schedule. If confirmed in humans, these results would pave the way for rapid deployment of single-shot prime/boost vaccination, an urgently needed global health intervention.

User engagement in clinical trials of digital mental health interventions: a systematic review.

INTRODUCTION: Digital mental health interventions (DMHIs) overcome traditional barriers enabling wider access to mental health support and allowing individuals to manage their treatment. How individuals engage with DMHIs impacts the intervention effect. This review determined whether the impact of user engagement was assessed in the intervention effect in Randomised Controlled Trials (RCTs) evaluating DMHIs targeting common mental disorders (CMDs). METHODS: This systematic review was registered on Prospero (CRD42021249503). RCTs published between 01/01/2016 and 17/09/2021 were included if evaluated DMHIs were delivered by app or website; targeted patients with a CMD without non-CMD comorbidities (e.g., diabetes); and were self-guided. Databases searched: Medline; PsycInfo; Embase; and CENTRAL. All data was double extracted. A meta-analysis compared intervention effect estimates when accounting for engagement and when engagement was ignored. RESULTS: We identified 184 articles randomising 43,529 participants. Interventions were delivered predominantly via websites (145, 78.8%) and 140 (76.1%) articles reported engagement data. All primary analyses adopted treatment policy strategies, ignoring engagement levels. Only 19 (10.3%) articles provided additional intervention effect estimates accounting for user engagement: 2 (10.5%) conducted a complier-average-causal effect (CACE) analysis (principal stratum strategy) and 17 (89.5%) used a less-preferred per-protocol (PP) population excluding individuals failing to meet engagement criteria (estimand strategies unclear). Meta-analysis for PP estimates, when accounting for user engagement, changed the standardised effect to -0.18 95% CI (-0.32, -0.04) from - 0.14 95% CI (-0.24, -0.03) and sample sizes reduced by 33% decreasing precision, whereas meta-analysis for CACE estimates were - 0.19 95% CI (-0.42, 0.03) from - 0.16 95% CI (-0.38, 0.06) with no sample size decrease and less impact on precision. DISCUSSION: Many articles report user engagement metrics but few assessed the impact on the intervention effect missing opportunities to answer important patient centred questions for how well DMHIs work for engaged users. Defining engagement in this area is complex, more research is needed to obtain ways to categorise this into groups. However, the majority that considered engagement in analysis used approaches most likely to induce bias.

A randomised controlled test in virtual reality of the effects on paranoid thoughts of virtual humans' facial animation and expression.

Virtual reality (VR) is increasingly used in the study and treatment of paranoia. This is based on the finding that people who mistakenly perceive hostile intent from other people also perceive similar threat from virtual characters. However, there has been no study of the programming characteristics of virtual characters that may influence their interpretation. We set out to investigate how the animation and expressions of virtual humans may affect paranoia. In a two-by-two factor, between-groups, randomized design, 122 individuals with elevated paranoia rated their perceptions of virtual humans, set in an eye-tracking enabled VR lift scenario, that varied in facial animation (static or animated) and expression (neutral or positive). Both facial animation (group difference = 102.328 [51.783, 152.872], p 

Digitally augmented, parent-led CBT versus treatment as usual for child anxiety problems in child mental health services in England and Northern Ireland: a pragmatic, non-inferiority, clinical effectiveness and cost-effectiveness randomised controlled trial.

BACKGROUND: Anxiety problems are common in children, yet few affected children access evidence-based treatment. Digitally augmented psychological therapies bring potential to increase availability of effective help for children with mental health problems. This study aimed to establish whether therapist-supported, digitally augmented, parent-led cognitive behavioural therapy (CBT) could increase the efficiency of treatment without compromising clinical effectiveness and acceptability. METHODS: We conducted a pragmatic, unblinded, two-arm, multisite, randomised controlled non-inferiority trial to evaluate the clinical effectiveness and cost-effectiveness of therapist-supported, parent-led CBT using the Online Support and Intervention (OSI) for child anxiety platform compared with treatment as usual for child (aged 5-12 years) anxiety problems in 34 Child and Adolescent Mental Health Services in England and Northern Ireland. We examined acceptability of OSI plus therapist support via qualitative interviews. Participants were randomly assigned (1:1) to OSI plus therapist support or treatment as usual, minimised by child age, gender, service type, and baseline child anxiety interference. Outcomes were assessed at week 14 and week 26 after randomisation. The primary clinical outcome was parent-reported interference caused by child anxiety at week 26 assessment, using the Child Anxiety Impact Scale-parent report (CAIS-P). The primary measure of health economic effect was quality-adjusted life-years (QALYs). Outcome analyses were conducted blind in the intention-to-treat (ITT) population with a standardised non-inferiority margin of 0·33 for clinical analyses. The trial was registered with ISRCTN, 12890382. FINDINGS: Between Dec 5, 2020, and Aug 3, 2022, 706 families (706 children and their parents or carers) were referred to the study information. 444 families were enrolled. Parents reported 255 (58%) child participants' gender to be female, 184 (41%) male, three (<1%) other, and one (<1%) preferred not to report their child's gender. 400 (90%) children were White and the mean age was 9·20 years (SD 1·79). 85% of families for whom clinicians provided information in the treatment as usual group received CBT. OSI plus therapist support was non-inferior for parent-reported anxiety interference on the CAIS-P (SMD 0·01, 95% CI -0·15 to 0·17; p<0·0001) and all secondary outcomes. The mean difference in QALYs across trial arms approximated to zero, and OSI plus therapist support was associated with lower costs than treatment as usual. OSI plus therapist support was likely to be cost effective under certain scenarios, but uncertainty was high. OSI plus therapist support acceptability was good. No serious adverse events were reported. INTERPRETATION: Digitally augmented intervention brought promising savings without compromising outcomes and as such presents a valuable tool for increasing access to psychological therapies and meeting the demand for treatment of child anxiety problems. FUNDING: Department for Health and Social Care and United Kingdom Research and Innovation Research Grant, National Institute for Health and Care (NIHR) Research Policy Research Programme, Oxford and Thames Valley NIHR Applied Research Collaboration, Oxford Health NIHR Biomedical Research Centre.

PROTEUS Study: A Prospective Randomized Controlled Trial Evaluating the Use of Artificial Intelligence in Stress Echocardiography.

BACKGROUND: Stress echocardiography (SE) is one of the most commonly used diagnostic imaging tests for coronary artery disease (CAD) but requires clinicians to visually assess scans to identify patients who may benefit from invasive investigation and treatment. EchoGo Pro provides an automated interpretation of SE based on artificial intelligence (AI) image analysis. In reader studies, use of EchoGo Pro when making clinical decisions improves diagnostic accuracy and confidence. Prospective evaluation in real world practice is now important to understand the impact of EchoGo Pro on the patient pathway and outcome. METHODS: PROTEUS is a randomized, multicenter, 2-armed, noninferiority study aiming to recruit 2,500 participants from National Health Service (NHS) hospitals in the UK referred to SE clinics for investigation of suspected CAD. All participants will undergo a stress echocardiogram protocol as per local hospital policy. Participants will be randomized 1:1 to a control group, representing current practice, or an intervention group, in which clinicians will receive an AI image analysis report (EchoGo Pro, Ultromics Ltd, Oxford, UK) to use during image interpretation, indicating the likelihood of severe CAD. The primary outcome will be appropriateness of clinician decision to refer for coronary angiography. Secondary outcomes will assess other health impacts including appropriate use of other clinical management approaches, impact on variability in decision making, patient and clinician qualitative experience and a health economic analysis. DISCUSSION: This will be the first study to assess the impact of introducing an AI medical diagnostic aid into the standard care pathway of patients with suspected CAD being investigated with SE. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT05028179, registered on 31 August 2021; ISRCTN: ISRCTN15113915; IRAS ref: 293515; REC ref: 21/NW/0199.

Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

A randomised controlled trial to compare clinical and cost-effectiveness of an online parent-led treatment for child anxiety problems with usual care in the context of COVID-19 delivered in Child and Adolescent Mental Health Services in the UK (Co-CAT): a study protocol for a randomised controlled trial.

BACKGROUND: In the context of COVID-19, NHS Child and Adolescent Mental Health Services (CAMHS) and other children's mental health services have faced major challenges in providing psychological treatments that (i) work when delivered remotely and (ii) can be delivered efficiently to manage increases in referrals as social distancing measures have been relaxed. Anxiety problems are a common reason for referral to CAMHS, children with pre-existing anxiety problems are particularly vulnerable in the context of COVID-19, and there were concerns about increases in childhood anxiety as schools reopened. The proposed research will evaluate the clinical and cost-effectiveness of a brief online parent-led cognitive behavioural treatment (CBT) delivered by the OSI (Online Support and Intervention for child anxiety) platform with remote support from a CAMHS therapist compared to 'COVID-19 treatment as usual' (C-TAU) in CAMHS and other children's mental health services throughout the COVID-19 pandemic. METHODS: We will conduct a two-arm, multi-site, randomised controlled non-inferiority trial to evaluate the clinical and cost-effectiveness of OSI with therapist support compared to CAMHS and other child mental health services 'COVID-19 treatment as usual' (C-TAU) during the COVID-19 outbreak and to explore parent and therapists' experiences. DISCUSSION: If non-inferiority is shown, the research will provide (1) a solution for efficient psychological treatment for child anxiety disorders while social distancing (for the COVID-19 context and future pandemics); (2) an efficient means of treatment delivery as 'normal service' resumes to enable CAMHS to cope with the anticipated increase in referrals; and (3) a demonstration of rapid, high-quality evaluation and application of online interventions within NHS CAMHS to drive forward much-needed further digital innovation and evaluation in CAMHS settings. The primary beneficiaries will be children with anxiety disorders and their families, NHS CAMHS teams, and commissioners who will access a potentially effective, cost-effective, and efficient treatment for child anxiety problems. TRIAL REGISTRATION: ISRCTN ISRCTN12890382 . Registered prospectively on 23 October 2020.

Effects of different types of written vaccination information on COVID-19 vaccine hesitancy in the UK (OCEANS-III): a single-blind, parallel-group, randomised controlled trial.

BACKGROUND: The effectiveness of the COVID-19 vaccination programme depends on mass participation: the greater the number of people vaccinated, the less risk to the population. Concise, persuasive messaging is crucial, particularly given substantial levels of vaccine hesitancy in the UK. Our aim was to test which types of written information about COVID-19 vaccination, in addition to a statement of efficacy and safety, might increase vaccine acceptance. METHODS: For this single-blind, parallel-group, randomised controlled trial, we aimed to recruit 15 000 adults in the UK, who were quota sampled to be representative. Participants were randomly assigned equally across ten information conditions stratified by level of vaccine acceptance (willing, doubtful, or strongly hesitant). The control information condition comprised the safety and effectiveness statement taken from the UK National Health Service website; the remaining conditions addressed collective benefit, personal benefit, seriousness of the pandemic, and safety concerns. After online provision of vaccination information, participants completed the Oxford COVID-19 Vaccine Hesitancy Scale (outcome measure; score range 7-35) and the Oxford Vaccine Confidence and Complacency Scale (mediation measure). The primary outcome was willingness to be vaccinated. Participants were analysed in the groups they were allocated. p values were adjusted for multiple comparisons. The study was registered with ISRCTN, ISRCTN37254291. FINDINGS: From Jan 19 to Feb 5, 2021, 15 014 adults were recruited. Vaccine hesitancy had reduced from 26·9% the previous year to 16·9%, so recruitment was extended to Feb 18 to recruit 3841 additional vaccine-hesitant adults. 12 463 (66·1%) participants were classified as willing, 2932 (15·6%) as doubtful, and 3460 (18·4%) as strongly hesitant (ie, report that they will avoid being vaccinated for as long as possible or will never get vaccinated). Information conditions did not alter COVID-19 vaccine hesitancy in those willing or doubtful (adjusted p values >0·70). In those strongly hesitant, COVID-19 vaccine hesitancy was reduced, in comparison to the control condition, by personal benefit information (mean difference -1·49, 95% CI -2·16 to -0·82; adjusted p=0·0015), directly addressing safety concerns about speed of development (-0·91, -1·58 to -0·23; adjusted p=0·0261), and a combination of all information (-0·86, -1·53 to -0·18; adjusted p=0·0313). In those strongly hesitant, provision of personal benefit information reduced hesitancy to a greater extent than provision of information on the collective benefit of not personally getting ill (-0·97, 95% CI -1·64 to -0·30; adjusted p=0·0165) or the collective benefit of not transmitting the virus (-1·01, -1·68 to -0·35; adjusted p=0·0150). Ethnicity and gender were found to moderate information condition outcomes. INTERPRETATION: In the approximately 10% of the population who are strongly hesitant about COVID-19 vaccines, provision of information on personal benefit reduces hesitancy to a greater extent than information on collective benefits. Where perception of risk from vaccines is most salient, decision making becomes centred on the personal. As such, messaging that stresses the counterbalancing personal benefits is likely to prove most effective. The messaging from this study could be used in public health communications. Going forwards, the study highlights the need for future health campaigns to engage with the public on the terrain that is most salient to them. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and NIHR Oxford Health Biomedical Research Centre.

Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.

BACKGROUND: Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications. METHODS: In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580. FINDINGS: The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI] 0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI -0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalised (absolute benefit in percentage 0·3%, 95% BCI -1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19. INTERPRETATION: Our findings do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK. FUNDING: UK Research and Innovation and UK Department of Health and Social Care.

Prescriber Commitment Posters to Increase Prudent Antibiotic Prescribing in English General Practice: A Cluster Randomized Controlled Trial.

Unnecessary antibiotic prescribing contributes to Antimicrobial Resistance posing a major public health risk. Estimates suggest as many as half of antibiotics prescribed for respiratory infections may be unnecessary. We conducted a three-armed unblinded cluster randomized controlled trial (ISRCTN trial registry 83322985). Interventions were a commitment poster (CP) advocating safe antibiotic prescribing or a CP plus an antimicrobial stewardship message (AM) on telephone appointment booking lines, tested against a usual care control group. The primary outcome measure was antibiotic item dispensing rates per 1000 population adjusted for practice demographics. The outcome measures for post-hoc analysis were dispensing rates of antibiotics usually prescribed for upper respiratory tract infections and broad spectrum antibiotics. In total, 196 practice units were randomized to usual care (n = 60), CP (n = 66), and CP&AM (n = 70). There was no effect on the overall dispensing rates for either interventions compared to usual care (CP 5.673, 95%CI -9.768 to 21.113, p = 0.458; CP&AM, -12.575, 95%CI -30.726 to 5.576, p = 0.167). Secondary analysis, which included pooling the data into one model, showed a significant effect of the AM (-18.444, 95%CI -32.596 to -4.292, p = 0.012). Fewer penicillins and macrolides were prescribed in the CP&AM intervention compared to usual care (-12.996, 95% CI -34.585 to -4.913, p = 0.018). Commitment posters did not reduce antibiotic prescribing. An automated patient antimicrobial stewardship message showed effects and requires further testing.