Importance: Recurrent urinary tract infection (UTI) is a common debilitating condition in women, with limited prophylactic options. d-Mannose has shown promise in trials based in secondary care, but effectiveness in placebo-controlled studies and community settings has not been established.Objective: To determine whether d-mannose taken for 6 months reduces the proportion of women with recurrent UTI experiencing a medically attended UTI.Design, Setting, and Participants: This 2-group, double-blind randomized placebo-controlled trial took place across 99 primary care centers in the UK. Participants were recruited between March 28, 2019, and January 31, 2020, with 6 months of follow-up. Participants were female, 18 years or older, living in the community, and had evidence in their primary care record of consultations for at least 2 UTIs in the preceding 6 months or 3 UTIs in 12 months. Invitation to participate was made by their primary care center. A total of 7591 participants were approached, 830 responded, and 232 were ineligible or did not proceed to randomization. Statistical analysis was reported in December 2022.Intervention: Two grams daily of d-mannose powder or matched volume of placebo powder.Main Outcomes and Measures: The primary outcome measure was the proportion of women experiencing at least 1 further episode of clinically suspected UTI for which they contacted ambulatory care within 6 months of study entry. Secondary outcomes included symptom duration, antibiotic use, time to next medically attended UTI, number of suspected UTIs, and UTI-related hospital admissions.Results: Of 598 women eligible (mean [range] age, 58 [18-93] years), 303 were randomized to d-mannose (50.7%) and 295 to placebo (49.3%). Primary outcome data were available for 583 participants (97.5%). The proportion contacting ambulatory care with a clinically suspected UTI was 150 of 294 (51.0%) in the d-mannose group and 161 of 289 (55.7%) in the placebo group (risk difference, −5%; 95% CI, −13% to 3%; P = .26). Estimates were similar in per protocol analyses, imputation analyses, and preplanned subgroups. There were no statistically significant differences in any secondary outcome measures.Conclusions and Relevance: In this randomized clinical trial, daily d-mannose did not reduce the proportion of women with recurrent UTI in primary care who experienced a subsequent clinically suspected UTI. d-Mannose should not be recommended for prophylaxis in this patient group.Trial Registration: isrctn.org Identifier: ISRCTN13283516

Objective Possible childhood appendicitis is a common emergency presentation. The exact value of blood tests is debated. This study sought to determine the diagnostic accuracy of four blood tests (white cell count (WCC), neutrophil(count or percentage), C reactive protein (CRP) and/or procalcitonin) for childhood appendicitis. Design A systematic review and diagnostic meta-analysis. Data sources included MEDLINE, EMBASE, Central, Web of Science searched from inception-March 2022 with reference searching and authors contacted for missing/unclear data. Eligibility criteria was studies reporting the diagnostic accuracy of the four blood tests compared to the reference standard (histology or follow-up). Risk of bias was assessed (QUADAS-2), pooled sensitivity and specificity were generated for each test and commonly presented cut-offs. To provide insight into clinical impact, we present strategies using a hypothetical cohort. Results 67 studies were included (34 839 children, 13 342 with appendicitis), all in the hospital setting. The most sensitive tests were WCC (≥10 000 cells/µL, 53 studies sensitivity 0.85 (95% CI 0.80 to 0.89)) and absolute neutrophil count (ANC) (≥7500 cells/µL, five studies sensitivity 0.90 (95% CI 0.85 to 0.94)). Combination of WCC or CRP increased sensitivity further(≥10 000 cells/µL or ≥10 mg/L, individual patient data (IPD) of 6 studies, 0.97 (95% CI 0.93 to 0.99)). Applying results to a hypothetical cohort(1000 children with appendicitis symptoms, of whom 400 have appendicitis) 60 and 40 children would be wrongly discharged based solely on WCC and ANC, respectively, 12 with combination of WCC or CRP. The most specific tests were CRP alone (≥50 mg/L, 38 studies, specificity 0.87 (95% CI 0.80 to 0.91)) or combined with WCC (≥10 000 cells/µL and ≥50 mg/L, IPD of six studies, 0.93 (95% CI 0.91 to 0.95)). Conclusions The best performing single blood tests for ruling-out paediatric appendicitis are WCC or ANC; with accuracy improved combining WCC and CRP. These tests could be used at the point of care in combination with clinical prediction rules. We provide insight into the best cut-offs for clinical application. PROSPERO registration number CRD42017080036

Introduction: Providing antiretroviral therapy (ART) for millions of people living with HIV requires efficient, client-centred models of differentiated ART delivery. In South Africa, the Centralised Chronic Medication Dispensing and Distribution (CCMDD) programme allows over 1 million people to collect chronic medication, including ART, from community pick-up points. We aimed to explore how CCMDD influences engagement in HIV care. Methods: We performed in-depth interviews and focus group discussions with clients receiving ART and healthcare workers in Durban, South Africa. We analysed transcripts using deductive thematic analysis, with a framework informed by ‘theories of practice’, which highlights the materialities , competencies , meanings and other life practices that underpin clients’ engagement in HIV care. Results: Between March 2018 to August 2018 we undertook 25 interviews and four focus groups with a total of 55 clients, and interviewed eight healthcare workers. The material challenges of standard clinic-based ART provision included long waiting times, poor confidentiality and restricted opening hours, which discouraged clients from engagement. In contrast, CCMDD allowed quicker and more convenient ART collection in the community. This required the development of new competencies around accessing care, and helped change the meanings associated with HIV, by normalising treatment collection. CCMDD was seen as a reward by clients for taking ART well, and helped reduce disruption to other life practices such as employment. At private pharmacies, some clients reported receiving inferior care compared with paying customers, and some worried about inadvertently revealing their HIV status. Clients and healthcare workers had to negotiate problems with CCMDD implementation, including some pharmacies reaching capacity or only allowing ART collection at restricted times. Conclusions: In South Africa, CCMDD overcame material barriers to attending clinics, changed the meanings associated with collecting ART and was less disruptive to other social practices in clients’ lives. Expansion of community-based ART delivery programmes may help to facilitate engagement in HIV care. Trial registration number: STREAM study clinical trial registration: NCT03066128 , registered February 2017.

Background: Colchicine has been proposed as a COVID-19 treatment.Aim: To determine whether colchicine reduces time to recovery and COVID-19-related admissions to hospital and/or deaths among people in the community.Design and setting: Prospective, multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial (PRINCIPLE).Method: Adults aged ≥65 years or ≥18 years with comorbidities or shortness of breath, and unwell for ≤14 days with suspected COVID-19 in the community, were randomised to usual care, usual care plus colchicine (500 µg daily for 14 days), or usual care plus other interventions. The co-primary endpoints were time to first self-reported recovery and admission to hospital/death related to COVID-19, within 28 days, analysed using Bayesian models.Results: The trial opened on 2 April 2020. Randomisation to colchicine started on 4 March 2021 and stopped on 26 May 2021 because the prespecified time to recovery futility criterion was met. The primary analysis model included 2755 participants who were SARS-CoV-2 positive, randomised to colchicine (n = 156), usual care (n = 1145), and other treatments (n = 1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.92 (95% credible interval (CrI) = 0.72 to 1.16) and an estimated increase of 1.4 days in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. COVID-19-related admissions to hospital/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 (95% CrI = 0.28 to 1.89) and an estimated difference of −0.4% (95% CrI = −2.7 to 2.4).Conclusion: Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.

In 2017, NHS England introduced proactive identification of frailty into the General Practitioners (GP) contract. There is currently little information as to how this policy has been operationalised by front-line clinicians, their working understanding of frailty and impact of recognition on patient care. We aimed to explore the conceptualisation and identification of frailty by multidisciplinary primary care clinicians in England. Qualitative semi-structured interviews were conducted with primary care staff across England including GPs, physician associates, nurse practitioners, paramedics and pharmacists. Thematic analysis was facilitated through NVivo (Version 12). Totally, 31 clinicians participated. Frailty was seen as difficult to define, with uncertainty about its value as a medical diagnosis. Clinicians conceptualised frailty differently, dependant on job-role, experience and training. Identification of frailty was most commonly informal and opportunistic, through pattern recognition of a frailty phenotype. Some practices had embedded population screening and structured reviews. Visual assessment and continuity of care were important factors in recognition. Most clinicians were familiar with the electronic frailty index, but described poor accuracy and uncertainty as to how to interpret and use this tool. There were different perspectives amongst professional groups as to whether frailty should be more routinely identified, with concerns of capacity and feasibility in the current climate of primary care workload. Concepts of frailty in primary care differ. Identification is predominantly ad hoc and opportunistic. A more cohesive approach to frailty, relevant to primary care, together with better diagnostic tools and resource allocation, may encourage wider recognition.

Introduction There is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications. Methods and analysis The Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50–64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 ‘hot hubs’ and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes. Ethics and dissemination Ethical approval Ref: 20/SC/0158 South Central - Berkshire Research Ethics Committee; IRAS Project ID: 281958; EudraCT Number: 2020-001209-22. Results will be presented to policymakers and at conferences and published in peer-reviewed journals. Trial registration number ISRCTN86534580.