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Navigating the complexities of end-stage kidney disease (ESKD) from risk factors to outcome: insights from the UK Biobank cohort

Background: The global prevalence of end-stage kidney disease (ESKD) is increasing despite optimal management of traditional risk factors such as hyperglycaemia, hypertension, and dyslipidaemia. This study examines the influence of cardiorenal risk factors, socioeconomic status, and ethnic and cardiovascular comorbidities on ESKD outcomes in the general population. Methods: This cross-sectional study analysed data from 502,408 UK Biobank study participants recruited between 2006 and 2010. Multivariable logistic regression models were fitted to assess risk factors for ESKD, with results presented as adjusted odds ratio (aOR) and 95% confidence intervals (95% CI). Results: A total of 1191 (0.2%) of the study participants reported ESKD. Diabetes increased ESKD risk by 62% [1.62 (1.36–1.93)], with early-onset diabetes (before age 40) conferring higher odds compared to later-onset (after age 40) [2.26 (1.57–3.24)]. Similarly, early-onset hypertension (before age 40), compared to later onset (after age 40), increased ESKD odds by 73% [1.73 (1.21–2.44)]. Cardiovascular comorbidities, including stroke, hypertension, myocardial infarction and angina, were strongly associated with ESKD [5.97 (3.99–8.72), 5.35 (4.38–6.56), 4.94 (3.56–6.78), and 4.89 (3.47–6.81)], respectively. Males were at 22% higher risk of ESKD than females [1.22 (1.04–1.43)]. Each additional year of diabetes duration increased ESKD odds by 2% [1.02 (1.01–1.03)]. Non-white ethnicity, compared to white and socioeconomically most deprived, compared to the least deprived quintiles, were at 70% and 83% higher odds of ESKD. Each unit of HbA1c rise increased the odds of ESKD by 2%. Compared to microalbuminuria, macroalbuminuria increased the odds of ESKD by almost 10-fold [9.47 (7.95–11.27)] while normoalbuminuria reduced the odds by 73% [0.27 (0.22–0.32)]. Conclusions: Early onset of diabetes and hypertension, male sex, non-white ethnicity, deprivation, poor glycaemic control, and prolonged hyperglycaemia are significant risk factors for ESKD. These findings highlight the complexity of ESKD and the need for multifactorial targeted interventions in high-risk populations. Clinical trial number: Not applicable.

plaTform fOr Urinary tract infection diagnostiC evAluatioN (TOUCAN): a protocol for a prospective diagnostic accuracy study of point-of-care testing in patients suspected of acute uncomplicated urinary tract infection in primary care clinics in England

Introduction Acute uncomplicated urinary tract infection (UTI) is a common condition with potentially serious sequelae that is mostly diagnosed and managed in primary care settings. Around half of all women have a UTI in their lifetime, and a quarter experience an infection caused by organisms resistant to more than one antibiotic. Reducing inappropriate prescribing of antibiotics is a core tenet of antimicrobial stewardship. However, current diagnostics for UTI are unfit for purpose in acute (highest prescribing) settings, being too slow to inform the required immediate decision-making and often confounded by sample contamination. Rapid point-of-care diagnostic tests (POCTs) that facilitate timely decision-making are potential solutions to this problem. Several such tests have reached advanced stages of technology readiness, but their diagnostic performance has not been evaluated in primary care with clinical users. To progress novel tests towards implementation, a diagnostic field study is required, to allow for parallel and sequential evaluation of multiple tests in a primary care population. Methods and analysis We will recruit participants assigned female at birth from primary care clinics in England who contact their clinic with symptoms of acute uncomplicated UTI. Eligible participants will complete a short questionnaire to capture symptoms and symptom severity and will provide a urine sample. Samples will be split and initially tested using novel index tests (POCTs) and conventional urinalysis ‘dipstick’ at the primary care clinic. The second part of the sample will be processed at a National Health Service-based reference laboratory using a modified reference standard including microscopy, microbiological culture, pathogen speciation and antimicrobial susceptibility testing. The UTI reference standard culture, although based on the national methods, is modified to provide accurate bacterial counts, better to define a microbiological diagnosis of UTI. Susceptibility testing will be performed using ‘gold-standard’ methods, not usually performed in diagnostic laboratories. The primary outcome will be the diagnostic performance (sensitivity, specificity, positive and negative predictive values) of POCTs for detection of UTI and antimicrobial susceptibility for POCTs that include antimicrobial susceptibility testing. Secondary outcomes will include the symptom profile of patients presenting with uncomplicated UTI, a theoretical determination of how use of POCT results might change prescribing, an understanding of POCT failure rate and qualitative capture of the experiences of those using the POCT to deliver the study in primary care clinics. Ethics and dissemination Ethical approval was received from the London Central Research Ethics Committee (23/LO/0371) and the UK Health Research Authority. We will publish the findings of The plaTform fOr Urinary tract infection diagnostiC evAluatioN evaluations in peer-reviewed medical journals and more broadly following a dissemination plan formulated by a communications specialist in consultation with patients and the public.

Developing a digital phenotype to subdivide adult immunosuppressed COVID-19 outcomes within the English Primary Care Sentinel Network

Background: Adults classified as immunosuppressed have been disproportionately affected by the COVID-19 pandemic. Compared to the immunocompetent, certain patients are at increased risk of suboptimal vaccine response and adverse health outcomes if infected. However, there has been insufficient work to pinpoint where these risks concentrate within the immunosuppressed spectrum; surveillance efforts typically treat the immunosuppressed as a single entity, leading to wide confidence intervals. A clinically meaningful and computerised medical record (CMR) compatible method to subdivide immunosuppressed COVID-19 data is urgently needed. Methods: We conducted a rapid scoping review into COVID-19 mortality across UK immunosuppressed categories to assess if differential mortality risk was a viable means of subdivision. We converted the risk hierarchy that surfaced into a pilot digital phenotype—a valueset and series of ontological rules ready to extract immunosuppressed patients from CMR data and stratify outcomes of interest in COVID-19 surveillance dataflows. Results: The rapid scoping review returned COVID-19 mortality data for all immunosuppressed subgroups assessed and revealed significant heterogeneity across the spectrum. There was a clear distinction between heightened COVID-19 mortality in haematological malignancy and transplant patients and mortality that approached the immunocompetent baseline amongst cancer therapy recipients, autoimmune patients, and those with HIV. This process, complemented by expert clinical input, informed the curation of the five-part digital phenotype now ready for testing in real-world data; its ontological rules will enable mutually exclusive, hierarchical extraction with nuanced time and treatment conditions. Unique categorisations have been introduced, including ‘Bone Marrow Compromised’ and those dedicated to differentiating prescriptions related and unrelated to cancer. Codification was supported by existing reference sets of medical codes; absent or redundant codes had to be resolved manually. Discussion: Although this work is in its earliest phases, the development process we report has been highly informative. Systematic review, clinical consensus building, and implementation studies will test the validity of our results and address criticisms of the rapid scoping exercise they are predicated on. Conclusion: Comprehensive testing for COVID-19 has differentiated mortality risks across the immunosuppressed spectrum. This risk hierarchy has been codified into a digital phenotype for differentiated COVID-19 surveillance; this marks a step towards the needs-based management of these patients that is urgently required.

Relationship of cardiorenal risk factors with albuminuria based on age, smoking, glycaemic status and BMI: a retrospective cohort study of the UK Biobank data.

INTRODUCTION: Smoking is harmful, and its cessation is recommended to prevent chronic kidney disease, which often begins with abnormal leakage of albumin in the urine, called albuminuria. Smoking cessation's effect on albuminuria depends on the pack-years smoked, length of abstinence, body mass index (BMI) and glycosylated haemoglobin (HbA1c). Using the UK Biobank data, we examined the relationship between these cardiorenal variables and albuminuria. METHODS: For this study, we selected a UK Biobank cohort with urinary albumin concentration (UAC) in the first and second visits. Participants were divided into progressor and regressor groups, where progressors were defined as those with increased UAC value, and regressors were those with decreased UAC value. Three different logistic regression models were fitted. In model 1, with a cohort design, we explored the impact of a change in age, HbA1c and BMI between the first and second visits and the UAC. In model 2 and 3, in a cross-sectional design, we explored which cardiorenal risk factors were associated with a rise or fall of UAC at the time point of the second visit. Results are expressed in OR and 95% CI. RESULTS: The prevalence of albuminuria was highest in ex-smokers who started smoking between the ages of 13 and 18. With a mean duration of 51 months, there was no statistically significant relationship between smoking status and BMI with albuminuria. Each year of ageing and each unit of increase in HbA1c (mmol/mol) increased the odds of progression of albuminuria by 20% and 3%, respectively. In ex-smokers, at the time point of the second visit, each year of smoking increased, and each year of abstinence decreased the odds by 4% and 6%, respectively. CONCLUSION: Smokers should be supported to stop smoking and remain abstinent despite short-term weight gain. Childhood smoking should be actively discouraged.

Creating a Modified Version of the Cambridge Multimorbidity Score to Predict Mortality in People Older Than 16 Years: Model Development and Validation

Background: No single multimorbidity measure is validated for use in NHS (National Health Service) England’s General Practice Extraction Service Data for Pandemic Planning and Research (GDPPR), the nationwide primary care data set created for COVID-19 pandemic research. The Cambridge Multimorbidity Score (CMMS) is a validated tool for predicting mortality risk, with 37 conditions defined by Read Codes. The GDPPR uses the more internationally used Systematized Nomenclature of Medicine clinical terms (SNOMED CT). We previously developed a modified version of the CMMS using SNOMED CT, but the number of terms for the GDPPR data set is limited making it impossible to use this version. Objective: We aimed to develop and validate a modified version of CMMS using the clinical terms available for the GDPPR. Methods: We used pseudonymized data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre (RSC), which has an extensive SNOMED CT list. From the 37 conditions in the original CMMS model, we selected conditions either with (1) high prevalence ratio (≥85%), calculated as the prevalence in the RSC data set but using the GDPPR set of SNOMED CT codes, divided by the prevalence included in the RSC SNOMED CT codes or (2) conditions with lower prevalence ratios but with high predictive value. The resulting set of conditions was included in Cox proportional hazard models to determine the 1-year mortality risk in a development data set (n=500,000) and construct a new CMMS model, following the methods for the original CMMS study, with variable reduction and parsimony, achieved by backward elimination and the Akaike information stopping criterion. Model validation involved obtaining 1-year mortality estimates for a synchronous data set (n=250,000) and 1-year and 5-year mortality estimates for an asynchronous data set (n=250,000). We compared the performance with that of the original CMMS and the modified CMMS that we previously developed using RSC data. Results: The initial model contained 22 conditions and our final model included 17 conditions. The conditions overlapped with those of the modified CMMS using the more extensive SNOMED CT list. For 1-year mortality, discrimination was high in both the derivation and validation data sets (Harrell C=0.92) and 5-year mortality was slightly lower (Harrell C=0.90). Calibration was reasonable following an adjustment for overfitting. The performance was similar to that of both the original and previous modified CMMS models. Conclusions: The new modified version of the CMMS can be used on the GDPPR, a nationwide primary care data set of 54 million people, to enable adjustment for multimorbidity in predicting mortality in people in real-world vaccine effectiveness, pandemic planning, and other research studies. It requires 17 variables to produce a comparable performance with our previous modification of CMMS to enable it to be used in routine data using SNOMED CT.

Effect of antihypertensive deprescribing on hospitalisation and mortality: long-term follow-up of the OPTiMISE randomised controlled trial

Background: Deprescribing of antihypertensive medications is recommended for some older patients with low blood pressure and frailty. The OPTiMISE trial showed that this deprescribing can be achieved with no differences in blood pressure control at 3 months compared with usual care. We aimed to examine effects of deprescribing on longer-term hospitalisation and mortality. Methods: This randomised controlled trial enrolled participants from 69 general practices across central and southern England. Participants aged 80 years or older, with systolic blood pressure less than 150 mm Hg and who were receiving two or more antihypertensive medications, were randomly assigned (1:1) to antihypertensive medication reduction (removal of one antihypertensive) or usual care. General practitioners and participants were aware of the treatment allocation following randomisation but individuals responsible for analysing the data were masked to the treatment allocation throughout the study. Participants were followed up via their primary and secondary care electronic health records at least 3 years after randomisation. The primary outcome was time to all-cause hospitalisation or mortality. Intention-to-treat analyses were done using Cox regression modelling. A per-protocol analysis of the primary outcome was also done, excluding participants from the intervention group who did not reduce treatment or who had medication reinstated during the initial trial 12-week follow-up period. This study is registered with the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT2016-004236-38) and the ISRCTN Registry (ISRCTN97503221). Findings: Between March 20, 2017, and Sept 30, 2018, a total of 569 participants were randomly assigned. Of these, 564 (99%; intervention=280; control=284) were followed up for a median of 4·0 years (IQR 3·7–4·3). Participants had a mean age of 84·8 years (SD 3·4) at baseline and 273 (48%) were women. Medication reduction was sustained in 109 participants at follow-up (51% of the 213 participants alive in the intervention group). Participants in the intervention group had a larger reduction in antihypertensives than the control group (adjusted mean difference –0·35 drugs [95% CI –0·52 to –0·18]). Overall, 202 (72%) participants in the intervention group and 218 (77%) participants in the control group experienced hospitalisation or mortality during follow-up (adjusted hazard ratio [aHR] 0·93 [95% CI 0·76 to 1·12]). There was some evidence that the proportion of participants experiencing the primary outcome in the per-protocol population was lower in the intervention group (aHR 0·80 [0·64 to 1·00]). Interpretation: Half of participants sustained medication reduction with no evidence of an increase in all-cause hospitalisation or mortality. These findings suggest that an antihypertensive deprescribing intervention might be safe for people aged 80 years or older with controlled blood pressure taking two or more antihypertensives. Funding: British Heart Foundation and National Institute for Health and Care Research.

Phenotype execution and modeling architecture to support disease surveillance and real-world evidence studies: English sentinel network evaluation

Objective: To evaluate Phenotype Execution and Modelling Architecture (PhEMA), to express sharable phenotypes using Clinical Quality Language (CQL) and intensional Systematised Nomenclature of Medicine (SNOMED) Clinical Terms (CT) Fast Healthcare Interoperability Resources (FHIR) valuesets, for exemplar chronic disease, sociodemographic risk factor, and surveillance phenotypes. Method: We curated 3 phenotypes: Type 2 diabetes mellitus (T2DM), excessive alcohol use, and incident influenza-like illness (ILI) using CQL to define clinical and administrative logic. We defined our phenotypes with valuesets, using SNOMED's hierarchy and expression constraint language, and CQL, combining valuesets and adding temporal elements where needed. We compared the count of cases found using PhEMA with our existing approach using convenience datasets. We assessed our new approach against published desiderata for phenotypes. Results: The T2DM phenotype could be defined as 2 intensionally defined SNOMED valuesets and a CQL script. It increased the prevalence from 7.2% to 7.3%. Excess alcohol phenotype was defined by valuesets that added qualitative clinical terms to the quantitative conceptual definitions we currently use; this change increased prevalence by 58%, from 1.2% to 1.9%. We created an ILI valueset with SNOMED concepts, adding a temporal element using CQL to differentiate new episodes. This increased the weekly incidence in our convenience sample (weeks 26-38) from 0.95 cases to 1.11 cases per 100 000 people. Conclusions: Phenotypes for surveillance and research can be described fully and comprehensibly using CQL and intensional FHIR valuesets. Our use case phenotypes identified a greater number of cases, whilst anticipated from excessive alcohol this was not for our other variable. This may have been due to our use of SNOMED CT hierarchy. Our new process fulfilled a greater number of phenotype desiderata than the one that we had used previously, mostly in the modeling domain. More work is needed to implement that sharing and warehousing domains.

Anti-TNF (adalimumab) injection for the treatment of adults with frozen shoulder during the pain predominant stage protocol for a multi-centre, randomised, double blind, parallel group, feasibility trial

Objectives: The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder. Methods and analysis: We are conducting a multi-centre, randomised feasibility study, with an embedded qualitative sub-study. We will recruit adults ≥18 years with a new episode of shoulder pain attributable to early stage frozen shoulder, recruited from at least five UK NHS musculoskeletal and related physiotherapy services. Participants (n=84) will be randomised (centralised computer generated 1:1 allocation) to receive either: 1) intra-articular injection of anti-TNF (adalimumab 160mg) or 2) placebo injection (saline [0.9% sodium chloride]), both under ultrasound guidance. A second injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be administered 2–3 weeks later. All participants will receive a physiotherapy advice leaflet providing education and advice about frozen shoulder and pain management. The primary feasibility objectives are: 1) the ability to screen and identify potential participants with pain predominant early stage frozen shoulder; 2) willingness of eligible participants to consent and be randomised to intervention; 3) practicalities of delivering the intervention, including time to first injection and number of participants receiving second injection; 4) standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months (i.e. 12 weeks) post-randomisation in order to estimate the sample size for a definitive trial. We will also assess follow up rates and viability of patient-reported outcome measures and range of shoulder motion for a definitive trial. Research Ethics Committee approval (REC 21/NE/0214). Trial registration number: ISRCTN 27075727; EudraCT number: 2021-003509-23; ClinicalTrials.gov NCT05299242.

Anti-tumour necrosis factor therapy for early-stage Dupuytren's disease (RIDD): a phase 2b, randomised, double-blind, placebo-controlled trial

Background: Dupuytren's disease is a common fibrotic condition that causes the fingers to flex irreversibly into the palm. Treatments for late-stage disease all have limitations, and there is no approved treatment for early-stage disease. We identified tumour necrosis factor as a therapeutic target in Dupuytren's disease, and in a dose ranging trial found 40 mg adalimumab in 0·4 mL to be most efficacious. Here we aimed to assess the effects of intranodular injection of adalimumab in early-stage disease. Methods: In this phase 2b, randomised, double-blind, placebo-controlled trial adults with early-stage Dupuytren's disease and an established clinically distinct nodule with a clear history of progression in the preceding 6 months were recruited from two clinical centres in the UK and were randomly assigned 1:1 to receive four injections of adalimumab or saline every 3 months. Participants and assessors were masked. The primary outcome was nodule hardness measured with a durometer at 12 months. Data were analysed by linear mixed effects regression models in the intention-to-treat population with multiple imputation for missing primary outcome data. The trial is registered at the ISRCTN registry, ISRCTN 27786905 and is complete. Findings: Between Feb 17, 2017, and Jan 11, 2019, 284 participants were screened in the UK and 140 were enrolled. 47 (34%) participants were female and 93 (66%) were male. Mean age of participants was 59·7 years (SD 10·0). Primary outcome data were available from 113 participants. Nodule hardness was lower (−4·6 AU [95% CI −7·1 to −2·2], p=0·0002) in the adalimumab compared with the saline group at 12 months. There were no related serious adverse events; the most common adverse events were minor injection site reactions. Interpretation: Intranodular injections of adalimumab in participants with early-stage Dupuytren's disease resulted in softening and reduction in size of the nodules. Longer follow-up would be required to assess the effect of tumour necrosis factor inhibition on disease progression, extension deficit and hand function. Funding: Health Innovation Challenge Fund (Wellcome Trust, Department of Health) and 180 Life Sciences.

Home-based rehabilitation programme compared with traditional physiotherapy for patients at risk of poor outcome after knee arthroplasty: The CORKA randomised controlled trial

Objectives To evaluate whether a home-based rehabilitation programme for people assessed as being at risk of a poor outcome after knee arthroplasty offers superior outcomes to traditional outpatient physiotherapy. Design A prospective, single-blind, two-arm randomised controlled superiority trial. Setting 14 National Health Service physiotherapy departments in the UK. Participants 621 participants identified at high risk of a poor outcome after knee arthroplasty using a bespoke screening tool. Interventions A multicomponent home-based rehabilitation programme delivered by rehabilitation assistants with supervision from qualified therapists versus usual care outpatient physiotherapy. Main outcome measures The primary outcome was the Late-Life Function and Disability Instrument (LLFDI) at 12 months. Secondary outcomes were the Oxford Knee Score (a disease-specific measure of function), Knee injury and Osteoarthritis Outcome Score Quality of Life subscale, Physical Activity Scale for the Elderly, 5 dimension, 5 level version of Euroqol (EQ-5D-5L) and physical function assessed using the Figure of 8 Walk test, 30 s Chair Stand Test and Single Leg Stance. Results 621 participants were randomised between March 2015 and January 2018. 309 were assigned to CORKA (Community Rehabilitation after Knee Arthroplasty) home-based rehabilitation, receiving a median five treatment sessions (IQR 4-7). 312 were assigned to usual care, receiving a median 4 sessions (IQR 2-6). The primary outcome, LLFDI function total score at 12 months, was collected for 279 participants (89%) in the home-based CORKA group and 287 participants (92%) in the usual care group. No clinically or statistically significant difference was found between the groups (intention-to-treat adjusted difference=0.49 points; 95% CI -0.89 to 1.88; p=0.48). There were no statistically significant differences between the groups on any of the patient-reported or physical secondary outcome measures at 6 or 12 months. There were 18 participants in the intervention group reporting a serious adverse event (5.8%), only one directly related to the intervention, all other adverse events recorded throughout the trial related to underlying chronic medical conditions. Conclusions The CORKA intervention was not superior to usual care. The trial detected no significant differences, clinical or statistical, between the two groups on either primary or secondary outcomes. CORKA offers an evaluation of an intervention utilising a different service delivery model for this patient group. Trial registration number ISRCTN13517704.

Outpatient physiotherapy versus home-based rehabilitation for patients at risk of poor outcomes after knee Arthroplasty: CORKA RCT

Background: Over 100,000 primary knee arthroplasty operations are undertaken annually in the UK. Around 15–30% of patients do not report a good outcome. Better rehabilitation strategies may improve patient-reported outcomes. Objectives: To compare the outcomes from a traditional outpatient physiotherapy model with those from a home-based rehabilitation programme for people assessed as being at risk of a poor outcome after knee arthroplasty. Design: An individually randomised, two-arm controlled trial with a blinded outcome assessment, a parallel health economic evaluation and a nested qualitative study. Setting: The trial took place in 14 NHS physiotherapy departments. Participants: People identified as being at high risk of a poor outcome after knee arthroplasty. Interventions: A multicomponent home-based rehabilitation package delivered by rehabilitation assistants with supervision from qualified therapists compared with usual-care outpatient physiotherapy. Main outcome measures: The primary outcome was the Late Life Function and Disability Instrument at 12 months. Secondary outcomes were the Oxford Knee Score (a disease-specific measure of function); Knee injury and Osteoarthritis Outcome Score; Quality of Life subscale; Physical Activity Scale for the Elderly; EuroQol-5 Dimensions, five-level version; and physical function assessed using the Figure-of-8 Walk Test, 30-Second Chair Stand Test and Single Leg Stance. Data on the use of health-care services, time off work and informal care were collected using participant diaries. Results: In total, 621 participants were randomised. A total of 309 participants were assigned to the COmmunity based Rehabilitation after Knee Arthroplasty (CORKA) home-based rehabilitation programme, receiving a median of five treatment sessions (interquartile range 4–7 sessions). A total of 312 participants were assigned to usual care, receiving a median of four sessions (interquartile range 2–6 sessions). The primary outcome, Late Life Function and Disability Instrument function total score at 12 months, was collected for 279 participants (89%) in the home-based CORKA group and 287 participants (92%) in the usual-care group. No clinically or statistically significant difference was found between the groups (intention-to-treat adjusted difference 0.49 points, 95% confidence interval –0.89 to 1.88 points; p = 0.48). There were no statistically significant differences between the groups in any of the patient-reported or physical secondary outcome measures at 6 or 12 months post randomisation. The health economic analysis found that the CORKA intervention was cheaper to provide than usual care (£66 less per participant). Total societal costs (combining health-care costs and other costs) were lower for the CORKA intervention than usual care (£316 less per participant). Adopting a societal perspective, CORKA had a 75% probability of being cost-effective at a threshold of £30,000 per quality-adjusted life-year. Adopting the narrower health and social care perspective, CORKA had a 43% probability of being cost-effective at the same threshold. Limitations: The interventions were of short duration and were set within current commissioning guidance for UK physiotherapy. Participants and treating therapists could not be blinded. Conclusions: This randomised controlled trial found no important differences in outcomes when post-arthroplasty rehabilitation was delivered using a home-based, rehabilitation assistant-delivered rehabilitation package or a traditional outpatient model. However, the health economic evaluation found that when adopting a societal perspective, the CORKA home-based intervention was cost-saving and more effective than, and thus dominant over, usual care, owing to reduced time away from paid employment for this group. Further research could look at identifying the risk of poor outcome and further evaluation of a cost-effective treatment, including the workforce model to deliver it. Trial registration: Current Controlled Trials ISRCTN13517704.

Disparities in COVID-19 mortality amongst the immunosuppressed: A systematic review and meta-analysis for enhanced disease surveillance

Background: Effective disease surveillance, including that for COVID-19, is compromised without a standardised method for categorising the immunosuppressed as a clinical risk group. Methods: We conducted a systematic review and meta-analysis to evaluate whether excess COVID-associated mortality compared to the immunocompetent could meaningfully subdivide the immunosuppressed. Our study adhered to UK Immunisation against infectious disease (Green Book) criteria for defining and categorising immunosuppression. Using OVID (EMBASE, MEDLINE, Transplant Library, and Global Health), PubMed, and Google Scholar, we examined relevant literature between the entirety of 2020 and 2022. We selected for cohort studies that provided mortality data for immunosuppressed subgroups and immunocompetent comparators. Meta-analyses, grey literature and any original works that failed to provide comparator data or reported all-cause or paediatric outcomes were excluded. Odds Ratios (OR) and 95% confidence intervals (CI) of COVID-19 mortality were meta-analysed by immunosuppressed category and subcategory. Subgroup analyses differentiated estimates by effect measure, country income, study setting, level of adjustment, use of matching and publication year. Study screening, extraction and bias assessment were performed blinded and independently by two researchers; conflicts were resolved with the oversight of a third researcher. PROSPERO registration number is CRD42022360755. Findings: We identified 99 unique studies, incorporating data from 1,542,097 and 56,248,181 unique immunosuppressed and immunocompetent patients with COVID-19 infection, respectively. Compared to immunocompetent people (pooled OR, 95%CI), solid organ transplants (2.12, 1.50-2.99) and malignancy (2.02, 1.69-2.42) patients had a very high risk of COVID-19 mortality. Patients with rheumatological conditions (1.28, 1.13-1.45) and HIV (1.20, 1.05-1.36) had just slightly higher risks than the immunocompetent baseline. Case type, setting income and mortality data matching and adjustment were significant modifiers of excess immunosuppressed mortality for some immunosuppressed subgroups. Interpretation: Excess COVID-associated mortality among the immunosuppressed compared to the immunocompetent was seen to vary significantly across subgroups. This novel means of subdivision has prospective benefit for targeting patient triage, shielding and vaccination policies during periods of high disease transmission.

Postpandemic Sentinel Surveillance of Respiratory Diseases in the Context of the World Health Organization Mosaic Framework: Protocol for a Development and Evaluation Study Involving the English Primary Care Network 2023-2024

Background: Prepandemic sentinel surveillance focused on improved management of winter pressures, with influenza-like illness (ILI) being the key clinical indicator. The World Health Organization (WHO) global standards for influenza surveillance include monitoring acute respiratory infection (ARI) and ILI. The WHO’s mosaic framework recommends that the surveillance strategies of countries include the virological monitoring of respiratory viruses with pandemic potential such as influenza. The Oxford-Royal College of General Practitioner Research and Surveillance Centre (RSC) in collaboration with the UK Health Security Agency (UKHSA) has provided sentinel surveillance since 1967, including virology since 1993. Objective: We aim to describe the RSC’s plans for sentinel surveillance in the 2023-2024 season and evaluate these plans against the WHO mosaic framework. Methods: Our approach, which includes patient and public involvement, contributes to surveillance objectives across all 3 domains of the mosaic framework. We will generate an ARI phenotype to enable reporting of this indicator in addition to ILI. These data will support UKHSA’s sentinel surveillance, including vaccine effectiveness and burden of disease studies. The panel of virology tests analyzed in UKHSA’s reference laboratory will remain unchanged, with additional plans for point-of-care testing, pneumococcus testing, and asymptomatic screening. Our sampling framework for serological surveillance will provide greater representativeness and more samples from younger people. We will create a biomedical resource that enables linkage between clinical data held in the RSC and virology data, including sequencing data, held by the UKHSA. We describe the governance framework for the RSC. Results: We are co-designing our communication about data sharing and sampling, contextualized by the mosaic framework, with national and general practice patient and public involvement groups. We present our ARI digital phenotype and the key data RSC network members are requested to include in computerized medical records. We will share data with the UKHSA to report vaccine effectiveness for COVID-19 and influenza, assess the disease burden of respiratory syncytial virus, and perform syndromic surveillance. Virological surveillance will include COVID-19, influenza, respiratory syncytial virus, and other common respiratory viruses. We plan to pilot point-of-care testing for group A streptococcus, urine tests for pneumococcus, and asymptomatic testing. We will integrate test requests and results with the laboratory-computerized medical record system. A biomedical resource will enable research linking clinical data to virology data. The legal basis for the RSC’s pseudonymized data extract is The Health Service (Control of Patient Information) Regulations 2002, and all nonsurveillance uses require research ethics approval. Conclusions: The RSC extended its surveillance activities to meet more but not all of the mosaic framework’s objectives. We have introduced an ARI indicator. We seek to expand our surveillance scope and could do more around transmissibility and the benefits and risks of nonvaccine therapies.

Pramipexole augmentation for the acute phase of treatment-resistant, unipolar depression: a placebo-controlled, double-blind, randomised trial in the UK

Background: About 30% of patients with depression treated with antidepressant medication do not respond sufficiently to the first agents used. Pramipexole might usefully augment antidepressant medication in such cases of treatment-resistant depression, but data on its effects and tolerability are scarce. We aimed to assess the efficacy and tolerability of pramipexole augmentation of ongoing antidepressant treatment, over 48 weeks, in patients with treatment-resistant depression. Methods: We did a multicentre, double-blind, placebo-controlled randomised trial in which adults with resistant major depressive disorder were randomly assigned (1:1; using an online randomisation system) to 48 weeks of pramipexole (titrated to 2·5 mg) or placebo added to their ongoing antidepressant medication. The study was conducted in nine National Health Service Trusts in England. Participants, investigators, and researchers involved in recruitment and assessment were masked to group allocation, and the central pharmacy team dispensing the medication was not masked. The primary outcome was change from baseline to week 12 in the total score of the 16-item Quick Inventory of Depressive Symptomology self-report version (QIDS-SR16). The primary analysis was performed on the intention-to-treat population that included all eligible, randomly assigned participants. People with lived experience were involved in the design, oversight, and interpretation of the study. The trial was registered with ISCTRN (ISRCTN84666271) and EudraCT (2019-001023-13) and is complete. Findings: Between Feb 16 and May 29, 2024, 217 participants attended a screening visit, of whom 66 were excluded due to ineligibility. 151 participants were randomly assigned (75 to the pramipexole group and 75 to the placebo group, after one participant was found to be ineligible after randomisation). 84 (56%) participants were female and 66 (44%) were male and the mean age of participants was 44·9 years (SD 14·0). Ethnicity data were not available. The mean QIDS-SR16 total score at baseline was 16·4 (SD 3·4) in the pramipexole group and 16·2 (3·5) in the placebo group. The mean dose of pramipexole received at week 12 was 2·3 mg (SD 0·45). Adjusted mean decrease from baseline to week 12 of the QIDS-SR16 total score was 6·4 (SD 4·9) for the pramipexole group and 2·4 (4·0) for the placebo group; the mean difference between groups was −3·91 (95% CI −5·37 to −2·45; p<0·0001). Termination of trial treatment due to adverse events was more frequent in the pramipexole group (15 participants [20%]) than in the placebo group (four participants [5%]), with reported adverse events consistent with known side-effects of pramipexole, in particular nausea, headache, and sleep disturbance or somnolence. Interpretation: In this trial involving participants with treatment-resistant depression, pramipexole augmentation of antidepressant treatment, at a target dose of 2·5 mg, demonstrated a reduction in symptoms relative to placebo at 12 weeks but was associated with some adverse effects. These results suggest that pramipexole is a clinically effective option for reducing symptoms in patients with treatment-resistant depression. Future trials directly comparing pramipexole with existing treatments for this disorder are needed. Funding: National Institute of Health and Care Research, Efficacy and Mechanism Evaluation Programme.

Assessing the feasibility and impact of clinical trial trustworthiness checks via an application to Cochrane Reviews: Stage 2 of the INSPECT-SR project

Background and Objectives: The aim of the INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is to develop a tool to identify problematic RCTs in systematic reviews. In stage 1 of the project, a list of potential trustworthiness checks was created. The checks on this list must be evaluated to determine which should be included in the INSPECT-SR tool. Methods: We attempted to apply 72 trustworthiness checks to randomized controlled trials (RCTs) in 50 Cochrane reviews. For each, we recorded whether the check was passed, failed, or possibly failed or whether it was not feasible to complete the check. Following application of the checks, we recorded whether we had concerns about the authenticity of each RCT. We repeated each meta-analysis after removing RCTs flagged by each check and again after removing RCTs where we had concerns about authenticity to estimate the impact of trustworthiness assessment. Trustworthiness assessments were compared to Risk of Bias and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments in the reviews. Results: Ninety-five RCTs were assessed. Following application of the checks, assessors had some or serious concerns about the authenticity of 25% and 6% of the RCTs, respectively. Removing RCTs with either some or serious concerns resulted in 22% of meta-analyses having no remaining RCTs. However, many checks proved difficult to understand or implement, which may have led to unwarranted skepticism in some instances. Furthermore, we restricted assessment to meta-analyses with no more than five RCTs (54% contained only 1 RCT), which will distort the impact on results. No relationship was identified between trustworthiness assessment and Risk of Bias or GRADE. Conclusion: This study supports the case for routine trustworthiness assessment in systematic reviews, as problematic studies do not appear to be flagged by Risk of Bias assessment. The study produced evidence on the feasibility and impact of trustworthiness checks. These results will be used, in conjunction with those from a subsequent Delphi process, to determine which checks should be included in the INSPECT-SR tool. Plain Language Summary: Systematic reviews collate evidence from randomized controlled trials (RCTs) to find out whether health interventions are safe and effective. However, it is now recognized that the findings of some RCTs are not genuine, and some of these studies appear to have been fabricated. Various checks for these “problematic” RCTs have been proposed, but it is necessary to evaluate these checks to find out which are useful and which are feasible. We applied a comprehensive list of “trustworthiness checks” to 95 RCTs in 50 systematic reviews to learn more about them and to see how often performing the checks would lead us to classify RCTs as being potentially inauthentic. We found that applying the checks led to concerns about the authenticity of around 1 in three RCTs. However, we found that many of the checks were difficult to perform and could have been misinterpreted. This might have led us to be overly skeptical in some cases. The findings from this study will be used, alongside other evidence, to decide which of these checks should be performed routinely to try to identify problematic RCTs, to stop them from being mistaken for genuine studies and potentially being used to inform health care decisions.

Population health and health sector cost impacts of the UK Soft Drinks Industry Levy: a modelling study.

Time trends in new diagnoses of 19 long-term conditions: a population-level cohort study in England using OpenSAFELY

Variation in duration of repeat prescriptions: a primary care cohort study in England

Background Many patients receive repeat prescriptions for routine medications used to treat chronic conditions. Doctors typically issue repeat prescriptions with durations ranging from 28 to 84 days. There is currently no national guidance in England for the optimal prescription duration for routine medications. Aim To evaluate current prescription durations for five common routine medications in England; explore and visualise geographical variation; and identify practice factors that are associated with shorter prescribing duration to inform policy making. Design and setting A retrospective cohort study of NHS primary care prescribing data in England from December 2018 to November 2019. Method The prescription duration was analysed for five common routine medications in England; ramipril, atorvastatin, simvastatin, levothyroxine, and amlodipine. Variation was assessed between regional clinical commissioning groups (CCGs), and practice factors associated with different durations were identified. Results Of the common medications included, 28-day prescriptions accounted for 48.5% (2.5 billion) tablets/ capsules issued, while 43.6% were issued for 56 days. There was very wide regional variation (7.2%–95.0%) in the proportion of 28-day prescriptions issued by CCGs. Practice dispensing status was the most likely predictor of prescription duration; dispensing practices had a higher 28-day prescribing proportion than non-dispensing practices. The proportion of patients with chronic conditions and the electronic health record system used by a practice were also associated with prescription duration. Conclusion This analysis of OpenPrescribing data showed that repeat prescriptions of 28 days are common for patients taking routine medications for chronic conditions, particularly in dispensing practices. This provides data to inform the policy debate on current practice. Configuration of electronic health record systems offer an opportunity to implement and evaluate new policies on repeat prescription duration in England.

Training needs for staff providing remote services in general practice: a mixed-methods study

Background Contemporary general practice includes many kinds of remote encounter. The rise in telephone, video and online modalities for triage and clinical care requires clinicians and support staff to be trained, both individually and as teams, but evidence-based competencies have not previously been produced for general practice. Aim To identify training needs, core competencies, and learning methods for staff providing remote encounters. Design and setting Mixed-methods study in UK general practice. Method Data were collated from longitudinal ethnographic case studies of 12 general practices; a multi-stakeholder workshop; interviews with policymakers, training providers, and trainees; published research; and grey literature (such as training materials and surveys). Data were coded thematically and analysed using theories of individual and team learning. Results Learning to provide remote services occurred in the context of high workload, understaffing, and complex workflows. Low confidence and perceived unmet training needs were common. Training priorities for novice clinicians included basic technological skills, triage, ethics (for privacy and consent), and communication and clinical skills. Established clinicians’ training priorities include advanced communication skills (for example, maintaining rapport and attentiveness), working within the limits of technologies, making complex judgements, coordinating multi-professional care in a distributed environment, and training others. Much existing training is didactic and technology focused. While basic knowledge was often gained using such methods, the ability and confidence to make complex judgements were usually acquired through experience, informal discussions, and on-the-job methods such as shadowing. Whole-team training was valued but rarely available. A draft set of competencies is offered based on the findings. Conclusion The knowledge needed to deliver high-quality remote encounters to diverse patient groups is complex, collective, and organisationally embedded. The vital role of non-didactic training, for example, joint clinical sessions, case-based discussions, and in-person, whole-team, on-the-job training, needs to be recognised.

Hair salons as a promising space to provide HIV and sexual and reproductive health services for young women in Lesotho: a citizen scientist mixed-methods study.

INTRODUCTION: Adolescent girls and young women in southern Africa are disproportionately affected by HIV and sexual and reproductive health (SRH) challenges. There is a need for more accessible and de-medicalized community spaces to offer HIV/SRH services for this key population. We aimed to assess the acceptability and feasibility of offering HIV/SRH services at hair salons in Lesotho. METHODS: We used an innovative citizen scientist mixed-methods approach, whereby hair stylists were recruited through social media, completed questionnaires, and recruited women clients aged 15-35 years as respondents. A stepwise verification process including GPS, pictures, and a local mobile payment system ensured data quality. Subsequently, we conducted individual in-depth interviews among 14 stylists and clients, following the rapid thematic analysis framework, supported by natural language processing. Clients and stylists were involved at the design, implementation, and results interpretation stage. RESULTS: We recruited 157 hair stylists (median age 29; [interquartile range 25-33]; across all ten districts of Lesotho) and 308 women clients (median age 26 [22-30]). Among stylists, 93.6% were comfortable offering oral HIV self-testing (HIVST), 92.4% pre-exposure prophylaxis (PrEP), and 91.7% post-exposure prophylaxis (PEP). Among clients, 93.5%, 88.3%, and 86.4% felt comfortable receiving the above-mentioned services, respectively. Immediate demand for the three services was 30.8%, 22.1%, and 14.9%. Acceptability and demand were higher for family planning methods and menstrual health products. 90.4% of stylists thought that offering HIV/SRH services would positively impact their business. The majority of clients visit their salon once or twice a month. Salons were more accessible than the nearest health facility in terms of cost and time, but only 21.0% have an additional confidential space. Qualitative analysis confirmed high acceptability of hair salons as an accessible, less judgemental space than clinics, but raised concerns regarding confidentiality and stylists' roles. CONCLUSIONS: This study suggests that offering HIV/SRH services in hair salons in Lesotho seems to be largely acceptable and feasible with some addressable barriers, based on survey data. A pilot intervention, guided by this study's recommendations, is warranted to translate these findings into practice.