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Abstract Aims We aim to evaluate change in the use of prognostic guideline‐directed medical therapies (GDMTs) for heart failure (HF) before and after a cancer diagnosis as well as the matched non‐cancer controls, including renin‐angiotensin‐system inhibitors (RASIs), beta‐blockers, and mineralocorticoid receptor antagonists (MRAs). Methods and results We conducted a longitudinal study in patients with HF in the UK Clinical Practice Research Datalink between 2005 and 2021. We selected patients with probable HF with reduced ejection fraction (HFrEF) based on diagnostic and prescription records. We described the longitudinal trends in the use and dosing of GDMTs before and after receiving an incident cancer diagnosis. HF patients with cancer were matched with a 1:1 ratio to HF patients without cancer to investigate the association between cancer diagnosis and treatment adherence, persistence, initiation, and dose titration as odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression models. Of 8504 eligible HFrEF patients with incident cancer, 4890 were matched to controls without cancer. The mean age was 75.7 (±8.4) years and 73.9% were male. In the 12 months following a cancer diagnosis, patients experienced reductions in the use and dosing of GDMT. Compared with the non‐cancer controls, patients with cancer had higher risks for poor adherence for all three medication classes (RASIs: OR = 1.51, 95% CI = 1.35–1.68; beta‐blockers: OR = 1.22, 95% CI = 1.08–1.37; MRAs: OR = 1.31, 95% CI = 1.08–1.59) and poor persistence (RASIs: OR = 2.04, 95% CI = 1.75–2.37; beta‐blockers: OR = 1.35, 95% CI = 1.12–1.63; MRAs: OR = 1.49, 95% CI = 1.16–1.93), and higher risks for dose down‐titration for RASIs (OR = 1.69, 95% CI = 1.40–2.04) and beta‐blockers (OR = 1.31, 95% CI = 1.05–1.62). Cancer diagnosis was not associated with treatment initiation or dose up‐titration. Event rates for HF hospitalization and mortality were higher in patients with poor adherence or persistence to GDMTs. Conclusions Following a cancer diagnosis, patients with HFrEF were more likely to have reduced use of GDMTs for HF.

Objective To investigate the prescribing trends of indapamide, a thiazide-like diuretic, and the long term comparative effectiveness of modified release versus immediate release indapamide.Design Cohort study.Setting IQVIA Medical Research Data UK database, incorporating data from The Health Improvement Network database, 1 January 2005 to 31 December 2020.Participants Of 1 904 289 patients with hypertension, 86 388 started indapamide treatment during the study period. 30 021 patients received modified release and 56 367 immediate release indapamide.Main outcome measures Monthly prescribing trends of modified release and immediate release indapamide are described. A pragmatic trial was emulated to compare the five year risks of composite cardiovascular events (myocardial infarction and stroke) and death between modified release and immediate release indapamide. Intention-to-treat and per protocol effects of treatment were estimated with pooled logistic regression models. Confounding and selection bias were accounted for by multivariable adjustments and inverse probability weights.Results 1 38 414 patients who used indapamide were identified among 1 904 289 patients with hypertension. A greater increase was seen in the proportion of users of immediate release indapamide (from 0.43% in 2005 to 2.31% in 2020) than in users of modified release indapamide (from 0.71% to 0.79%). 86 388 patients (30 021 and 56 367 who started modified release and immediate release indapamide, respectively) were eligible for the trial emulation. In the intention-to-treat analysis, no difference was found in the risk of cardiovascular events (hazard ratio 0.99, 95% confidence interval (CI) 0.90 to 1.08) or death (hazard ratio 0.97, 0.92 to 1.02) between modified release and immediate release indapamide. In the per protocol analysis, a lower risk of cardiovascular events was found with modified release indapamide than with immediate release indapamide (risk difference −0.39%, 95% CI −0.71% to −0.06%; hazard ratio 0.81, 95% CI 0.68 to 0.98), which was mainly driven by myocardial infarction (risk difference −0.36%, 95% CI −0.64% to −0.08%; hazard ratio 0.80, 95% CI 0.64 to 1.01). Similar risks of death (hazard ratio 1.03, 95% CI 0.90 to 1.17) were found for the two formulations.Conclusions In patients treated with indapamide for hypertension, starting treatment with modified release or immediate release indapamide had similar risks for cardiovascular events or all cause mortality. In an exploratory secondary analysis, sustained treatment with modified release preparations was associated with a lower the risk of cardiovascular events but not all cause mortality compared with immediate release preparations. These findings need to be confirmed in prospective studies.

ABSTRACT Precise mosquito identification is integral to effective arbovirus surveillance. Nonetheless, the conventional morphological approach to identifying mosquito species is laborious, demands expertise and presents challenges when specimens are damaged. DNA barcoding offers a promising alternative, surmounting challenges inherent in morphological identification. To integrate DNA barcoding into arbovirus surveillance effectively, a robust dataset of mosquito barcode sequences is required. This study established a comprehensive repository of Cytochrome Oxidase I (COI) barcodes, encompassing 177 samples representing 45 mosquito species from southern and northern Western Australia (WA), including 16 species which have not been previously barcoded. The average intraspecific and interspecific genetic distances were 1% and 6.8%, respectively. Anopheles annulipes sensu lato had the highest intraspecific distance at 9.1%, signifying a genetically diverse species. While validating the potential of COI barcodes to accurately differentiate mosquito species, we identified that some species pairs have low COI divergence. This includes Aedes clelandi and Ae. hesperonotius, Tripteroides atripes and Tp. punctolaeralis and Ae. turneri and Ae. stricklandi. In addition, we observed ambiguity in identification of the members of Culex sitiens subgroup (Cx. annulirostris, Cx. palpalis and Cx. sitiens) and three members of Cx. pipiens complex (Cx. australicus, Cx. globocoxitus, Cx. quinquefasciatus). In summary, despite presenting challenges in the identification of some mosquito species, the COI barcode accurately identified most of the species and generated a valuable resource that will support the WA arbovirus surveillance program and enhance public health intervention strategies for mosquito‐borne disease control.

Decentralized clinical trials (DCTs) are becoming increasingly popular. Digital clinical trial platforms are software environments where users complete designated clinical trial tasks, providing investigators and trial participants with efficient tools to support trial activities and streamline trial processes. In particular, digital platforms with a modular architecture lend themselves to DCTs, where individual trial activities can correspond to specific platform modules. While design features can allow users to customize their platform experience, the real strengths of digital platforms for DCTs are enabling centralized data capture and remote monitoring of trial participants and in using digital technologies to streamline workflows and improve trial management. When selecting a platform for use in a DCT, sponsors and investigators must consider the specific trial requirements. All digital platforms are limited in their functionality and technical capabilities. Integrating additional functional modules into a central platform may solve these challenges, but few commercial platforms are open to integrating third-party components. The lack of common data standardization protocols for clinical trials will likely limit the development of one-size-fits-all digital platforms for DCTs. This viewpoint summarizes the current role of digital platforms in supporting decentralized trial activities, including a discussion of the potential benefits and challenges of digital platforms for investigators and participants. We will highlight the role of the digital platform in the development of DCTs and emphasize where existing technology is functionally limiting. Finally, we will discuss the concept of the ideal fully integrated and unified DCT and the obstacles developers must address before it can be realized.

Summary: Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes. Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype. Findings: Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 [95% CI 1.14–1.86] and 0.96 [95% CI 0.70–1.30] per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 [95% CI 1.18–2.22] and 0.66 [95% CI 0.44–1.00] per hour of MSFsc, respectively; interaction p

Abstract The global demand from multi-sectoral partners for operational tools for One Health implementation and capacity building is increasing, yet a validated global inventory of One Health tools did not exist. Here, we map and analyze available One Health tools and assess their suitability to support One Health implementation, including the One Health Joint Plan of Action 2022–2026 (OH JPA). Our objectives were to identify (i) publicly available One Health tools to support capacity building and OH JPA implementation; (ii) optimal outcomes for countries/regions using available One Health tools; (iii) linkages to OH JPA Action Tracks and pathways in the One Health Theory of Change (TOC); and (iv) gaps and priorities for the development of additional One Health tools. One Health High Level Expert Panel (OHHLEP) members compiled information on One Health tools that were publicly available and released up to June 30, 2023, via online sources and partner networks including the Quadripartite organizations. Inclusion criteria addressed One Health relevance, use at the national, subnational, or regional level in ≥5 locations, and publicly available information. Tools were assessed for applicability by OH JPA action track, TOC pathway, scope, and intended outcomes, as well as the extent to which tools addressed gender equality, social inclusion, and environmental dimensions of One Health. Of 132 candidate tools, 50 (38%) met the inclusion criteria. These tools addressed all six OH JPA Action Tracks, but relatively fewer tools addressed Action Tracks 4 (Food Safety), 5 (Antimicrobial Resistance), and 6 (Environmental Integration). Tools were available to support all three TOC outcome pathways, and many addressed more than one Action Track and TOC outcome pathway. Most available One Health tools addressed assessment and to a lesser extent implementation, with fewer tools available for action planning, prioritization, and monitoring. Gaps and opportunities for improving One Health tools were identified, including the integration of the environment dimension, gender equality, and social inclusion. Ultimately, our findings will contribute to further the advancement of One Health globally, including via OH JPA implementation, while spurring adjustments to existing One Health tools and the development of new ones to address key gaps. One Health impact statement The One Health approach is gaining momentum globally, and this study represents the first integrated mapping and analysis of globally available One Health tools. Our findings aim to improve the quality, applicability, and availability of tools to support One Health implementation at the subnational, national, regional, and global levels, including through the Quadripartite’s One Health Joint Plan of Action. By using the OHHLEP definition of One Health to assess available One Health tools and map them onto the One Health Joint Plan of Action, we identify the need for a systematic approach and enhanced integration across dimensions of One Health to lead to sustainable One Health systems.

Many organisms live in fragmented populations, which has profound consequences on the dynamics of associated parasites. Metapopulation theory offers a canonical framework for predicting the effects of fragmentation on spatiotemporal host–parasite dynamics. However, empirical studies of parasites in classical metapopulations remain rare, particularly for vector-borne parasites. Here, we quantify spatiotemporal patterns and possible drivers of infection probability for several ectoparasites (fleas, Ixodes trianguliceps and Ixodes ricinus) and vector-borne microparasites (Babesia microti, Bartonella spp., Hepatozoon spp.) in a classically functioning metapopulation of water vole hosts. Results suggest that the relative importance of vector or host dynamics on microparasite infection probabilities is related to parasite life-histories. Bartonella, a microparasite with a fast life-history, was positively associated with both host and vector abundances at several spatial and temporal scales. In contrast, B. microti, a tick-borne parasite with a slow life-history, was only associated with vector dynamics. Further, we provide evidence that life-history shaped parasite dynamics, including occupancy and colonization rates, in the metapopulation. Lastly, our findings were consistent with the hypothesis that landscape connectivity was determined by distance-based dispersal of the focal hosts. We provide essential empirical evidence that contributes to the development of a comprehensive theory of metapopulation processes of vector-borne parasites.

Abstract Background Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. Objective To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Design Prospective, randomised, open-label, blinded endpoint multicentre clinical trial. Setting Four hundred and twenty-four UK primary care practices. Participants Aged 60 years and over with ischaemic heart disease but no gout. Interventions Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care. Main outcome measures The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis. Results From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (n = 2979) or the usual care arm (n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a ‘within trial’ cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval −0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective. Limitations The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis. Conclusions The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout. Future work The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies. Trial registration This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? The purpose of the ALL-HEART study was to determine whether giving allopurinol to people with ischaemic heart disease (also commonly known as coronary heart disease) would reduce their risk of having a heart attack, stroke or of dying from cardiovascular disease. Allopurinol is a medication usually given to patients with gout to prevent acute gout flares. It is not currently used to treat ischaemic heart disease. What did we do? We randomly allocated people aged over 60 years with ischaemic heart disease to take up to 600 mg of allopurinol daily (in addition to their usual care) or to continue with their usual care. We then monitored participants for several years and recorded any major health events such as heart attacks, strokes and deaths. We obtained most of the follow-up data from centrally held electronic hospital admissions and death records, making the study easier for participants and more cost-efficient. We asked participants in both groups to complete questionnaires to assess their quality of life during the study. We also collected data to determine whether there was any economic benefit to the NHS of using allopurinol in patients with ischaemic heart disease. What did we find? There was no difference in the risk of heart attacks, strokes or death from cardiovascular disease between the participants given allopurinol and those in the group continuing their usual care. We also found no difference in the risks of other cardiovascular events, deaths from any cause or quality-of-life measurements between the allopurinol and usual care groups. What does this mean? The results of the ALL-HEART study suggest that we should not recommend that allopurinol be given to people with ischaemic heart disease to prevent further cardiovascular events or deaths. Scientific summary Background Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid (SUA) and is widely used in patients with gout to prevent acute gout flares. Xanthine oxidase promotes inflammation and atherosclerosis via the production of reactive oxygen species and xanthine oxidase levels are raised in several conditions including coronary artery disease. The role of SUA in cardiovascular (CV) disease is controversial, with some studies associating higher SUA levels with worse CV outcomes, but more recent genome-wide association studies suggest no major role of uric acid levels in determining CV outcomes. Some observational studies have suggested that allopurinol therapy may improve CV outcomes, while others have not found an association. Small interventional studies have shown that allopurinol therapy improves some CV parameters, including endothelial function, left ventricular hypertrophy, blood pressure, carotid intimal media thickness and arterial stiffness. Allopurinol therapy was also found to improve outcomes after acute coronary syndrome (ACS) in one study and to improve chest pain in patients with chronic stable angina with documented coronary artery disease in another. However, results have not been consistent across different studies. Before the ALL-HEART study, no large, randomised trial of the effects of allopurinol therapy on CV outcomes in patients with ischaemic heart disease (IHD) had been performed. Objectives Primary Does allopurinol therapy added to usual care improve major CV outcomes in patients aged over 60 years with IHD but no gout? Secondary Does allopurinol therapy added to usual care improve all-cause mortality or other CV outcomes in patients with IHD? What is the cost-effectiveness of adding allopurinol up to 600 mg daily to usual care in patients with IHD? Does allopurinol therapy added to usual care improve quality of life assessed by general health survey [EuroQol-5 Dimensions, five-level version (EQ-5D-5L)] or coronary heart disease-specific questionnaire (Seattle angina questionnaire)? Methods Design and participants The ALL-HEART study was a prospective, randomised, open-label, blinded endpoint (PROBE) multicentre trial undertaken in patients with IHD. Participants were primarily recruited from 424 primary care practices via 18 regional centres in the UK, with a small number also referred into the study from secondary care centres. Eligible patients were aged 60 years or over, with a history of IHD [myocardial infarction (MI), angina or other evidence of IHD]. Exclusion criteria were: history of gout; known severe renal impairment [estimated glomerular filtration rate (eGFR) < 30 ml/minute/1.73 m2]; moderate-to-severe heart failure (HF) [New York Heart Association (NYHA) III–IV]; significant hepatic disease [e.g. alanine transaminase (ALT) > 3 × upper limit of normal, cirrhosis, ascites] (investigator opinion); currently taking part in another interventional clinical trial of an investigational medicinal product or medical device (or taken part in one within the last 3 months); previous allergy to allopurinol; previous serious adverse cutaneous (skin) reaction to any drug (e.g. Stevens–Johnson syndrome, toxic epidermal necrolysis, hospitalisation due to skin reaction to drug) (investigator opinion); already taking urate-lowering therapy (including allopurinol, febuxostat, sulfinpyrazone, benzbromarone, probenecid, rasburicase); taking azathioprine, mercaptopurine, ciclosporin or theophylline; malignancy (except non-metastatic, non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years (investigator opinion). The exclusion criterion relating to renal impairment was originally ‘known renal impairment eGFR < 60 ml/minute/1.73 m2’ for patients recruited from the start of the trial (7 February 2014) until 4 April 2016 when an updated version of the protocol was implemented at all study sites to allow the inclusion of patients with moderate renal impairment in the study with the purpose of making the study results more generalisable. Fifty-two per cent of the target number of patients had been randomised by this date. Randomisation At a single screening and randomisation visit usually held at the patient’s primary care practice by a research nurse, patients were consented, screened and randomised to receive allopurinol therapy or to continue their usual care. Baseline demographics, medical history, CV risk factors and concomitant medications were recorded. Blood pressure, height and weight were measured. Baseline blood tests were taken for urea, creatinine and electrolytes, full blood count and SUA. Participants were randomised before screening blood results were available. When the screening results were available, a nurse telephoned the patient to advise them to start taking randomised therapy. If the screening visit eGFR result was below the exclusion limit, the participant did not receive any allopurinol and was excluded from the modified intention-to-treat (mITT) analysis population, whichever arm of the study they had been randomised to. Randomisation was via a web-based randomisation facility located at the Robertson Centre for Biostatistics, University of Glasgow, accessed using a web-based application or an interactive voice response system. Randomisation was based on randomised permuted blocks of variable size, stratified by history of MI, history of stroke and primary care practice. Randomised intervention Allopurinol 100 or 300 mg tablets were prescribed to participants by their primary care physicians via the usual NHS prescription system. Participants with a screening eGFR result ≥ 60 ml/minute/1.73 m2 were prescribed allopurinol at 100 mg daily for 2 weeks, then 300 mg daily for 2 weeks then 600 mg daily (given as 300 mg twice daily) thereafter if tolerated for the duration of the study. After 4 April 2016, participants with a screening eGFR result 30–59 ml/minute/1.73 m2 were prescribed allopurinol at 100 mg daily for 2 weeks, then 300 mg daily thereafter if tolerated for the duration of the study. If there were tolerability issues, the dose could be decreased at the discretion of a physician. Participants who stopped randomised therapy were encouraged to continue with study follow-up. The comparison arm of the study was ‘usual care’; no placebo was given as this was a pragmatic open-label study. Randomised therapy was blinded to the endpoint adjudication committee, but not to participants, study staff or treating healthcare professionals. If allopurinol was started in participants randomised to the usual care group at any point in the study (e.g. for clinical reasons such as developing gout), this was recorded. Other study procedures At the screening visit, participants completed the EQ-5D-5L questionnaire to assess general health outcomes and the Seattle angina questionnaire to assess coronary artery disease-specific quality of life. Participants who had taken any allopurinol therapy attended a 6-week study visit. Blood samples were taken for urea, creatinine and electrolytes, full blood count and SUA. Participants were then followed up remotely by electronic record-linkage with centralised databases of hospitalisations, cancers and deaths held by Public Health Scotland (PHS) and NHS Digital and by annual questionnaires (online, by post or by telephone). Data on adverse events, skin rashes, gout flares and self-reported adherence to randomised therapy were collected at the 6-week visit, then by annual questionnaire (but could also be reported at any time by participants or health professionals). Participants completed the EQ-5D-5L and Seattle angina questionnaires again after 1 year and at the end of the trial. The trial recruitment period was extended once, and the trial follow-up period was extended twice. Recruitment exceeded the target of 5215 randomised participants to a final total of 5937 randomised participants due to an increase in recruitment rate in the last weeks of recruitment. The follow-up period of the trial ended on 30 September 2021. After this date, participants stopped randomised therapy and continued to receive their usual care. Study outcomes The primary and secondary outcomes were as follows. Primary outcome: Composite of non-fatal MI, non-fatal stroke or CV death. Secondary outcomes: Non-fatal MI. Non-fatal stroke. CV death. All-cause mortality. Hospitalisation for ACS. Coronary revascularisation. Hospitalisation for ACS or coronary revascularisation. Hospitalisation for HF. All CV hospitalisations. Quality of life. Cost-effectiveness. Adverse events Serious adverse events (SAEs) occurring during the study (until 30 September 2021) were recorded and any events ongoing at that time were followed up for a further 30 days, unless consent had been withdrawn. Treatment-related adverse events (adverse reactions), gout flares and rashes were also recorded. Allopurinol therapy was stopped if participants developed a rash that may have been due to allopurinol. For any SAEs that were potential study endpoints, detailed information was obtained from medical records and death certificates to support the production of an anonymised endpoint package that was adjudicated by an independent clinical endpoint adjudication committee, blinded to randomised therapy allocation. Statistical analysis The power calculation suggested that 5215 participants would need to be randomised 1 : 1 to give 80% power to detect a 20% reduction in the primary outcome for the intervention (allowing for a 4% dropout for withdrawal of consent and non-CV deaths). A primary event rate of 14% over an average of 4 years follow-up was estimated from other trials in similar patient groups. The study ended when 631 adjudicated first primary events had occurred. Baseline characteristics are presented by treatment group as means [standard deviation (SD)] and medians [interquartile range (IQR)] for continuous variables and as numbers (%) for categorical variables. Clinical outcomes were analysed on a time-to-first event basis using Cox proportional hazards models. Treatment effects (allopurinol vs. usual care) were estimated as hazard ratios (HR) and 95% confidence intervals (CIs) for the Cox models. Analyses were adjusted for the stratification variables history of MI and history of stroke and p-values were calculated from Wald statistics. The primary analysis was a mITT analysis. Health economic analysis A health economic analysis was planned to determine whether allopurinol was a cost-effective intervention in the context of the NHS setting in the UK in patients with IHD. The analysis plan was based around NHS costs and estimation of quality-adjusted life-years (QALYs) and was to include a ‘within trial’ cost–utility analysis if the primary outcome was not statistically different between randomised study arms. Trial approvals and committees The study was approved by an ethics committee, Medicines and Healthcare Products Regulatory Agency (MHRA) and Health Research Authority (HRA). An Independent Data Monitoring Committee oversaw trial safety. A Trial Steering Committee including independent and patient/lay members oversaw trial progress. Results From 7 February 2014 to 29 September 2017, 6134 patients consented to enrol in the trial and were assessed for eligibility. Also, 167 of the 6134 consented participants were not eligible and 30 others were not randomised. The final randomisation was completed on 2 October 2017. Of the 5937 randomised participants, 216 were excluded post randomisation from the mITT analysis population (184 did not meet the eGFR entry criteria once their screening blood results were available; 32 were later found to have not met all of the inclusion/exclusion criteria). Five thousand seven hundred and twenty-one participants (2853 in the allopurinol arm and 2868 in the usual care arm) were included in the mITT analysis population for the efficacy analysis. The population for safety analyses consisted of 2805 participants in the allopurinol arm (excluding the 48 participants in the allopurinol arm who never received any randomised therapy) and 2868 participants in the usual care arm. The mean duration of follow-up in the trial was 4.8 years. Two hundred and fifty-eight participants (9.0%) in the allopurinol group and 76 participants (2.6%) in the usual care group withdrew consent for all follow-up. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment. Baseline characteristics were well balanced in the two groups. The mean age at study entry was 72.0 years (SD 6.8), 4321 participants (75.5%) were male, 5676 (99.2%) were white and 1241 (21.7%) had a history of diabetes mellitus. The median duration of IHD at study entry was 10.1 years (IQR 5.1–16.1). Three thousand four hundred and sixty-four (60.5%) participants were recruited in England and 2257 (39.5%) participants in Scotland. The most commonly taken dose of allopurinol was 600 mg daily. In the 2447 participants in the allopurinol arm with both a baseline and 6-week SUA result, SUA fell from a mean of 0.34 (SD 0.08) mmol/l at baseline to a mean of 0.18 (SD 0.09) mmol/l 6 weeks after randomisation. Forty-five participants in the usual care arm started allopurinol therapy during follow-up (for clinical reasons, mainly gout). Primary and secondary outcomes There was no significant difference between the randomised treatment groups in the rates of the primary outcome or any of the secondary time-to-event outcomes. Three hundred and fourteen (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years) experienced a primary outcome, HR 1.04 (95% CI 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, HR 1.02 (95% CI 0.87 to 1.20); p = 0.77. Results for the primary outcome were consistent across all pre-specified subgroups. In a supporting on-treatment analysis, results for the time-to-event clinical outcomes were broadly similar to those in the mITT analysis. There was limited evidence of any effect of allopurinol on quality-of-life outcomes, with no differences in EQ-5D-5L outcomes or Seattle angina questionnaire outcomes at the end of the first year or at the final visit, except for a nominally significant but only slightly greater fall in the physical domain score of the Seattle angina questionnaire at the end of the first year [treatment difference = 1.219 (95% CI 0.027 to 2.410); p = 0.045] in the allopurinol arm. Health economic analysis There was strong evidence that allopurinol treatment was associated with incremental costs relative to usual care [incremental cost per patient £115.4, 95% CI (£17.0 to £210.2)], with little evidence of improvement in relation to incremental QALYs [incremental QALYs −0.000, 95% CI (−0.061 to 0.060)]. The cost-effectiveness acceptability curve asymptoted at a probability of 0.456, meaning that even with a willingness to pay of an infinite amount, the probability of cost-effectiveness was only 0.465. At a willingness to pay of £20,000 the probability of cost-effectiveness was 0.41. Adverse events There was no difference in SAE rates between treatment arms, except for the grouping of endocrine disorders where no events occurred in the allopurinol treatment group but 14 in the usual care group. However, these endocrine events included events with a spread of different types. Fifteen participants had SAEs that were considered potentially treatment related and none of these were fatal. There was no difference between treatment arms in the rates of incident cancers. Adjudicated causes of death were well balanced between the treatment groups, including deaths from COVID-19 and COVID-19 pneumonia. Conclusions The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve CV outcomes compared to usual care in patients with IHD. There were also no benefits on quality of life. There was no evidence that allopurinol used in line with the study protocol is cost-effective within the NHS system. We conclude that allopurinol should not be recommended for the secondary prevention of CV events in patients with IHD but no gout. Recommendations for research Future research should explore other therapeutic options for the improvement of CV outcomes and quality of life in patients with IHD. Further exploration of the effects of allopurinol on CV outcomes in patients with co-existing IHD and clinical gout or hyperuricaemia could be considered (patients with gout were excluded from this study). Trial registration The ALL-HEART trial is registered with the EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.

Abstract Objectives The Royal College of Surgeons of England (RCS) Good Surgical Practice guidance identifies essential criteria for surgical operation note documentation. The current quality improvement project aims to identify if using pre-templated operation notes for documenting fractured neck of femur surgery results in improved documentation when compared to freehand orthopaedic operation notes. Methods A total of fourteen categories were identified from the RCS guidance as required across all the operations identified in this study. All operations for the month of October 2021 were identified and the operation notes analysed. Pre-templated operation notes were compared to freehand operation notes. Results Ninety-seven cases were identified, of which 74 were freehand operation notes and 23 were pre-templated fractured neck of femur operation notes. All fourteen categories were completed in 13 (57%) of the templated operation notes versus 0 (0%) in the freehand operation notes (odds ratio 0.0052, 95% CI 0.0003 to 0.0945, p

The health of humans, domestic and wild animals, plants, and the environment are inter-dependent. Global anthropogenic change is a key driver of disease emergence and spread and leads to biodiversity loss and ecosystem function degradation, which are themselves drivers of disease emergence. Pathogen spill-over events and subsequent disease outbreaks, including pandemics, in humans, animals and plants may arise when factors driving disease emergence and spread converge. One Health is an integrated approach that aims to sustainably balance and optimize human, animal and ecosystem health. Conventional disease surveillance has been siloed by sectors, with separate systems addressing the health of humans, domestic animals, cultivated plants, wildlife and the environment. One Health surveillance should include integrated surveillance for known and unknown pathogens, but combined with this more traditional disease-based surveillance, it also must include surveillance of drivers of disease emergence to improve prevention and mitigation of spill-over events. Here, we outline such an approach, including the characteristics and components required to overcome barriers and to optimize an integrated One Health surveillance system.

Summary: Background: There is no real-world evidence regarding the association between beta-blocker use and mortality or cardiovascular outcomes in patients with obstructive sleep apnoea (OSA). We aimed to investigate the impact of beta-blocker use on all-cause mortality and cardiovascular diseases (CVDs) in patients with OSA. Methods: We conducted a target trial emulation study of 37,581 patients with newly diagnosed OSA from 1st January 2000 to 30th November 2021 using the IMRD-UK database (formerly known as the THIN database). We compared the treatment strategies of initiating beta-blocker treatment within one year versus non-beta-blocker treatment through the method of clone-censor-weight. Covariates, including patients’ demographics, lifestyle, comorbidities, and recent medications, were measured and controlled. Patients were followed up for all-cause mortality or composite CVD outcomes (angina, myocardial infarction, stroke/transient ischaemic attack, heart failure, or atrial fibrillation). We estimated the five-year absolute risks, risk differences and risk ratio with 95% confidence intervals (CIs) with standardised, weighted pooled logistic regression, which is a discrete-time hazard model for survival analysis. Several sensitivity analyses were performed, including multiple imputation addressing the missing data. Findings: The median follow-up time was 4.1 (interquartile range, 1.9–7.8) years. The five-year absolute risk of all-cause mortality and CVD outcomes were 4.9% (95% CI, 3.8–6.0) and 13.0% (95% CI, 11.4–15.0) among beta-blocker users, and 4.0% (95% CI, 3.8–4.2) and 9.4% (95% CI, 9.1–9.7) among non-beta-blocker users, respectively. The five-year absolute risk difference and risk ratio between the two groups for all-cause mortality and CVD outcomes were 0.9% (95% CI, −0.2 to 2.1) and 1.22 (95% CI, 0.96–1.54), and 3.5% (95% CI, 2.1–5.5) and 1.37 (95% CI, 1.22–1.62), respectively. Findings were consistent across the sensitivity analyses. Interpretation: Beta-blocker treatment was associated with an increased risk of CVD and a trend for an increased risk of mortality among patients with OSA. Further studies are needed to confirm our findings. Funding: Innovation and Technology Commission of the Hong Kong Special Administration Region Government.

Abstract Background The COVID-19 pandemic significantly impacted the conduct of clinical trials through delay, interruption or cancellation. Decentralised methods in clinical trials could help to continue trials during a pandemic. This paper presents the results of an exploratory study conducted early in the pandemic to gain insight into and describe the experiences of organisations involved in clinical trials, with regard to the impact of COVID-19 on the conduct of trials, and the adoption of decentralised methods prior to, and as mitigation for the impact, of COVID-19. Methods A survey with 11 open-ended and four multiple choice questions was conducted in June 2020 among member organisations of the public-private “Trials@Home” consortium. The survey investigated (1) the impact and challenges of COVID-19 on the continuation of ongoing clinical trials, (2) the adoption of decentralised methods in clinical trials prior to and as a mitigation strategy for COVID-19, (3) the challenges of conducting clinical trials during COVID-19, (4) the expected permanency of COVID-19-driven changes to the adoption of decentralised methods in clinical trials, and (5) lessons learned from conducting clinical trials during the COVID-19 pandemic. A thematic, inductive analysis of open survey questions was performed, complemented with descriptive statistics (frequencies and distributions). Results The survey had a response rate of 81%. All organisations included in the analysis (n = 18) implemented (some) decentralised methods in their clinical trials prior to COVID-19, and 15 (83%) implemented decentralised methods as mitigation for COVID-19. Decentralised methods for IMP supply, patient-health care provider interaction and communication, clinic visits and source document verification were used more often as mitigation strategies than they were used prior to COVID-19. Many respondents expect to maintain those decentralised methods they implemented during COVID-19 in ongoing trials, as well as implement them in future trials. Conclusions Decentralised methods are a widely implemented mitigation strategy for trial conduct in the face of the COVID-19 pandemic. The results of this survey show that there is an interest to continue the use of decentralised methods in future trials, but important points of attention have been identified that need solutions to help guide the transition from the traditional trial model to a more decentralised trial model.

Abstract There have been numerous risk tools developed to enable triaging of SARS-CoV-2 positive patients with diverse levels of complexity. Here we presented a simplified risk-tool based on minimal parameters and chest X-ray (CXR) image data that predicts the survival of adult SARS-CoV-2 positive patients at hospital admission. We analysed the NCCID database of patient blood variables and CXR images from 19 hospitals across the UK using multivariable logistic regression. The initial dataset was non-randomly split between development and internal validation dataset with 1434 and 310 SARS-CoV-2 positive patients, respectively. External validation of the final model was conducted on 741 Accident and Emergency (A&E) admissions with suspected SARS-CoV-2 infection from a separate NHS Trust. The LUCAS mortality score included five strongest predictors (Lymphocyte count, Urea, C-reactive protein, Age, Sex), which are available at any point of care with rapid turnaround of results. Our simple multivariable logistic model showed high discrimination for fatal outcome with the area under the receiving operating characteristics curve (AUC-ROC) in development cohort 0.765 (95% confidence interval (CI): 0.738–0.790), in internal validation cohort 0.744 (CI: 0.673–0.808), and in external validation cohort 0.752 (CI: 0.713–0.787). The discriminatory power of LUCAS increased slightly when including the CXR image data. LUCAS can be used to obtain valid predictions of mortality in patients within 60 days of SARS-CoV-2 RT-PCR results into low, moderate, high, or very high risk of fatality.

Abstract Background Death at home has been identified as a key quality indicator for Canadian health care systems and is often assumed to reflect the wishes of the entire Canadian public. Although research in other countries has begun to question this assumption, there is a dearth of rigorous evidence of a national scope in Canada. This study addresses this gap and extends it by exploring three factors that moderate preferences for setting of death: situational severity (entailing both symptoms and supports), perceptions of family obligation, and respondent age. Methods Two thousand five hundred adult respondents from the general population were recruited using online panels between August 2019 and January 2020. The online survey included three vignettes, representing distinct dying scenarios which increased in severity based on symptom management alongside availability of formal and informal support. Following each vignette respondents rated their preference for each setting of death (home, acute/intensive care, palliative care unit, nursing home) for that scenario. They also provided sociodemographic information and completed a measure of beliefs about family obligations for end-of-life care. Results Home was the clearly preferred setting only for respondents in the mild severity scenario. As the dying scenario worsened, preferences fell for home death and increased for the other options, such that in the severe scenario, most respondents preferred a palliative care or hospice setting. This pattern was particularly distinct among respondents who also were less supportive of family obligation norms, and for adults 65 years of age and older. Conclusions Home is not universally the preferred setting for dying. The public, especially older persons and those expressing lower expectations of families in general, express greater preference for palliative care settings in situations where they might have less family or formal supports accompanied by more severe and uncontrolled symptoms. Findings suggest a) the need for public policy and health system quality indicators to reflect the nuances of public preferences, b) the need for adequate investment in hospices and palliative care settings, and c) continuing efforts to ensure that home-based formal services are available to help people manage symptoms and meet their preferences for setting of death.

Abstract Background Decentralised clinical trials (DCTs) are clinical trials where all or most trial activities occur in or near participants’ homes instead of hospitals or research sites. While more convenient for participants, DCTs may offer limited opportunities to build trust with investigators and trial teams. This qualitative analysis explored DCT stakeholder views to inform strategies for maximising participant recruitment, retention, and adherence. Methods A secondary analysis of original interview transcripts focused on participant engagement: recruitment, retention, and adherence. Semi-structured interviews were conducted with a purposive sample of stakeholders, including trial managers and administrators, investigators, nurses, vendors, and patient representatives. Interview data were coded using a thematic approach to generate descriptive themes. Results Forty-eight stakeholders were interviewed. Three components of participant engagement in DCTs were identified: identifying and attracting potential participants, retaining participants and encouraging adherence, and involvement of patients and the public. Interviewees believed that a potential participant’s beliefs about research value and their trust in the research team strongly influenced the likelihood of taking part in a DCT. Early involvement of patients was identified as one way to gauge participant priorities. However, perceived burden was seen as a barrier to recruitment. Factors influencing retention and adherence were related to the same underlying motivators that drove recruitment: personal values, circumstances, and burden. Being part of a DCT should not conflict with the original motivations to participate. Conclusion Recruitment, retention, and adherence in DCTs are driven by factors that have previously been found to affect conventional clinical trials. Increasing patient and public involvement can address many of these factors. In contrast to conventional trials, DCTs are perceived as requiring greater emphasis on communication, and contact, to engender trust between participants and researchers despite a relative lack of in-person interaction.

Abstract Background Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here, we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence. In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK. Methods Patients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating general practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalisation and death data in the NHS will be used to compare cardiovascular event rates between the two policies. Results This pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients) and 15 to bendroflumethiazide (3437 patients), a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch. Conclusion The pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study; currently, 102 GP practices (> 12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas. Trial registration ISRCTN Registry, ISRCTN46635087 . Registered on 11 August 2017

Japanese encephalitis virus (JEV) first emerged in the Torres Strait of north-eastern Australia in 1995, with three human cases, and widespread infection of pigs on a number of islands. The virus was shown to belong to genotype II. Further cases occurred in 1998, including the first case on mainland Australia on Cape York. A second genotype of JEV, genotype Ia, was reported in mosquitoes and pigs in 2000–04, possibly displacing genotype II. JEV re-emerged in Australia with a fatal human case on the Tiwi Islands, Northern Territory, in 2021, and shown to belong to genotype IV. This case was followed about a year later by a large outbreak of JE; first detected in piggeries in four states, Queensland, New South Wales, Victoria, and South Australia, resulting in reproductive losses affecting 80 piggeries and 42 human cases, with seven fatal cases. The wide geographic spread of cases suggested that the virus had been circulating for a number of months or even years prior to detection, and has led to significant concern that the virus will become endemic to Australia, in a similar ecology to Murray Valley encephalitis virus. Known competent mosquito vectors and ardeid birds, as maintenance hosts, occur in Australia, and it is probable that feral pigs will provide an additional wildlife reservoir of virus. Little is known of the properties of genotype IV, but it is expected to have a similar ecology and pathogenesis to other JEV genotypes.

Sindbis virus (SINV) is a widely dispersed mosquito-borne alphavirus. Reports of Sindbis disease are largely restricted to northern Europe and South Africa. SINV is frequently sampled in Australian mosquito-based arbovirus surveillance programs, but human disease has rarely been reported. Molecular epidemiological studies have characterized six SINV genotypes (G1–G6) based on E2 gene phylogenies, mostly comprising viruses derived from the African–European zoogeographical region and with limited representation of Australasian SINV. In this study, we conducted whole genome sequencing of 66 SINV isolates sampled between 1960 and 2014 from countries of the Australasian region: Australia, Malaysia, and Papua New Guinea. G2 viruses were the most frequently and widely sampled, with three distinct sub-lineages defined. No new G6 SINV were identified, confirming geographic restriction of these viruses to south-western Australia. Comparison with global SINV characterized large-scale nucleotide and amino acid sequence divergence between African–European G1 viruses and viruses that circulate in Australasia (G2 and G3) of up to 26.83% and 14.55%, respectively, divergence that is sufficient for G2/G3 species demarcation. We propose G2 and G3 are collectively a single distinct alphavirus species that we name Argyle virus, supported by the inapparent or mild disease phenotype and the higher evolutionary rate compared with G1. Similarly, we propose G6, with 24.7% and 12.61% nucleotide and amino acid sequence divergence, is a distinct alphavirus species that we name Thomson’s Lake virus.

Photo-point monitoring through repeat photography allows assessment of long-term ecosystem changes, and photos may be collected using citizen science methods. Such efforts can generate large photo collections, but are susceptible to varying participation and data quality. To date, there have been few assessments of the success of citizen science projects using repeat photography methods in meeting their objectives. We report on the success of the PhotoMon Project, a photo-point monitoring program at Pinery Provincial Park, Canada, at meeting its primary goals of affordably collecting seasonal reference photographs of significant ecosystems within the park, while providing a stewardship opportunity for park visitors. We investigated how the quantity of submitted photos varied over time (quantity), and how closely those photos matched the suite of criteria of the PhotoMon Project (quality). Photo submissions occurred year-round and at all sites, although a low proportion of park visitors participated in the program. Photo quantity varied among sites and seasonally, reaching a low during the winter, but with proportional participation in the project lowest in summer. Photo quality was consistent year-round, with most photos meeting most program criteria. Common issues with photo quality included photo lighting and orientation. We conclude that the program met its scientific goal of compiling seasonal reference photos, but that comparatively few park visitors engage in the program. We suggest changes to increase visitor motivation to participate, but recognize that these may compromise the program’s current affordability and ease of management.

Abstract Introduction Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines. For commonly prescribed drugs, even small differences in effectiveness or safety could have significant public health implications. However, conventional clinical trials that randomise individual subjects are costly and unwieldy. Such trials are also often criticised as having low external validity. We describe an approach to rapidly generate externally valid evidence of comparative safety and effectiveness using the example of two widely used diuretics for the management of hypertension. Methods and analysis The EVIDENCE (Evaluating Diuretics in Normal Care) study has a prospective, cluster-randomised, open-label, blinded end-point design. By randomising prescribing policy in primary care practices, the study compares the safety and effectiveness of commonly used diuretics in treating hypertension. Participating practices are randomised 1:1 to a policy of prescribing either indapamide or bendroflumethiazide when clinically indicated. Suitable patients who are not already taking the policy diuretic are switched accordingly. All patients taking the study medications are written to explaining the rationale for changing the prescribing policy and notifying them they can opt-out of any switch. The prescribing policies’ effectiveness and safety will be compared using rates of major adverse cardiovascular events (hospitalisation with myocardial infarction, heart failure or stroke or cardiovascular death), routinely collected in national healthcare administrative datasets. The study will seek to recruit 250 practices to provide a study population of approximately 50,000 individuals with a mean follow-up time of two years. A primary intention-to-treat time-to-event analysis will be used to estimate the relative effect of the two policies. Ethics and dissemination EVIDENCE has been approved by the East of Scotland Research Ethics Service (17/ES/0016, current approved protocol version 5, 26 August 2021). The results will be disseminated widely in peer reviewed journals, guideline committees, National Health Service (NHS) organisations and patient groups. Trial registration ISRCTN 46635087 . Registered on 11 August 2017 (pre-recruitment).

Given prevalent alcohol misuse-emotional comorbidities among young adults, we developed an internet-based integrated treatment called Take Care of Me. Although the treatment had an impact on several secondary outcomes, effects were not observed for the primary outcome. Therefore, the goal of the current study was to examine heterogeneity in treatment responses. The initial RCT randomized participants to either a treatment or psychoeducational control condition. We conducted an exploratory latent class analysis to distinguish individuals based on pre-treatment risk and then used moderated regressions to examine differential treatment responses based on class membership. We found evidence for three distinct groups. Most participants fell in the “low severity” group (n = 123), followed by the “moderate severity” group (n = 57) who had a higher likelihood of endorsing a previous mental health diagnosis and treatment and higher symptom severity than the low group. The “high severity” group (n = 42) endorsed a family history of alcoholism, and the highest symptom severity and executive dysfunction. Moderated regressions revealed significant class differences in treatment responses. In the treatment condition, high severity (relative to low) participants reported higher alcohol consumption and hazardous drinking and lower quality of life at follow-up, whereas moderate severity (relative to low) individuals had lower alcohol consumption at follow-up, and lower hazardous drinking at end-of-treatment. No class differences were found for participants in the control group. Higher risk individuals in the treatment condition had poorer responses to the program. Tailoring interventions to severity may be important to examine in future research.

Abstract Background To manage the risk factors and to improve clinical outcomes, patients with stroke commonly receive multiple cardiovascular medications. However, there is a lack of evidence on the optimum combination of medication therapy in the primary care setting after ischemic stroke. Therefore, this study aimed to investigate the effect of multiple cardiovascular medications on long-term survival after an incident stroke event (ischemic stroke or transient ischemic attack (TIA)). Methods This study consisted of 52,619 patients aged 45 and above with an incident stroke event between 2007 and 2016 in The Health Improvement Network database. We estimated the risk of all-cause mortality in patients with multiple cardiovascular medications versus monotherapy using a marginal structural model. Results During an average follow-up of 3.6 years, there were 9230 deaths (7635 in multiple cardiovascular medication groups and 1595 in the monotherapy group). Compared with patients prescribed monotherapy only, the HRs of mortality were 0.82 (95% CI 0.75–0.89) for two medications, 0.65 (0.59–0.70) for three medications, 0.61 (0.56–0.67) for four medications, 0.60 (0.54–0.66) for five medications and 0.66 (0.59–0.74) for ≥ six medications. Patients with any four classes of antiplatelet agents (APAs), lipid-regulating medications (LRMs), angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), beta-blockers, diuretics and calcium channel blockers (CCBs) had the lowest risk of mortality (HR 0.51, 95% CI 0.46–0.57) versus any one class. The combination containing APAs, LRMs, ACEIs/ARBs and CCBs was associated with a 61% (95% CI 53–68%) lower risk of mortality compared with APAs alone. Conclusion Our results suggested that combination therapy of four or five cardiovascular medications may be optimal to improve long-term survival after incident ischemic stroke or TIA. APAs, LRMs, ACEIs/ARBs and CCBs were the optimal constituents of combination therapy in the present study.

Abstract The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F1F0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from Q203‐induced death, highlighting the attractiveness of the bd‐type terminal oxidase for drug development. Here, we employed a facile whole‐cell screen approach to identify the cytochrome bd inhibitor ND‐011992. Although ND‐011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic‐tolerant, non‐replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.

Bedaquiline (BDQ) is a known tuberculosis treatment, but the precise mechanism of cell death is unclear. Here, the authors explore the metabolic profiles of M. tuberculosis upon BDQ treatment and find reliance on glycolysis and synergistic cell death when oxidative phosphorylation is also targeted.

Many metalloenzymes are highly specific for their cognate metal ion but the molecular principles underlying this specificity often remain unclear. Here, the authors characterize the structural and biochemical basis for the different metal specificity of two evolutionarily related superoxide dismutases.

We present an analysis of Titan data acquired by the Cassini Visual and Infrared Mapping Spectrometer (VIMS) at the landing site of the Dragonfly mission, using a new version of our radiative transfer model for Titan, with significant updates for the spectroscopic parameters of atmospheric gases and photochemical aerosols. Our updated radiative transfer model is validated against the in situ spectroscopic measurements of the Huygens probe during its descent and once landed. We confirm that aerosols with a fractal dimension of 2.3–2.4 provide the best fit to the observations. We apply our radiative transfer model to four VIMS data cubes over the Selk crater region including the Dragonfly landing and exploration areas, further validating our model by producing consistent aerosol population and surface albedo maps. These infrared albedo maps, further corrected from the photometry, enable us to study the Selk crater region in terms of surface composition, landscape formation, and evolution. Our results suggest that the Selk crater is in an intermediate state of degradation and that the mountainous terrains of the area (including the crater rim and ejecta) are likely to be dominated by fine grains of tholin-like sediment. This organic sediment would be transported to the lowlands (crater floor and surrounding plains), possibly with water ice particles, by rivers, and further deposited and processed to form the sand particles that feed the neighboring dune fields. These results provide information for the operational and scientific preparation of the Dragonfly mission, paving the way for future exploration of Titan’s surface composition and geology.

Objective: Many young adults struggle with comorbid alcohol misuse and emotional problems (i.e., depression and anxiety). However, there is currently a paucity of evidence-based, integrated, accessible treatment options for individuals with these comorbidities. The main goal of this study was to examine efficacy of a novel online, minimally guided, integrated program for comorbid alcohol misuse and emotional problems in young adults. Method: The study was an open-label two-arm RCT. Participants (N = 222, Mage = 24.6, 67.6% female) were randomized to one of two conditions: the Take Care of Me program (an 8-week, online integrated treatment condition consisting of 12 modules), or an online psychoeducational control condition. Intervention modules incorporated content based on principles of cognitive behavioral therapy and motivational interviewing. Participants completed assessment data at baseline, at the end of treatment (i.e., 8 weeks), and at follow-up (i.e., 24 weeks). Data were analyzed using generalized linear mixed models. Results: We observed that participants in the treatment condition showed larger reductions in depression, hazardous drinking, as well as increases in psychological quality of life and confidence at the end of treatment. We did not find group differences on total alcohol use at follow-up, but participants in the treatment group reduced their hazardous drinking and improved their quality of life at 24-week follow-up. Conclusions: Our study provides promising initial evidence for the first iteration of the comorbid alcohol misuse and emotional problems online program.

At the end of December, 2019, a new disease of unknown aetiology appeared in Wuhan, China. It was quickly identified as a novel betacoronavirus, and related to SARS-CoV and a number of other bat-borne SARS-like coronaviruses. The virus rapidly spread to all provinces in China, as well as a number of countries overseas, and was declared a Public Health Emergency of International Concern by the Director-General of the World Health Organization on 30 January 2020. This paper describes the evolution of the outbreak, and the known properties of the novel virus, SARS-CoV-2 and the clinical disease it causes, COVID-19, and comments on some of the important gaps in our knowledge of the virus and the disease it causes. The virus is the third zoonotic coronavirus, after SARS-CoV and MERS-CoV, but appears to be the only one with pandemic potential.

The importance of host-produced hydrogen sulfide (H2S) in microbial pathogenesis is poorly understood. Here, Saini et al. show that H2S alters Mycobacterium tuberculosis (Mtb) central metabolism, stimulates respiration to promote growth and TB disease, and upregulates the Dos regulon.

A fatal case of Japanese encephalitis (JE) occurred in northern Australia in early 2021. Sequence studies showed that the virus belonged to genotype IV (GIV), a genotype previously believed to be restricted to the Indonesian archipelago. This was the first locally acquired case of Japanese encephalitis virus (JEV) GIV to occur outside Indonesia, and the second confirmed fatal human case caused by a GIV virus. A closely related GIV JEV strain subsequently caused a widespread outbreak in eastern Australia in 2022 that was first detected by fetal death and abnormalities in commercial piggeries. Forty-two human cases also occurred with seven fatalities. This has been the first major outbreak of JEV in mainland Australia, and geographically the largest virgin soil outbreak recorded for JEV. This outbreak provides an opportunity to discuss and document the factors involved in the virus’ spread and its ecology in a novel ecological milieu in which other flaviviruses, including members of the JE serological complex, also occur. The probable vertebrate hosts and mosquito vectors are discussed with respect to virus spread and its possible endemicity in Australia, and the need to develop a One Health approach to develop improved surveillance methods to rapidly detect future outbreak activity across a large geographical area containing a sparse human population. Understanding the spread of JEV in a novel ecological environment is relevant to the possible threat that JEV may pose in the future to other receptive geographic areas, such as the west coast of the United States, southern Europe or Africa.

In order to sustain a persistent infection, Mycobacterium tuberculosis (Mtb) must adapt to a changing environment that is shaped by the developing immune response. This necessity to adapt is evident in the flexibility of many aspects of Mtb metabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, the bc1/aa3 complex appears to play a dominant role, while the alternative bd oxidase is largely redundant. However, the presence of two terminal oxidases in this obligate pathogen implies that respiratory requirements might change during infection. We report that the cytochrome bd oxidase is specifically required for resisting the adaptive immune response. While the bd oxidase was dispensable for growth in resting macrophages and the establishment of infection in mice, this complex was necessary for optimal fitness after the initiation of adaptive immunity. This requirement was dependent on lymphocyte-derived interferon gamma (IFNγ), but did not involve nitrogen and oxygen radicals that are known to inhibit respiration in other contexts. Instead, we found that ΔcydA mutants were hypersusceptible to the low pH encountered in IFNγ-activated macrophages. Unlike wild type Mtb, cytochrome bd-deficient bacteria were unable to sustain a maximal oxygen consumption rate (OCR) at low pH, indicating that the remaining cytochrome bc1/aa3 complex is preferentially inhibited under acidic conditions. Consistent with this model, the potency of the cytochrome bc1/aa3 inhibitor, Q203, is dramatically enhanced at low pH. This work identifies a critical interaction between host immunity and pathogen respiration that influences both the progression of the infection and the efficacy of potential new TB drugs.

Objective Effervescent, soluble, dispersible formulations contain considerable amounts of sodium. In 2013, we previously confirmed the association between sodium-containing medications and cardiovascular risks. This study aimed to determine the changes in the prescribing pattern in clinical practice following this publication.Design A longitudinal cross-sectional study.Setting Primary care in the UK from 2009 to 2018.Participants Prescribing information in The Health Improvement Network (THIN) and Prescription Cost Analysis (PCA) databases in the UK.Outcome measurements Prescription rates per 10 000 inhabitants were calculated using the number of prescriptions or the number of drug-using patients over the total number of inhabitants, and the prescription rates were measured at annual intervals. Prescribing trends from 2009 to 2018 were indexed with yearly data from THIN and PCA. Interrupted time series analysis (ITSA) was conducted with monthly data in THIN.Results From the THIN database, a total of 3 651 419 prescription records from 446 233 patients were included. The prescribing rate of sodium-containing medications changed from 848.3/10 000 inhabitants in 2009 to 571.6/10 000 inhabitants in 2018. The corresponding figures from PCA data were of 631.0/10 000 inhabitants in 2009 and 423.8/10 000 inhabitants in 2018. ITSA showed the prescribing trend reduced significantly during the postpublication period (prescribing rate: slope change=−0.26; 95% CI −0.45 to –0.07; p=0.009; proportion of patients: slope change=−0.22; 95% CI −0.35 to –0.09; p

Background:. The impact of left-handedness on orthopaedic surgeons and trainees has not been well described. We investigated the prevalence and perceived impact of left-handedness among orthopaedic surgeons and trainees. Methods:. We distributed a survey regarding handedness to active members of the American Orthopaedic Association and the Council of Orthopaedic Residency Directors affiliates, including department chairs, program directors, and residency and fellowship program coordinators. Program coordinators were asked to distribute the survey to their current residents and fellows. Results:. Of 510 survey respondents, 78 (15%) were identified as left hand dominant (LHD). Regarding scalpel/cautery use, 64% of LHD respondents reported using their left hand primarily and 10% reported using their right hand primarily; 26% of LHD respondents described themselves as ambidextrous in scalpel/cautery use, compared with 4.7% of right hand dominant (RHD) respondents (p < 0.001). Regarding suturing, 53% of LHD respondents reported using their left hand primarily and 38% reported using their right hand primarily; 9.0% of LHD respondents described themselves as ambidextrous when suturing, compared with 1.9% of RHD respondents (p = 0.012). Only 5.1% of LHD respondents reported having received laterality-specific psychomotor training, whereas 17% perceived a need for such training during residency; RHD respondents reported similar rates. Ambidexterity in scalpel/cautery use or suturing among LHD respondents was not associated with the perception that their left-handedness was advantageous. LHD attending surgeons were more likely than LHD trainees to perceive their handedness as advantageous (p = 0.007). Conclusions:. Fifteen percent of orthopaedic surgeons and trainees who responded to our survey were LHD. LHD respondents reported significantly higher rates of ambidexterity in both scalpel/cautery use and suturing compared with RHD respondents. Ambidexterity was not associated with a self-perception that left-handedness was advantageous. LHD-attending surgeons were significantly more likely than LHD residents/fellows to perceive their left-handedness as advantageous. There may be benefits to pairing LHD residents with LHD faculty surgeons early in their training to provide mentorship and insight regarding performing surgical procedures left handed. Level of Evidence:. Level IV.

Abstract Background Recruitment to clinical trials can be challenging. Methods that improve the efficiency of trial recruitment are needed to increase successful study completions. The aim of this study was to ascertain whether sending an audio-visual presentation on a digital versatile disc (DVD), along with usual study invitation materials, would improve recruitment to the Febuxostat versus Allopurinol Streamlined Trial (FAST), a clinical trial in patients with established gout. Methods Potential participants for the FAST study who were identified by searches of GP records in Scottish primary care practices between August 2013 and July 2014 were included in this study. Individuals were randomly allocated to receive either a standard invitation (letter and information leaflet) or a standard invitation and a DVD containing an audio-visual presentation explaining the background and operation of FAST. Data on invitation response rates, screening attendances and randomisations were collected by research nurses. Results One thousand fifty potential participants were invited to take part in FAST during this period. 509 individuals were randomised to receive the DVD presentation and the standard invitation and 541 received a standard invitation only. DVD recipients were less likely to respond to the initial invitation (adjusted OR 0.76, CI 0.58–0.99) and marginally less likely to return a positive response (OR 0.75, CI 0.59–0.96). There was no statistically significant difference between the groups in attendance for screening or randomisation. The DVD did not influence the age, gender, or socioeconomic deprivation scores of those responding positively to a letter of invitation. Conclusions The inclusion of a DVD presentation with FAST study invitations did not make any practical difference to the rate of positive response to invitation. Further innovation and evaluation will be required to improve recruitment to clinical trials. Trial registration EU Clinical Trials Register. EudraCT Number: 2011–001883-23. ISRCTN registry. ISRCTN72443278.

The selection of papers included in this issue of Microbiology Australia present a broad brush of zoonotic diseases, from those known or described in ancient times such as rabies, first described in the Eshnunna cuneiform law tablets from ancient Mesopotamia dating back to the 18th–19th centuries BC, and glanders, thought to be first described in donkeys by Aristotle in Ancient Greece in 420–450 BC and subsequently by the Romans, to some discovered or recognised as zoonotic within the past 30 years, such as the recently described zoonotic bat-borne pathogens in Australia, and Clostridium difficile, only recently recognised as a zoonotic pathogen. The selection of papers also demonstrates the wide range of zoonotic origins, including arthropod-borne viruses and potentially seafood-borne parasites.

In early 2022, the Japanese encephalitis virus (JEV) was identified as the cause of stillborn and mummified piglets in pig farms in southeastern Australia. Human cases and additional pig farms with infected piglets were subsequently identified across a widespread area encompassing four states. To inform surveillance and control programs, we synthesized existing information on Australian vectors of JEV, much of which was generated in response to incursions of JEV into the northern state of Queensland between 1995 and 2005. Members of the Culex sitiens subgroup, particularly Culex annulirostris, should be considered the primary vectors of JEV in Australia, as they yielded >87% of field detections of JEV, were highly efficient laboratory vectors of the virus, readily fed on pigs and birds (the key amplifying hosts of the virus) when they were available, and are widespread and often occur in large populations. Three introduced species, Culex quinquefasciatus, Culex gelidus and Culex tritaeniorhynchus may also serve as vectors, but more information on their geographical distribution, abundance and bionomics in the Australian context is required. Mosquitoes from other genera, such as Aedes and Verrallina, whilst considered relatively poor vectors, could play a regional or supplemental role in transmission, especially facilitating vertical transmission as a virus overwintering mechanism. Additional factors that could impact JEV transmission, including mosquito survival, dispersal and genetics, are also discussed. Possible directions for investigation are provided, especially in the context of the virus emerging in a region with different mosquito fauna and environmental drivers than northern Australia.

Abstract Background The use of information technology (IT) is now the preferred method of capturing and storing clinical research data. The Treatment In Morning versus Evening (TIME) study predominantly uses electronic data capture and IT to compare morning dosing of hypertensive medication against evening dosing. Registration, consent, participant demographics and follow-up data are all captured via the study website. The aim of this article is to assess the success of the TIME methodology compared with similar studies. Methods To assess the TIME study, published literature on similar clinical trials was reviewed and compared against TIME recruitment, follow-up and email interaction data. Results The TIME website registered 31,695 individuals, 21,116 of whom were randomised. Recruitment cost per randomised participant varied by strategy: £17.40 by GP practice, £3.08 by UK Biobank and £58.82 for GoShare. Twelve-month follow-up retention rates were 96%. A total of 1089 participants have withdrawn from their assigned time of dosing, 2% of whom have declined follow-up by record linkage or further contact. When the TIME data are compared with similar study data, study recruitment is very successful. However, TIME suffers difficulties with participant follow-up and withdrawal rates similar to those of conventional studies. Conclusions The TIME study has been successful in recruitment. Follow-up, retention rates and withdrawal rates are all acceptable, but ongoing work is required to ensure participants remain engaged with the study. Various recruitment strategies are necessary, and all viable options should be encouraged to maintain participant engagement throughout the life of studies using IT.