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Abstract Background HIV incidence remains high in South Africa, with ~ 60% of all new HIV infections among adolescent girls and women (Country factsheets HIV and AIDS Estimates, 2022). Oral pre-exposure prophylaxis (PrEP), approved for HIV prevention in South Africa since 2015, is hampered by low uptake and adherence, particularly among adolescent girls and young women (AGYW). Combining oral PrEP with oral contraceptives could increase PrEP uptake, persistence and address unmet needs for contraception. We investigated the acceptability of a dual prevention pill (DPP), combining oral PrEP and a combined oral contraceptive (COC) for HIV and pregnancy prevention among women in Johannesburg, South Africa. Methods Between March-July 2021, we conducted 12 focus group discussions (FGDs) with adolescent girls and women (n = 74) aged 16–40 stratified by ages (16–17, 18–24, 25–40), half of whom were COC users. We explored adolescent girls and women’s opinions about the DPP concept, existing HIV and pregnancy prevention options, and input on perceived facilitators and barriers to DPP use. FGDs were conducted in English or isiZulu, using a standardized interview guide. FGDs were audio-recorded, transcribed to English and analyzed using ethnographic content analysis. Results The majority viewed the DPP favorably as a multipurpose option preventing unplanned pregnancy and HIV. Most saw it as a convenient “two-in-one” solution, requiring one clinic visit for both PrEP and COCs. AGYW were viewed as the most likely to benefit from the DPP due to the likelihood of multiple partners and unplanned sex, possibly preventing school dropout from unplanned pregnancy or HIV acquisition. The DPP was perceived to be more reliable than condoms, especially when condom negotiation is limited. Benefits were also seen by participants in rape cases, protecting against pregnancy and HIV. DPP use barriers included side effect concerns, unsupportive partners and judgmental healthcare providers. Conclusions/significance The DPP was perceived as acceptable for HIV and pregnancy prevention to AGYW in Johannesburg and its dual indications helpful in supporting improved PrEP uptake and persistence. DPP implementation programs need to consider solutions to potential barriers, like education on DPP benefits, coupled with reliable side effect support and healthcare provider sensitization as part of routine sexual health services to encourage uptake and adherence.

Abstract Background Behaviour change interventions can result in lasting improvements in physical activity (PA). A broad implementation of behaviour change interventions are likely to be associated with considerable additional costs, and the evidence is unclear whether they represent good value for money. The aim of this study was to investigate costs and cost-effectiveness of behaviour change interventions to increase PA in community-dwelling adults. Methods A search for trial-based economic evaluations investigating behaviour change interventions versus usual care or alternative intervention for adults living in the community was conducted (September 2023). Studies that reported intervention costs and incremental cost-effectiveness ratios (ICERs) for PA or quality-adjusted life years (QALYs) were included. Methodological quality was assessed using the Consensus Health Economic Criteria (CHEC-list). A Grading of Recommendations Assessment, Development and Evaluation style approach was used to assess the certainty of evidence (low, moderate or high certainty). Results Sixteen studies were included using a variety of economic perspectives. The behaviour change interventions were heterogeneous with 62% of interventions being informed by a theoretical framework. The median CHEC-list score was 15 (range 11 to 19). Median intervention cost was US$313 per person (range US$83 to US$1,298). In 75% of studies the interventions were reported as cost-effective for changes in PA (moderate certainty of evidence). For cost per QALY/gained, 45% of the interventions were found to be cost-effective (moderate certainty of evidence). No specific type of behaviour change intervention was found to be more effective. Conclusions There is moderate certainty that behaviour change interventions are cost-effective approaches for increasing PA. The heterogeneity in economic perspectives, intervention costs and measurement should be considered when interpreting results. There is a need for increased clarity when reporting the functional components of behaviour change interventions, as well as the costs to implement them.

BACKGROUND: It is unclear whether genetic variants affecting vitamin D metabolism are associated with melanoma prognosis. Two functional missense variants in the vitamin D-binding protein gene (GC), rs7041 and rs4588, determine 3 common haplotypes, Gc1s, Gc1f, and Gc2, of which Gc1f may be associated with decreased all-cause death among melanoma patients based on results of a prior study, but the association of Gc1f with melanoma-specific death is unclear. METHODS: We investigated the association of the Gc1s, Gc1f, and Gc2 haplotypes with melanoma-specific and all-cause death among 4490 individuals with incident, invasive primary melanoma in 2 population-based studies using multivariable Cox-proportional hazards regression. RESULTS: In the pooled analysis of both datasets, the patients with the Gc1f haplotype had a 37% lower risk of melanoma-specific death than the patients without Gc1f (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.47 to 0.83, P = .001), with adjustments for age, sex, study center, first- or higher-order primary melanoma, tumor site, pigmentary phenotypes, and Breslow thickness. Associations were similar in both studies. In pooled analyses stratified by Breslow thickness, the corresponding melanoma-specific death HRs for those patients with the Gc1f haplotype compared with those without Gc1f were 0.89 (95% CI = 0.63 to 1.27) among participants with tumor Breslow thickness equal to or less than 2.0 mm and 0.40 (95% CI = 0.25 to 0.63) among participants with tumor Breslow thickness greater than 2.0 mm (Pinteraction = .003). CONCLUSIONS: Our findings suggest that individuals with the GC haplotype Gc1f may have a lower risk of dying from melanoma-specifically from thicker, higher-risk melanoma-than individuals without this Gc1f haplotype.

Introduction Behaviour change interventions are advocated as a key approach to manage behavioural risk factors such as insufficient physical activity, poor diet and smoking. Integrated motivational interviewing and cognitive behavioural therapy (MI-CBT) interventions have become increasingly popular to promote behaviour change; however, there is a lack of agreement as to what constitutes necessary components of MI-CBT interventions for lifestyle behaviour change. The primary objective of this study is to use a consensus method to develop guidelines to design and deliver MI-CBT interventions for lifestyle behaviour change.Methods A three-round modified Delphi study will be conducted with an expert, international panel of clinicians and researchers. An online survey will be developed from assessments of key MI-CBT literature and practice guides to identify commonly used components of individually delivered MI and CBT interventions. In each round, participants will rate the extent to which they agree with each component using a Likert scale. Responses from Rounds 1 and 2 will be presented to participants in subsequent rounds. Responses will be represented using bar graphs and include the median and IQR of participants’ responses. To encourage consensus, participants will be asked to consider the group responses before finalising their opinion to the statements. If at least 80% of the experts agree to a statement in Rounds 2 or 3, it will be included in a final list of necessary statements.Discussion This modified Delphi process will help transparency in the design and implementation of MI-CBT interventions. The consensus statement will also help reporting and comparability among effectiveness studies for MI-CBT intervention studies, and help inform research, policy and practice.Ethics and dissemination Ethical approval has been granted by the La Trobe University Human Research Ethics Committee (approval number HEC24066). The results will be disseminated via peer-reviewed publications, conferences and international professional associations.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Abstract Background The ankle is usually highly effective in modulating the swing foot’s trajectory to ensure safe ground clearance but there are few reports of ankle kinetics and mechanical energy exchange during the gait cycle swing phase. Previous work has investigated ankle swing mechanics during normal walking but with developments in devices providing dorsiflexion assistance, it is now essential to understand the minimal kinetic requirements for increasing ankle dorsiflexion, particularly for devices employing energy harvesting or utilizing lighter and lower power energy sources or actuators. Methods Using a real-time treadmill-walking biofeedback technique, swing phase ankle dorsiflexion was experimentally controlled to increase foot-ground clearance by 4 cm achieved via increased ankle dorsiflexion. Swing phase ankle moments and dorsiflexor muscle forces were estimated using AnyBody modeling system. It was hypothesized that increasing foot-ground clearance by 4 cm, employing only the ankle joint, would require significantly higher dorsiflexion moments and muscle forces than a normal walking control condition. Results Results did not confirm significantly increased ankle moments with augmented dorsiflexion, with 0.02 N.m/kg at toe-off reducing to zero by the end of swing. Tibialis Anterior muscle force incremented significantly from 2 to 4 N/kg after toe-off, due to coactivation with the Soleus. To ensure an additional 4 cm mid swing foot-ground clearance, an estimated additional 0.003 Joules/kg is required to be released immediately after toe-off. Conclusion This study highlights the interplay between ankle moments, muscle forces, and energy demands during swing phase ankle dorsiflexion, offering insights for the design of ankle assistive technologies. External devices do not need to deliver significantly greater ankle moments to increase ankle dorsiflexion but, they should offer higher mechanical power to provide rapid bursts of energy to facilitate quick dorsiflexion transitions before reaching Minimum Foot Clearance event. Additionally, for ankle-related bio-inspired devices incorporating artificial muscles or humanoid robots that aim to replicate natural ankle biomechanics, the inclusion of supplementary Tibialis Anterior forces is crucial due to Tibialis Anterior and Soleus co-activation. These design strategies ensures that ankle assistive technologies are both effective and aligned with the biomechanical realities of human movement.

MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (ORper-allele = 1.25, 95% CI 1.03-1.51, and Ptrend = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HRper-allele = 0.63, 95% CI 0.42-0.95, and Ptrend = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.

Stroke rehabilitation interventions require multiple training sessions and repeated assessments to evaluate the improvements from training. Biofeedback-based treadmill training often involves 10 or more sessions to determine its effectiveness. The training and assessment process incurs time, labor, and cost to determine whether the training produces positive outcomes. Predicting the effectiveness of gait training based on baseline minimum foot clearance (MFC) data would be highly beneficial, potentially saving resources, costs, and patient time. This work proposes novel features using the Short-term Fourier Transform (STFT)-based magnitude spectrum of MFC data to predict the effectiveness of biofeedback training. This approach enables tracking non-stationary dynamics and capturing stride-to-stride MFC value fluctuations, providing a compact representation for efficient processing compared to time-domain analysis alone. The proposed STFT-based features outperform existing wavelet, histogram, and Poincaré-based features with a maximum accuracy of 95%, F1 score of 96%, sensitivity of 93.33% and specificity of 100%. The proposed features are also statistically significant (p

Abstract Background Understanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies. Methods We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action. Results Our bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Conclusions Our data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.

Human-wildlife cooperation occurs when humans and free-living wild animals actively coordinate their behavior to achieve a mutually beneficial outcome. These interactions provide important benefits to both the human and wildlife communities involved, have wider impacts on the local ecosystem, and represent a unique intersection of human and animal cultures. The remaining active forms are human-honeyguide and human-dolphin cooperation, but these are at risk of joining several inactive forms (including human-wolf and human-orca cooperation). Human-wildlife cooperation faces a unique set of conservation challenges, as it requires multiple components-a motivated human and wildlife partner, a suitable environment, and compatible interspecies knowledge-which face threats from ecological and cultural changes. To safeguard human-wildlife cooperation, we recommend: (i) establishing ethically sound conservation strategies together with the participating human communities; (ii) conserving opportunities for human and wildlife participation; (iii) protecting suitable environments; (iv) facilitating cultural transmission of traditional knowledge; (v) accessibly archiving Indigenous and scientific knowledge; and (vi) conducting long-term empirical studies to better understand these interactions and identify threats. Tailored safeguarding plans are therefore necessary to protect these diverse and irreplaceable interactions. Broadly, our review highlights that efforts to conserve biological and cultural diversity should carefully consider interactions between human and animal cultures. Please see AfricanHoneyguides.com/abstract-translations for Kiswahili and Portuguese translations of the abstract.

Abstract Brexucabtagene autoleucel (brexu‐cel) is an autologous CD19 CAR T‐cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA‐2, brexu‐cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real‐world intention‐to‐treat (ITT) outcomes for brexu‐cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu‐cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow‐up of 13.3 months, median progression‐free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6‐ and 12‐month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS > 1 and previous MF. Cumulative incidence of non‐relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA‐2 and other real‐world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention.

Abstract Introduction To date only a limited number of reviews have focused on how exposure and outcome measures are defined in the existing literature on associations between tobacco retailer density (‘density’) and smoking behaviour (‘smoking’). Therefore this systematic review classified and summarised how both density and smoking variables are operationalised in the existing literature, and provides several methodological recommendations for future density and smoking research. Methods Two literature searches between March and April 2018 and April 2022 were conducted across 10 databases. Inclusion and exclusion criteria were developed and keyword database searches were undertaken. Studies were imported into Covidence. Cross-sectional studies that met the inclusion criteria were extracted and a quality assessment was undertaken. Studies were categorised according to the density measure used, and smoking was re-categorised using a modified classification tool. Results Large heterogeneity was found in the operationalisation of both measures in the 47 studies included for analysis. Density was most commonly measured directly from geocoded locations using circular buffers at various distances (n = 14). After smoking was reclassified using a smoking classification tool, past-month smoking was the most common smoking type reported (n = 26). Conclusions It is recommended that density is measured through length-distance and travel time using the street network and weighted (e.g. by the size of an area), or by using Kernel Density Estimates as these methods provide a more accurate measure of geographical to tobacco and e-cigarette retailer density. The consistent application of a smoking measures classification tool, such as the one developed for this systematic review, would enable better comparisons between studies. Future research should measure exposure and outcome measures in a way that makes them comparable with other studies. Implications This systematic review provides a strong case for improving data collection and analysis methodologies in studies assessing tobacco retailer density and smoking behaviour to ensure that both exposure and outcome measures are clearly defined and captured. As large heterogeneity was found in the operationalisation of both density and smoking behaviour measures in the studies included for analysis, there is a need for future studies to capture, measure and classify exposure measures accurately, and to define outcome measures in a manner that makes them comparable with other studies.

Tripping is the largest cause of falls, and low swing foot ground clearance during the mid-swing phase, particularly at the critical gait event known as Minimum Foot Clearance (MFC), is the major risk factor for tripping-related falls. Intervention strategies to increase MFC height can be effective if applied in real-time based on feed-forward prediction. The current study investigated the capability of machine learning models to classify the MFC into various categories using toe-off kinematics data. Specifically, three MFC sub-categories (less than 1.5 cm, between 1.5 and 2.0 cm, and higher than 2.0 cm) were predicted to apply machine learning approaches. A total of 18,490 swing phase gait cycles’ data were extracted from six healthy young adults, each walking for 5 min at a constant speed of 4 km/h on a motorized treadmill. K-Nearest Neighbor (KNN), Random Forest, and XGBoost were utilized for prediction based on the data from toe-off for five consecutive frames (0.025 s duration). Foot kinematics data were obtained from an inertial measurement unit attached to the mid-foot, recording tri-axial linear accelerations and angular velocities of the local coordinate. KNN, Random Forest, and XGBoost achieved 84%, 86%, and 75% accuracy, respectively, in classifying MFC into the three sub-categories with run times of 0.39 s, 13.98 s, and 170.98 s, respectively. The KNN-based model was found to be more effective if incorporated into an active exoskeleton as the intelligent system to control MFC based on the preceding gait event, i.e., toe-off, due to its quicker computation time. The machine learning-based prediction model shows promise for the prediction of critical MFC data, indicating higher tripping risk.

BackgroundGenome-wide association studies have reported that genetic variation at ANRIL (CDKN2B-AS1) is associated with risk of several chronic diseases including coronary artery disease, coronary artery calcification, myocardial infarction, and type 2 diabetes mellitus. ANRIL is located at the CDKN2A/B locus, which encodes multiple melanoma tumor suppressors. We investigated the association of these variants with melanoma prognostic characteristics.MethodsThe Genes, Environment, and Melanoma Study enrolled 3,285 European origin participants with incident invasive primary melanoma. For each of ten disease-associated SNPs at or near ANRIL, we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and ORs for presence of ulceration and tumor-infiltrating lymphocytes (TIL). We also assessed effect modification by tumor NRAS/BRAF mutational status.ResultsRs518394, rs10965215, and rs564398 passed false discovery and were each associated (P ≤ 0.005) with TILs, although only rs564398 was independently associated (P = 0.0005) with TILs. Stratified by NRAS/BRAF mutational status, rs564398*A was significantly positively associated with TILs among NRAS/BRAF mutant, but not wild-type, cases. We did not find SNP associations with Breslow thickness or ulceration.ConclusionsANRIL rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to NRAS/BRAF-mutant cases.ImpactPathways related to ANRIL variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.

Abstract Lions are one of the world’s most iconic species but are threatened with extinction. Developing effective range-wide conservation plans are crucial but hampered by the relative lack of knowledge on specific threats facing each population and the socio-political context for conservation. Here, we present a range-wide examination of the relative fragility of lion populations, examining socio-political factors alongside ecological ones. We found Ethiopia’s Maze National Park had the most ecologically fragile geographic population while Kavango-Zambezi was the least. At a country level, lion populations had highest ecological fragility in Cameroon and Malawi. When we examined socio-political fragility, Somalia was the most fragile lion range country, followed by South Sudan. When socio-political and ecological fragility were combined, lion populations in Maze National Park and Bush-Bush (Somalia) and more broadly, Somalian and Malawian lion populations were the most fragile. These insights should help inform more nuanced and appropriately targeted lion conservation plans.

Abstract Background Potentially preventable hospitalisations of ear, nose, and throat conditions in the Murray Primary Health Network region have been found to be higher than the state average of Victoria, Australia. This study aimed to examine the association between selected patient-level characteristics and the likelihood of residing in a Murray PHN postcode with higher than expected numbers of potentially preventable ENT hospitalisations. Methods Unit record hospital separation data were obtained from the Victorian Admitted Episodes Dataset. Postcodes were classified as having higher than expected numbers of potentially preventable hospitalisations across three subgroups of ENT using indirect standardisation techniques. Differences between patients from ‘higher than expected’ postcodes and ‘other’ postcodes with respect to the distribution of demographic and other patient characteristics were determined using chi-squared tests for each ENT subgroup. The results were confirmed by logistic regression analyses using resident of a postcode with higher than expected hospitalisations as the outcome variable. Results Of the 169 postcodes located in the catchment area, 15 were identified as having higher than expected numbers of upper respiratory tract infection hospitalisations, 14 were identified for acute tonsillitis, and 12 were identified for otitis media. Patients from postcodes with ‘higher than expected’ hospitalisations for these conditions were more likely than others to be aged between 0 and 9 years, Indigenous, or from a culturally and linguistically diverse background. Conclusion Further investigation of the identified postcodes is warranted to determine access to and utilisation of primary healthcare services in the management of PPH ENT conditions in the region.

Introduction A theory of change is a visual representation of the pathway by which a programme anticipates it will achieve its goal. It usually starts with discussions around the goal and works backwards through outcomes and outputs to activities.Methods We used a theory of change to improve coherence across three research entities at the WHO. Part of the remit of all three entities is to strengthen capacity in low-income and middle-income countries for implementation research.Results Representatives from the three entities were able to formulate a joint goal for strengthening capacity in implementation research. They identified three pathways by which this could be achieved: (a) conducting implementation research, (b) strengthening implementation research systems and (c) using implementation research for public health priorities.Conclusion The process of developing the theory of change and the logic framework it created, provided a means to track progress towards the goal and to guide improvements in programmes within their lifetime. The process we used to develop the theory of change and the pathways to achieve the joint goal are adaptable and could be used by other organisations that also aim to strengthen research capacity. This would lead to more coherence, better translation of research findings into decision-making and ultimately improvements in public health.

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.

Cardiopulmonary exercise testing (CPET) is the 'gold standard' method for evaluating functional capacity, with oxygen pulse (O2Pulse) inflections serving as a potential indicator of myocardial ischaemia. However, the reliability and agreement of identifying these inflections have not been thoroughly investigated. This study aimed to assess the inter- and intra-observer reliability and agreement of a subjective quantification method for identifying O2Pulse inflections during CPET, and to propose a more robust and objective novel algorithm as an alternative methodology. A retrospective analysis was conducted using baseline data from the HIIT or MISS UK trial. The O2Pulse curves were visually inspected by two independent examiners, and compared against an objective algorithm. Fleiss' Kappa was used to determine the reliability of agreement between the three groups of observations. The results showed almost perfect agreement between the algorithm and both examiners, with a Fleiss' Kappa statistic of 0.89. The algorithm also demonstrated excellent inter-rater reliability (ICC) when compared to both examiners (0.92-0.98). However, a significant level (P ≤0.05) of systematic bias was observed in Bland-Altman analysis for comparisons involving the novice examiner. In conclusion, this study provides evidence for the reliability of both subjective and novel objective methods for identifying inflections in O2Pulse during CPET. These findings suggest that further research into the clinical significance of O2Pulse inflections is warranted, and that the adoption of a novel objective means of quantification may be preferable to ensure equality of outcome for patients.

Introduction: Manual handling personnel and those performing manual handling tasks in non-traditional manual handling industries continue to suffer debilitating and costly workplace injuries. Smart assistive devices are one solution to reducing musculoskeletal back injuries. Devices that provide targeted assistance need to be able to predict when and where to provide augmentation via predictive algorithms trained on functional datasets. The aim of this study was to describe how an increase in load impacts spine kinematics during a ground-to-platform manual handling task. Methods: Twenty-nine participants performed ground-to-platform lifts for six standardised loading conditions (50%, 60%, 70%, 80%, 90%, and 100% of maximum lift capacity). Six thoracic and lumbar spine segments were measured using inertial measurement units that were processed using an attitude-heading-reference filter and normalised to the duration of the lift. The lift was divided into four phases weight-acceptance, standing, lift-to-height and place-on-platform. Statistical significance of sagittal angles from the six spine segments were identified through statistical parametric mapping one-way analysis of variance with repeated measures and post hoc paired t-tests.Results: Two regions of interest were identified during a period of peak flexion and a period of peak extension. There was a significant increase in spine range of motion and peak extension angle for all spine segments when the load conditions were increased (p < 0.001). There was a decrease in spine angles (more flexion) during the weight acceptance to standing phase at the upper thoracic to upper lumbar spine segments for some condition comparisons. A significant increase in spine angles (more extension) during the place-on-platform phase was seen in all spine segments when comparing heavy loads (>80% maximum lift capacity, inclusive) to light loads (

Abstract Background Adaptive gait involves the ability to adjust the leading foot in response to the requirement of dynamic environments during walking. Accurate adjustments of the minimum toe clearance (MTC) height and step length can prevent older people from falling when walking and responding to hazards. Although older people with diabetes fall more frequently than healthy older adults, no previous studies have quantified their adaptive gait abilities. This study aimed to investigate the effects of diabetes mellitus on step length and MTC height adjustments using a non-immersive virtual-reality system. Methods Sixteen young adults (26 ± 5 years, 7 females), 16 healthy older adults (68 ± 5 years, 6 females), and 16 older adults with diabetes (70 ± 5 years, 6 females) completed adaptability tests while walking on a treadmill. A computer system visualised a continuous real-time signal of absolute step length and MTC on a monitor. Each person responded to four discrete participant-specific step length and MTC visual targets that were presented on the same signal. Tasks were to match the peaks of interest on each signal to presented targets. Targets were 10% longer or shorter than the mean baseline step length, and 2.5 cm, and 3.5 cm higher than the mean baseline MTC. When a target was displayed, it remained unchanged for 10 consecutive foot displacement adaptation attempts. Then, the target was removed and a new target or the same target was present after 10 consecutive steps and remained for 10 steps. Each target was randomly presented three times (3 × 10). Step length and MTC height adjustments in response to targets were measured and compared among groups. Results Mean preferred walking speeds were not different among groups significantly when no targets were presented on the monitor in baseline walking. However, when participants walked on a treadmill while attempting to match step lengths or MTC heights to displayed targets on the monitor, the group with diabetes had reduced step length and MTC adjustments compared with other groups significantly. They showed greater errors (differences between their step lengths/MTC heights and presented targets) on the monitor. Conclusions This study quantified reduced abilities for older individuals with diabetes to adjust both step length and MTC in response to stimuli compared to healthy older counterparts. Reduced step length and MTC height adjustments can increase falls in at risk populations. The presented virtual-reality system has merits for assessing and training step and MTC adaptation.

Abstract Heatwaves are one of the leading causes of climate-induced mortality. Using the examples of recent heatwaves in Europe, the United States and Asia, we illustrate how the communication of dangerous conditions based on temperature maps alone can lead to insufficient societal perception of health risks. Comparison of maximum daily values of temperature with physiological heat stress indices accounting for impacts of both temperature and humidity, illustrates substantial differences in geographical extent and timing of their respective peak values during these recent events. This signals the need to revisit how meteorological heatwaves and their expected impacts are communicated. Close collaboration between climate and medical communities is needed to select the best heat stress indicators, establish them operationally, and introduce them to the public.