<div><h4>Rectal artesunate suppositories for the pre-referral treatment of suspected severe malaria.</h4><i>Watson JA, Peto TJ, White NJ</i><br /><AbstractText>In this Policy Forum article, James A. Watson and colleagues discuss recent guidelines relating to pre-referral treatment of suspected severe malaria with rectal artesunate suppositories in remote areas.</AbstractText><br /><br />Copyright: © 2023 Watson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 08 Nov 2023; 20:e1004312</small></div>

<div><h4>Sociodemographic characteristics and longitudinal progression of multimorbidity: A multistate modelling analysis of a large primary care records dataset in England.</h4><i>Chen S, Marshall T, Jackson C, Cooper J, ... Yau C, Barrett JK</i><br /><b>Background</b><br />Multimorbidity, characterised by the coexistence of multiple chronic conditions in an individual, is a rising public health concern. While much of the existing research has focused on cross-sectional patterns of multimorbidity, there remains a need to better understand the longitudinal accumulation of diseases. This includes examining the associations between important sociodemographic characteristics and the rate of progression of chronic conditions.<br /><b>Methods and findings</b><br />We utilised electronic primary care records from 13.48 million participants in England, drawn from the Clinical Practice Research Datalink (CPRD Aurum), spanning from 2005 to 2020 with a median follow-up of 4.71 years (IQR: 1.78, 11.28). The study focused on 5 important chronic conditions: cardiovascular disease (CVD), type 2 diabetes (T2D), chronic kidney disease (CKD), heart failure (HF), and mental health (MH) conditions. Key sociodemographic characteristics considered include ethnicity, social and material deprivation, gender, and age. We employed a flexible spline-based parametric multistate model to investigate the associations between these sociodemographic characteristics and the rate of different disease transitions throughout multimorbidity development. Our findings reveal distinct association patterns across different disease transition types. Deprivation, gender, and age generally demonstrated stronger associations with disease diagnosis compared to ethnic group differences. Notably, the impact of these factors tended to attenuate with an increase in the number of preexisting conditions, especially for deprivation, gender, and age. For example, the hazard ratio (HR) (95% CI; p-value) for the association of deprivation with T2D diagnosis (comparing the most deprived quintile to the least deprived) is 1.76 ([1.74, 1.78]; p < 0.001) for those with no preexisting conditions and decreases to 0.95 ([0.75, 1.21]; p = 0.69) with 4 preexisting conditions. Furthermore, the impact of deprivation, gender, and age was typically more pronounced when transitioning from an MH condition. For instance, the HR (95% CI; p-value) for the association of deprivation with T2D diagnosis when transitioning from MH is 2.03 ([1.95, 2.12], p < 0.001), compared to transitions from CVD 1.50 ([1.43, 1.58], p < 0.001), CKD 1.37 ([1.30, 1.44], p < 0.001), and HF 1.55 ([1.34, 1.79], p < 0.001). A primary limitation of our study is that potential diagnostic inaccuracies in primary care records, such as underdiagnosis, overdiagnosis, or ascertainment bias of chronic conditions, could influence our results.<br /><b>Conclusions</b><br />Our results indicate that early phases of multimorbidity development could warrant increased attention. The potential importance of earlier detection and intervention of chronic conditions is underscored, particularly for MH conditions and higher-risk populations. These insights may have important implications for the management of multimorbidity.<br /><br />Copyright: © 2023 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 03 Nov 2023; 20:e1004310</small></div>

<div><h4>Patents and regulatory exclusivities on FDA-approved insulin products: A longitudinal database study, 1986-2019.</h4><i>Olsen A, Beall RF, Knox RP, Tu SS, Kesselheim AS, Feldman WB</i><br /><b>Background</b><br />Insulin is the primary treatment for type 1 and some type 2 diabetes but remains costly in the United States, even though it was discovered more than a century ago. High prices can lead to nonadherence and are often sustained by patents and regulatory exclusivities that limit competition on brand-name products. We sought to examine how manufacturers have used patents and regulatory exclusivities on insulin products approved from 1986 to 2019 to extend periods of market exclusivity.<br /><b>Methods and findings</b><br />We used the publicly available Food and Drug Administration (FDA) Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) to identify all approved biosynthetic insulin products. Individual products approved under the same New Drug Application (NDA)-e.g., a vial and pen-were considered as separate products for the purposes of analysis. We recorded all patents and regulatory exclusivities listed in the Orange Book on each product and used Google Patents to extract the timing of patent application and whether patents were obtained on delivery devices or others aspects of the product. The primary outcome was the duration of expected protection, which was determined by subtracting the FDA approval date for each product from its last-to-expire patent or regulatory exclusivity (whichever occurred later). We performed a secondary analysis that considered overall protection on insulin lines-defined as groups of products approved under the same NDA with the same active ingredients manufactured by the same company. We also examined competition from follow-on insulin products-defined as products approved with the same active ingredients as originators but manufactured by different companies (approved via a specific drug approval pathway under section 505(b)(2) of the Food, Drug, and Cosmetic Act). During the study period, the FDA approved 56 individual products across 25 different insulin lines and 5 follow-ons across 3 different insulin lines. Thirty-three (59%) of the 56 products were drug-device combinations. Manufacturers of 9 products approved during the study period obtained patents filed after FDA approval that extended their duration of expected protection (by a median of 6 years). Approximately 63% of all patents on drug-device combinations approved during the study period were related to delivery devices. The median duration of expected protection on insulin products was 16.0 years, and the median protection on insulin lines was 17.6 years. An important limitation of our analysis is that manufacturers may continue to add patents on existing insulin products while competitors may challenge patents; therefore, periods of protection may change over time.<br /><b>Conclusions</b><br />Among several strategies that insulin manufacturers have employed to extend periods of market exclusivity on brand-name insulin products are filing patents after FDA approval and obtaining a large number of patents on delivery devices. Policy reforms are needed to promote timely competition in the pharmaceutical market and ensure that patients have access to low-cost drugs.<br /><br />Copyright: © 2023 Olsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 31 Oct 2023; 20:e1004309</small></div>

<div><h4>Correction: Recommended reporting items for epidemic forecasting and prediction research: The EPIFORGE 2020 guidelines.</h4><i>Pollett S, Johansson MA, Reich NG, Brett-Major D, ... Brady O, Rivers C</i><br /><AbstractText>[This corrects the article DOI: 10.1371/journal.pmed.1003793.].</AbstractText><br /><br />Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.<br /><br /><small>PLoS Med: 31 Oct 2023; 20:e1004316</small></div>

<div><h4>Income-based differences in healthcare utilization in relation to mortality in the Swedish population between 2004-2017: A nationwide register study.</h4><i>Flodin P, Allebeck P, Gubi E, Burström B, Agardh EE</i><br /><b>Background</b><br />Despite universal healthcare, socioeconomic differences in healthcare utilization (HCU) persist in modern welfare states. However, little is known of how HCU inequalities has developed over time. The aim of this study is to assess time trends of differences in utilization of primary and specialized care for the lowest (Q1) and highest (Q5) income quantiles and compare these to mortality.<br /><b>Methods and findings</b><br />Using a repeated cross-sectional register-based study design, data on utilization of (i) primary; (ii) specialized outpatient; and (iii) inpatient care, as well as (iv) cause of death, were linked to family income and sociodemographic control variables (for instance, country of origin and marital status). The study sample comprised all individuals 16 years or older residing in Sweden any year during the study period and ranged from 7.1 million in year 2004 to 8.0 million year 2017. HCU and mortality for all disease as well as for the 5 disease groups causing most deaths were compared for the Q1 and Q5 using logistic regression, adjusting for sex, age, marital status, and birth country. The primary outcome measures were adjusted odds ratios (ORs), and regression coefficients of annual changes in these ORs log-transformed. Additionally, we conducted negative binominal regression to calculate adjusted rate ratios (RRs) comparing Q1 and Q5 with regard to number of disease specific healthcare encounters ≤5 years prior to death. In 2017, for all diseases combined, Q1 utilized marginally more primary and specialized outpatient care than Q5 (OR 1.07, 95% CI [1.07, 1.08]; p < 0.001, and OR 1.04, 95% CI [1.04, 1.05]; p < 0.001, respectively), and considerably more inpatient care (OR 1.44, 95% CI [1.43, 1.45]; p < 0.001). The largest relative inequality was observed for mortality (OR 1.78, 95% CI [1.74, 1.82]; p < 0.001). This pattern was broadly reproduced for each of the 5 disease groups. Time trends in HCU inequality varied by level of care. Each year, Q1 (versus Q5) used more inpatient care and suffered increasing mortality rates. However, utilization of primary and specialized outpatient care increased more among Q5 than in Q1. Finally, group differences in number of healthcare encounters ≤5 years prior to death demonstrated a similar pattern. For each disease group, primary and outpatient care encounters were fewer in Q1 than in Q5, while inpatient encounters were similar or higher in Q1. A main limitation of this study is the absence of data on self-reported need for care, which impedes quantifications of HCU inequalities each year.<br /><b>Conclusions</b><br />Income-related differences in the utilization of primary and specialized outpatient care were considerably smaller than for mortality, and this discrepancy widened with time. Facilitating motivated use of primary and outpatient care among low-income groups could help mitigate the growing health inequalities.<br /><br />Copyright: © 2023 Flodin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 31 Oct 2023; 20:e1004230</small></div>

<div><h4>Frequency of multiple changes to prespecified primary outcomes of clinical trials completed between 2009 and 2017 in German university medical centers: A meta-research study.</h4><i>Holst M, Haslberger M, Yerunkar S, Strech D, Hemkens LG, Carlisle BG</i><br /><b>Background</b><br />Clinical trial registries allow assessment of deviations of published trials from their protocol, which may indicate a considerable risk of bias. However, since entries in many registries can be updated at any time, deviations may go unnoticed. We aimed to assess the frequency of changes to primary outcomes in different historical versions of registry entries, and how often they would go unnoticed if only deviations between published trial reports and the most recent registry entry are assessed.<br /><b>Methods and findings</b><br />We analyzed the complete history of changes of registry entries in all 1746 randomized controlled trials completed at German university medical centers between 2009 and 2017, with published results up to 2022, that were registered in ClinicalTrials.gov or the German WHO primary registry (German Clinical Trials Register; DRKS). Data were retrieved on 24 January 2022. We assessed deviations between registry entries and publications in a random subsample of 292 trials. We determined changes of primary outcomes (1) between different versions of registry entries at key trial milestones, (2) between the latest registry entry version and the results publication, and (3) changes that occurred after trial start with no change between latest registry entry version and publication (so that assessing the full history of changes is required for detection of changes). We categorized changes as major if primary outcomes were added, dropped, changed to secondary outcomes, or secondary outcomes were turned into primary outcomes. We also assessed (4) the proportion of publications transparently reporting changes and (5) characteristics associated with changes. Of all 1746 trials, 23% (n = 393) had a primary outcome change between trial start and latest registry entry version, with 8% (n = 142) being major changes, that is, primary outcomes were added, dropped, changed to secondary outcomes, or secondary outcomes were turned into primary outcomes. Primary outcomes in publications were different from the latest registry entry version in 41% of trials (120 of the 292 sampled trials; 95% confidence interval (CI) [35%, 47%]), with major changes in 18% (54 of 292; 95% CI [14%, 23%]). Overall, 55% of trials (161 of 292; 95% CI [49%, 61%]) had primary outcome changes at any timepoint over the course of a trial, with 23% of trials (67 of 292; 95% CI [18%, 28%]) having major changes. Changes only within registry records, with no apparent discrepancy between latest registry entry version and publication, were observed in 14% of trials (41 of 292; 95% CI [10%, 19%]), with 4% (13 of 292; 95% CI [2%, 7%]) being major changes. One percent of trials with a change reported this in their publication (2 of 161 trials; 95% CI [0%, 4%]). An exploratory logistic regression analysis indicated that trials were less likely to have a discrepant registry entry if they were registered more recently (odds ratio (OR) 0.74; 95% CI [0.69, 0.80]; p<0.001), were not registered on ClinicalTrials.gov (OR 0.41; 95% CI [0.23, 0.70]; p = 0.002), or were not industry-sponsored (OR 0.29; 95% CI [0.21, 0.41]; p<0.001). Key limitations include some degree of subjectivity in the categorization of outcome changes and inclusion of a single geographic region.<br /><b>Conclusions</b><br />In this study, we observed that changes to primary outcomes occur in 55% of trials, with 23% trials having major changes. They are rarely transparently reported in the results publication and often not visible in the latest registry entry version. More transparency is needed, supported by deeper analysis of registry entries to make these changes more easily recognizable. Protocol registration: Open Science Framework (https://osf.io/t3qva; amendment in https://osf.io/qtd2b).<br /><br />Copyright: © 2023 Holst et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 31 Oct 2023; 20:e1004306</small></div>

<div><h4>Impact of cervical screening by human papillomavirus genotype: Population-based estimations.</h4><i>Wang J, Elfström KM, Lagheden C, Eklund C, ... Sparén P, Dillner J</i><br /><b>Background</b><br />Cervical screening programs use testing for human papillomavirus (HPV) genotypes. Different HPV types differ greatly in prevalence and oncogenicity. We estimated the impact of cervical screening and follow-up for each HPV type.<br /><b>Methods and findings</b><br />For each type of HPV, we calculated the number of women needed to screen (NNS) and number of women needing follow-up (NNF) to detect or prevent one cervical cancer case, using the following individual level input data (i) screening and cancer data for all women aged 25 to 80 years, resident in Sweden during 2004 to 2011 (N = 3,568,938); (ii) HPV type-specific prevalences and screening histories among women with cervical cancer in Sweden in 2002 to 2011(N = 4,254); (iii) HPV 16/18/other HPV prevalences in the population-based HPV screening program (N = 656,607); and (iv) exact HPV genotyping in a population-based cohort (n = 12,527). Historical screening attendance was associated with a 72% reduction of cervical cancer incidence caused by HPV16 (71.6%, 95% confidence interval (CI) [69.1%, 73.9%]) and a 54% reduction of cancer caused by HPV18 (53.8%, 95% CI [40.6%, 63.1%]). One case of HPV16-caused cervical cancer could be prevented for every 5,527 women attending screening (number needed to screen, NNS). Prevention of one case of HPV16-caused cervical cancer required follow-up of 147 HPV16-positive women (number needed to follow-up, NNF). The NNS and NNF were up to 40 to 500 times higher for HPV types commonly screened for with lower oncogenic potential (HPV35,39,51,56,59,66,68). For women below 30 years of age, NNS and NNF for HPV16 were 4,747 and 289, respectively, but >220,000 and >16,000 for HPV35,39,51,56,59,66,68. All estimates were either age-standarized or age-stratified. The primary limitation of our study is that NNS is dependent on the HPV prevalence that can differ between populations and over time. However, it can readily be recalculated in other settings and monitored when HPV type-specific prevalence changes. Other limitations include that in some age groups, there was little data and extrapolations had to be made. Finally, there were very few cervical cancer cases associated with certain HPV types in young age group.<br /><b>Conclusions</b><br />In this study, we observed that the impact of cervical cancer screening varies depending on the HPV type screened for. Estimating and monitoring the impact of screening by HPV type can facilitate the design of effective and efficient HPV-based cervical screening programs.<br /><b>Trial registration</b><br />ClinicalTrials.gov with numbers NCT00479375, NCT01511328.<br /><br />Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 27 Oct 2023; 20:e1004304</small></div>

<div><h4>Long-term risk of arrhythmias in patients with inflammatory bowel disease: A population-based, sibling-controlled cohort study.</h4><i>Sun J, Roelstraete B, Svennberg E, Halfvarson J, ... Olén O, Ludvigsson JF</i><br /><b>Background</b><br />Although previous evidence has suggested an increased risk of cardiovascular disease (CVD) in patients with inflammatory bowel disease (IBD), its association with arrhythmias is inconclusive. In this study, we aimed to explore the long-term risk of arrhythmias in patients with IBD.<br /><b>Methods and findings</b><br />Through a nationwide histopathology cohort, we identified patients with biopsy-confirmed IBD in Sweden during 1969 to 2017, including Crohn\'s disease (CD: n = 24,954; median age at diagnosis: 38.4 years; female: 52.2%), ulcerative colitis (UC: n = 46,856; 42.1 years; 46.3%), and IBD-unclassified (IBD-U: n = 12,067; 43.8 years; 49.6%), as well as their matched reference individuals and IBD-free full siblings. Outcomes included overall and specific arrhythmias (e.g., atrial fibrillation/flutter, bradyarrhythmias, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest). Flexible parametric survival models estimated hazard ratios (aHR) with 95% confidence intervals (95% CIs), after adjustment for birth year, sex, county of residence, calendar year, country of birth, educational attainment, number of healthcare visits, and cardiovascular-related comorbidities. Over a median of approximately 10 years of follow-up, 1,904 (7.6%) patients with CD, 4,154 (8.9%) patients with UC, and 990 (8.2%) patients with IBD-U developed arrhythmias, compared with 6.7%, 7.5%, and 6.0% in reference individuals, respectively. Compared with reference individuals, overall arrhythmias were increased in patients with CD [54.6 versus 46.1 per 10,000 person-years; aHR = 1.15 (95% CI [1.09, 1.21], P < 0.001)], patients with UC [64.7 versus 53.3 per 10,000 person-years; aHR = 1.14 (95% CI [1.10, 1.18], P < 0.001)], and patients with IBD-U [78.1 versus 53.5 per 10,000 person-years; aHR = 1.30 (95% CI [1.20, 1.41], P < 0.001)]. The increased risk persisted 25 years after diagnosis, corresponding to 1 extra arrhythmia case per 80 CD, 58 UC, and 29 IBD-U cases over the same period. Patients with IBD also had a significantly increased risk of specific arrhythmias, except for bradyarrhythmias. Sibling comparison analyses confirmed the main findings. Study limitations include lack of clinical data to define IBD activity, not considering the potential role of IBD medications and disease activity, and the potential residual confounding from unmeasured factors for arrhythmias.<br /><b>Conclusions</b><br />In this study, we observed that patients with IBD were at an increased risk of developing arrhythmias. The excess risk persisted even 25 years after IBD diagnosis. Our findings indicate a need for awareness of this excess risk among healthcare professionals.<br /><br />Copyright: © 2023 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 19 Oct 2023; 20:e1004305</small></div>

<div><h4>Risk factors for extended-spectrum beta-lactamase (ESBL)-producing E. coli carriage among children in a food animal-producing region of Ecuador: A repeated measures observational study.</h4><i>Amato HK, Loayza F, Salinas L, Paredes D, ... Trueba G, Graham JP</i><br /><b>Background</b><br />The spread of antibiotic-resistant bacteria may be driven by human-animal-environment interactions, especially in regions with limited restrictions on antibiotic use, widespread food animal production, and free-roaming domestic animals. In this study, we aimed to identify risk factors related to commercial food animal production, small-scale or \"backyard\" food animal production, domestic animal ownership, and practices related to animal handling, waste disposal, and antibiotic use in Ecuadorian communities.<br /><b>Methods and findings</b><br />We conducted a repeated measures study from 2018 to 2021 in 7 semirural parishes of Quito, Ecuador to identify determinants of third-generation cephalosporin-resistant E. coli (3GCR-EC) and extended-spectrum beta-lactamase E. coli (ESBL-EC) in children. We collected 1,699 fecal samples from 600 children and 1,871 domestic animal fecal samples from 376 of the same households at up to 5 time points per household over the 3-year study period. We used multivariable log-binomial regression models to estimate relative risks (RR) of 3GCR-EC and ESBL-EC carriage, adjusting for child sex and age, caregiver education, household wealth, and recent child antibiotic use. Risk factors for 3GCR-EC included living within 5 km of more than 5 commercial food animal operations (RR: 1.26; 95% confidence interval (CI): 1.10, 1.45; p-value: 0.001), household pig ownership (RR: 1.23; 95% CI: 1.02, 1.48; p-value: 0.030) and child pet contact (RR: 1.23; 95% CI: 1.09, 1.39; p-value: 0.001). Risk factors for ESBL-EC were dog ownership (RR: 1.35; 95% CI: 1.00, 1.83; p-value: 0.053), child pet contact (RR: 1.54; 95% CI: 1.10, 2.16; p-value: 0.012), and placing animal feces on household land/crops (RR: 1.63; 95% CI: 1.09, 2.46; p-value: 0.019). The primary limitations of this study are the use of proxy and self-reported exposure measures and the use of a single beta-lactamase drug (ceftazidime with clavulanic acid) in combination disk diffusion tests for ESBL confirmation, potentially underestimating phenotypic ESBL production among cephalosporin-resistant E. coli isolates. To improve ESBL determination, it is recommended to use 2 combination disk diffusion tests (ceftazidime with clavulanic acid and cefotaxime with clavulanic acid) for ESBL confirmatory testing. Future studies should also characterize transmission pathways by assessing antibiotic resistance in commercial food animals and environmental reservoirs.<br /><b>Conclusions</b><br />In this study, we observed an increase in enteric colonization of antibiotic-resistant bacteria among children with exposures to domestic animals and their waste in the household environment and children living in areas with a higher density of commercial food animal production operations.<br /><br />Copyright: © 2023 Amato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 13 Oct 2023; 20:e1004299</small></div>

<div><h4>Measuring people\'s views on health system performance: Design and development of the people\'s voice survey.</h4><i>Lewis TP, Kapoor NR, Aryal A, Bazua-Lobato R, ... Leslie HH, Kruk ME</i><br /><AbstractText>Todd Lewis and co-authors discuss development and use of the People\'s Voice Survey for health system assessment.</AbstractText><br /><br />Copyright: © 2023 Lewis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 06 Oct 2023; 20:e1004294</small></div>

<div><h4>Prioritizing persons deprived of liberty in global guidelines for tuberculosis preventive treatment.</h4><i>Narayan A, Salindri AD, Keshavjee S, Muyoyeta M, ... Altice FL, Andrews JR</i><br /><AbstractText>In this Policy Forum piece, Aditya Narayan and colleagues discuss the challenges and opportunities for tuberculosis preventive treatment in carceral settings.</AbstractText><br /><br />Copyright: © 2023 Narayan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Oct 2023; 20:e1004288</small></div>

<div><h4>Assessing eligibility for lung cancer screening using parsimonious ensemble machine learning models: A development and validation study.</h4><i>Callender T, Imrie F, Cebere B, Pashayan N, ... van der Schaar M, Janes SM</i><br /><b>Background</b><br />Risk-based screening for lung cancer is currently being considered in several countries; however, the optimal approach to determine eligibility remains unclear. Ensemble machine learning could support the development of highly parsimonious prediction models that maintain the performance of more complex models while maximising simplicity and generalisability, supporting the widespread adoption of personalised screening. In this work, we aimed to develop and validate ensemble machine learning models to determine eligibility for risk-based lung cancer screening.<br /><b>Methods and findings</b><br />For model development, we used data from 216,714 ever-smokers recruited between 2006 and 2010 to the UK Biobank prospective cohort and 26,616 high-risk ever-smokers recruited between 2002 and 2004 to the control arm of the US National Lung Screening (NLST) randomised controlled trial. The NLST trial randomised high-risk smokers from 33 US centres with at least a 30 pack-year smoking history and fewer than 15 quit-years to annual CT or chest radiography screening for lung cancer. We externally validated our models among 49,593 participants in the chest radiography arm and all 80,659 ever-smoking participants in the US Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial. The PLCO trial, recruiting from 1993 to 2001, analysed the impact of chest radiography or no chest radiography for lung cancer screening. We primarily validated in the PLCO chest radiography arm such that we could benchmark against comparator models developed within the PLCO control arm. Models were developed to predict the risk of 2 outcomes within 5 years from baseline: diagnosis of lung cancer and death from lung cancer. We assessed model discrimination (area under the receiver operating curve, AUC), calibration (calibration curves and expected/observed ratio), overall performance (Brier scores), and net benefit with decision curve analysis. Models predicting lung cancer death (UCL-D) and incidence (UCL-I) using 3 variables-age, smoking duration, and pack-years-achieved or exceeded parity in discrimination, overall performance, and net benefit with comparators currently in use, despite requiring only one-quarter of the predictors. In external validation in the PLCO trial, UCL-D had an AUC of 0.803 (95% CI: 0.783, 0.824) and was well calibrated with an expected/observed (E/O) ratio of 1.05 (95% CI: 0.95, 1.19). UCL-I had an AUC of 0.787 (95% CI: 0.771, 0.802), an E/O ratio of 1.0 (95% CI: 0.92, 1.07). The sensitivity of UCL-D was 85.5% and UCL-I was 83.9%, at 5-year risk thresholds of 0.68% and 1.17%, respectively, 7.9% and 6.2% higher than the USPSTF-2021 criteria at the same specificity. The main limitation of this study is that the models have not been validated outside of UK and US cohorts.<br /><b>Conclusions</b><br />We present parsimonious ensemble machine learning models to predict the risk of lung cancer in ever-smokers, demonstrating a novel approach that could simplify the implementation of risk-based lung cancer screening in multiple settings.<br /><br />Copyright: © 2023 Callender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Oct 2023; 20:e1004287</small></div>

<div><h4>Ethnic differences in early onset multimorbidity and associations with health service use, long-term prescribing, years of life lost, and mortality: A cross-sectional study using clustering in the UK Clinical Practice Research Datalink.</h4><i>Eto F, Samuel M, Henkin R, Mahesh M, ... Finer S, Mathur R</i><br /><b>Background</b><br />The population prevalence of multimorbidity (the existence of at least 2 or more long-term conditions [LTCs] in an individual) is increasing among young adults, particularly in minority ethnic groups and individuals living in socioeconomically deprived areas. In this study, we applied a data-driven approach to identify clusters of individuals who had an early onset multimorbidity in an ethnically and socioeconomically diverse population. We identified associations between clusters and a range of health outcomes.<br /><b>Methods and findings</b><br />Using linked primary and secondary care data from the Clinical Practice Research Datalink GOLD (CPRD GOLD), we conducted a cross-sectional study of 837,869 individuals with early onset multimorbidity (aged between 16 and 39 years old when the second LTC was recorded) registered with an English general practice between 2010 and 2020. The study population included 777,906 people of White ethnicity (93%), 33,915 people of South Asian ethnicity (4%), and 26,048 people of Black African/Caribbean ethnicity (3%). A total of 204 LTCs were considered. Latent class analysis stratified by ethnicity identified 4 clusters of multimorbidity in White groups and 3 clusters in South Asian and Black groups. We found that early onset multimorbidity was more common among South Asian (59%, 33,915) and Black (56% 26,048) groups compared to the White population (42%, 777,906). Latent class analysis revealed physical and mental health conditions that were common across all ethnic groups (i.e., hypertension, depression, and painful conditions). However, each ethnic group also presented exclusive LTCs and different sociodemographic profiles: In White groups, the cluster with the highest rates/odds of the outcomes was predominantly male (54%, 44,150) and more socioeconomically deprived than the cluster with the lowest rates/odds of the outcomes. On the other hand, South Asian and Black groups were more socioeconomically deprived than White groups, with a consistent deprivation gradient across all multimorbidity clusters. At the end of the study, 4% (34,922) of the White early onset multimorbidity population had died compared to 2% of the South Asian and Black early onset multimorbidity populations (535 and 570, respectively); however, the latter groups died younger and lost more years of life. The 3 ethnic groups each displayed a cluster of individuals with increased rates of primary care consultations, hospitalisations, long-term prescribing, and odds of mortality. Study limitations include the exclusion of individuals with missing ethnicity information, the age of diagnosis not reflecting the actual age of onset, and the exclusion of people from Mixed, Chinese, and other ethnic groups due to insufficient power to investigate associations between multimorbidity and health-related outcomes in these groups.<br /><b>Conclusions</b><br />These findings emphasise the need to identify, prevent, and manage multimorbidity early in the life course. Our work provides additional insights into the excess burden of early onset multimorbidity in those from socioeconomically deprived and diverse groups who are disproportionately and more severely affected by multimorbidity and highlights the need to ensure healthcare improvements are equitable.<br /><br />Copyright: © 2023 Eto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Oct 2023; 20:e1004300</small></div>

<div><h4>Screening uptake of colonoscopy versus fecal immunochemical testing in first-degree relatives of patients with non-syndromic colorectal cancer: A multicenter, open-label, parallel-group, randomized trial (ParCoFit study).</h4><i>González-López N, Quintero E, Gimeno-Garcia AZ, Bujanda L, ... González-Dávila E, Oncology Group of Asociación Española de Gastroenterología</i><br /><b>Background</b><br />Colonoscopy screening is underused by first-degree relatives (FDRs) of patients with non-syndromic colorectal cancer (CRC) with screening completion rates below 50%. Studies conducted in FDR referred for screening suggest that fecal immunochemical testing (FIT) was not inferior to colonoscopy in terms of diagnostic yield and tumor staging, but screening uptake of FIT has not yet been tested in this population. In this study, we investigated whether the uptake of FIT screening is superior to the uptake of colonoscopy screening in the familial-risk population, with an equivalent effect on CRC detection.<br /><b>Methods and findings</b><br />This open-label, parallel-group, randomized trial was conducted in 12 Spanish centers between February 2016 and December 2021. Eligible individuals included asymptomatic FDR of index cases <60 years, siblings or ≥2 FDR with CRC. The primary outcome was to compare screening uptake between colonoscopy and FIT. The secondary outcome was to determine the efficacy of each strategy to detect advanced colorectal neoplasia (adenoma or serrated polyps ≥10 mm, polyps with tubulovillous architecture, high-grade dysplasia, and/or CRC). Screening-naïve FDR were randomized (1:1) to one-time colonoscopy versus annual FIT during 3 consecutive years followed by a work-up colonoscopy in the case of a positive test. Randomization was performed before signing the informed consent using computer-generated allocation algorithm based on stratified block randomization. Multivariable regression analysis was performed by intention-to-screen. On December 31, 2019, when 81% of the estimated sample size was reached, the trial was terminated prematurely after an interim analysis for futility. Study outcomes were further analyzed through 2-year follow-up. The main limitation of this study was the impossibility of collecting information on eligible individuals who declined to participate. A total of 1,790 FDR of 460 index cases were evaluated for inclusion, of whom 870 were assigned to undergo one-time colonoscopy (n = 431) or FIT (n = 439). Of them, 383 (44.0%) attended the appointment and signed the informed consent: 147/431 (34.1%) FDR received colonoscopy-based screening and 158/439 (35.9%) underwent FIT-based screening (odds ratio [OR] 1.08; 95% confidence intervals [CI] [0.82, 1.44], p = 0.564). The detection rate of advanced colorectal neoplasia was significantly higher in the colonoscopy group than in the FIT group (OR 3.64, 95% CI [1.55, 8.53], p = 0.003). Study outcomes did not change throughout follow-up.<br /><b>Conclusions</b><br />In this study, compared to colonoscopy, FIT screening did not improve screening uptake by individuals at high risk of CRC, resulting in less detection of advanced colorectal neoplasia. Further studies are needed to assess how screening uptake could be improved in this high-risk group, including by inclusion in population-based screening programs.<br /><b>Trial registration</b><br />This trial was registered with ClinicalTrials.gov (NCT02567045).<br /><br />Copyright: © 2023 González-López et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Oct 2023; 20:e1004298</small></div>

<div><h4>Gender and water, sanitation, and hygiene: Three opportunities to build from recent reporting on global progress, 2000-2022.</h4><i>Willetts J, MacArthur J, Carrard N</i><br /><AbstractText>In this Perspective, Juliet Willetts and colleagues discuss opportunities to stimulate progress in gender-related aspects of water, sanitation and hygiene.</AbstractText><br /><br />Copyright: © 2023 Willetts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Oct 2023; 20:e1004297</small></div>

<div><h4>Comprehensive mandatory policies are needed to fully protect all children from unhealthy food marketing.</h4><i>Dillman Carpentier FR, Stoltze FM, Popkin BM</i><br /><AbstractText>The World Health Organization (WHO) have released a new guideline, \"Policies to protect children from the harmful impact of food marketing\" [1] which recommends the development of comprehensive laws to reduce children\'s exposure to unhealthy food marketing. This new guideline extends previous recommendations [2] to limit the adverse effects of unhealthy food marketing on the health of the world\'s children. We consider here whether these new recommendations go far enough.</AbstractText><br /><br />Copyright: © 2023 Dillman Carpentier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 25 Sep 2023; 20:e1004291</small></div>

<div><h4>Recommendations on data sharing in HIV drug resistance research.</h4><i>Inzaule SC, Siedner MJ, Little SJ, Avila-Rios S, ... Jordan MR, Shafer RW</i><br /><AbstractText>Author summary  • Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens.  • HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens.  • Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines.  • Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing.  • In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions.  • Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.</AbstractText><br /><br />Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.<br /><br /><small>PLoS Med: 22 Sep 2023; 20:e1004293</small></div>

<div><h4>Impact of taxes and warning labels on red meat purchases among US consumers: A randomized controlled trial.</h4><i>Taillie LS, Bercholz M, Prestemon CE, Higgins ICA, ... Hall MG, Jaacks LM</i><br /><b>Background</b><br />Policies to reduce red meat intake are important for mitigating climate change and improving public health. We tested the impact of taxes and warning labels on red meat purchases in the United States. The main study question was, will taxes and warning labels reduce red meat purchases?<br /><b>Methods and findings</b><br />We recruited 3,518 US adults to participate in a shopping task in a naturalistic online grocery store from October 18, 2021 to October 28, 2021. Participants were randomized to one of 4 conditions: control (no tax or warning labels, n = 887), warning labels (health and environmental warning labels appeared next to products containing red meat, n = 891), tax (products containing red meat were subject to a 30% price increase, n = 874), or combined warning labels + tax (n = 866). We used fractional probit and Poisson regression models to assess the co-primary outcomes, percent, and count of red meat purchases, and linear regression to assess the secondary outcomes of nutrients purchased. Most participants identified as women, consumed red meat 2 or more times per week, and reported doing all of their household\'s grocery shopping. The warning, tax, and combined conditions led to lower percent of red meat-containing items purchased, with 39% (95% confidence interval (CI) [38%, 40%]) of control participants\' purchases containing red meat, compared to 36% (95% CI [35%, 37%], p = 0.001) of warning participants, 34% (95% CI [33%, 35%], p < 0.001) of tax participants, and 31% (95% CI [30%, 32%], p < 0.001) of combined participants. A similar pattern was observed for count of red meat items. Compared to the control, the combined condition reduced calories purchased (-312.0 kcals, 95% CI [-590.3 kcals, -33.6 kcals], p = 0.027), while the tax (-10.4 g, 95% CI [-18.2 g, -2.5 g], p = 0.01) and combined (-12.8 g, 95% CI [-20.7 g, -4.9 g], p = 0.001) conditions reduced saturated fat purchases; no condition affected sodium purchases. Warning labels decreased the perceived healthfulness and environmental sustainability of red meat, while taxes increased perceived cost. The main limitations were that the study differed in sociodemographic characteristics from the US population, and only about 30% to 40% of the US population shops for groceries online.<br /><b>Conclusions</b><br />Warning labels and taxes reduced red meat purchases in a naturalistic online grocery store. Trial Registration: http://www.clinicaltrials.gov/ NCT04716010.<br /><br />Copyright: © 2023 Taillie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 18 Sep 2023; 20:e1004284</small></div>

<div><h4>Estimating the proportion of clinically suspected cholera cases that are true Vibrio cholerae infections: A systematic review and meta-analysis.</h4><i>Wiens KE, Xu H, Zou K, Mwaba J, ... Lee EC, Azman AS</i><br /><b>Background</b><br />Cholera surveillance relies on clinical diagnosis of acute watery diarrhea. Suspected cholera case definitions have high sensitivity but low specificity, challenging our ability to characterize cholera burden and epidemiology. Our objective was to estimate the proportion of clinically suspected cholera that are true Vibrio cholerae infections and identify factors that explain variation in positivity.<br /><b>Methods and findings</b><br />We conducted a systematic review of studies that tested ≥10 suspected cholera cases for V. cholerae O1/O139 using culture, PCR, and/or a rapid diagnostic test. We searched PubMed, Embase, Scopus, and Google Scholar for studies that sampled at least one suspected case between January 1, 2000 and April 19, 2023, to reflect contemporary patterns in V. cholerae positivity. We estimated diagnostic test sensitivity and specificity using a latent class meta-analysis. We estimated V. cholerae positivity using a random-effects meta-analysis, adjusting for test performance. We included 119 studies from 30 countries. V. cholerae positivity was lower in studies with representative sampling and in studies that set minimum ages in suspected case definitions. After adjusting for test performance, on average, 52% (95% credible interval (CrI): 24%, 80%) of suspected cases represented true V. cholerae infections. After adjusting for test performance and study methodology, the odds of a suspected case having a true infection were 5.71 (odds ratio 95% CrI: 1.53, 15.43) times higher when surveillance was initiated in response to an outbreak than in non-outbreak settings. Variation across studies was high, and a limitation of our approach was that we were unable to explain all the heterogeneity with study-level attributes, including diagnostic test used, setting, and case definitions.<br /><b>Conclusions</b><br />In this study, we found that burden estimates based on suspected cases alone may overestimate the incidence of medically attended cholera by 2-fold. However, accounting for cases missed by traditional clinical surveillance is key to unbiased cholera burden estimates. Given the substantial variability in positivity between settings, extrapolations from suspected to confirmed cases, which is necessary to estimate cholera incidence rates without exhaustive testing, should be based on local data.<br /><br />Copyright: © 2023 Wiens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 14 Sep 2023; 20:e1004286</small></div>

<div><h4>Real-time surveillance of international SARS-CoV-2 prevalence using systematic traveller arrival screening: An observational study.</h4><i>Kucharski AJ, Chung K, Aubry M, Teiti I, ... Olivier S, Cao-Lormeau VM</i><br /><b>Background</b><br />Effective Coronavirus Disease 2019 (COVID-19) response relies on good knowledge of population infection dynamics, but owing to under-ascertainment and delays in symptom-based reporting, obtaining reliable infection data has typically required large dedicated local population studies. Although many countries implemented Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing among travellers, it remains unclear how accurately arrival testing data can capture international patterns of infection, because those arrival testing data were rarely reported systematically, and predeparture testing was often in place as well, leading to nonrepresentative infection status among arrivals.<br /><b>Methods and findings</b><br />In French Polynesia, testing data were reported systematically with enforced predeparture testing type and timing, making it possible to adjust for nonrepresentative infection status among arrivals. Combining statistical models of polymerase chain reaction (PCR) positivity with data on international travel protocols, we reconstructed estimates of prevalence at departure using only testing data from arrivals. We then applied this estimation approach to the United States of America and France, using data from over 220,000 tests from travellers arriving into French Polynesia between July 2020 and March 2022. We estimated a peak infection prevalence at departure of 2.1% (95% credible interval: 1.7, 2.6%) in France and 1% (95% CrI: 0.63, 1.4%) in the USA in late 2020/early 2021, with prevalence of 4.6% (95% CrI: 3.9, 5.2%) and 4.3% (95% CrI: 3.6, 5%), respectively, estimated for the Omicron BA.1 waves in early 2022. We found that our infection estimates were a leading indicator of later reported case dynamics, as well as being consistent with subsequent observed changes in seroprevalence over time. We did not have linked data on traveller demography or unbiased domestic infection estimates (e.g., from random community infection surveys) in the USA and France. However, our methodology would allow for the incorporation of prior data from additional sources if available in future.<br /><b>Conclusions</b><br />As well as elucidating previously unmeasured infection dynamics in these countries, our analysis provides a proof-of-concept for scalable and accurate leading indicator of global infections during future pandemics.<br /><br />Copyright: © 2023 Kucharski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 08 Sep 2023; 20:e1004283</small></div>

<div><h4>Cost-effectiveness analysis of interventions to improve diagnosis and preventive therapy for paediatric tuberculosis in 9 sub-Saharan African countries: A modelling study.</h4><i>Mafirakureva N, Mukherjee S, de Souza M, Kelly-Cirino C, ... Casenghi M, Dodd PJ</i><br /><b>Background</b><br />Over 1 million children aged 0 to 14 years were estimated to develop tuberculosis in 2021, resulting in over 200,000 deaths. Practical interventions are urgently needed to improve diagnosis and antituberculosis treatment (ATT) initiation in children aged 0 to 14 years and to increase coverage of tuberculosis preventive therapy (TPT) in children at high risk of developing tuberculosis disease. The multicountry CaP-TB intervention scaled up facility-based intensified case finding and strengthened household contact management and TPT provision at HIV clinics. To add to the limited health-economic evidence on interventions to improve ATT and TPT in children, we evaluated the cost-effectiveness of the CaP-TB intervention.<br /><b>Methods and findings</b><br />We analysed clinic-level pre/post data to quantify the impact of the CaP-TB intervention on ATT and TPT initiation across 9 sub-Saharan African countries. Data on tuberculosis diagnosis and ATT/TPT initiation counts with corresponding follow-up time were available for 146 sites across the 9 countries prior to and post project implementation, stratified by 0 to 4 and 5 to 14 year age-groups. Preintervention data were retrospectively collected from facility registers for a 12-month period, and intervention data were prospectively collected from December 2018 to June 2021 using project-specific forms. Bayesian generalised linear mixed-effects models were used to estimate country-level rate ratios for tuberculosis diagnosis and ATT/TPT initiation. We analysed project expenditure and cascade data to determine unit costs of intervention components and used mathematical modelling to project health impact, health system costs, and cost-effectiveness. Overall, ATT and TPT initiation increased, with country-level incidence rate ratios varying between 0.8 (95% uncertainty interval [UI], 0.7 to 1.0) and 2.9 (95% UI, 2.3 to 3.6) for ATT and between 1.6 (95% UI, 1.5 to 1.8) and 9.8 (95% UI, 8.1 to 11.8) for TPT. We projected that for every 100 children starting either ATT or TPT at baseline, the intervention package translated to between 1 (95% UI, -1 to 3) and 38 (95% UI, 24 to 58) deaths averted, with a median incremental cost-effectiveness ratio (ICER) of US$634 per disability-adjusted life year (DALY) averted. ICERs ranged between US$135/DALY averted in Democratic of the Congo and US$6,804/DALY averted in Cameroon. The main limitation of our study is that the impact is based on pre/post comparisons, which could be confounded.<br /><b>Conclusions</b><br />In most countries, the CaP-TB intervention package improved tuberculosis treatment and prevention services for children aged under 15 years, but large variation in estimated impact and ICERs highlights the importance of local context.<br /><b>Trial registration</b><br />This evaluation is part of the TIPPI study, registered with ClinicalTrials.gov (NCT03948698).<br /><br />Copyright: © 2023 Mafirakureva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 06 Sep 2023; 20:e1004285</small></div>

<div><h4>Modern slavery in the United Kingdom: The illegal migration act risks undermining efforts to combat exploitation.</h4><i>Oram S</i><br /><AbstractText>The Illegal Migration Act, which recently passed through the United Kingdom (UK) parliament, poses a serious threat to the well-being of victims of modern slavery and efforts to combat exploitation. The Act gives the UK Government greater powers to deny support and allow the detention and deportation of potential victims and has been widely criticised, including by medical associations and charities. Measures included in the Act risk perpetuating the deprivation of safety, dignity, and medical care experienced by victims, instead of providing the protections to which they should be entitled.</AbstractText><br /><br />Copyright: © 2023 Sian Oram. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 05 Sep 2023; 20:e1004279</small></div>

<div><h4>Tuberculosis prevalence after 4 years of population-wide systematic TB symptom screening and universal testing and treatment for HIV in the HPTN 071 (PopART) community-randomised trial in Zambia and South Africa: A cross-sectional survey (TREATS).</h4><i>Klinkenberg E, Floyd S, Shanaube K, Mureithi L, ... Ayles H, TREATS study team</i><br /><b>Background</b><br />Tuberculosis (TB) prevalence remains persistently high in many settings, with new or expanded interventions required to achieve substantial reductions. The HIV Prevention Trials Network (HPTN) 071 (PopART) community-randomised trial randomised 14 communities to receive the \"PopART\" intervention during 2014 to 2017 (7 arm A and 7 arm B communities) and 7 communities to receive standard-of-care (arm C). The intervention was delivered door-to-door by community HIV care providers (CHiPs) and included universal HIV testing, facilitated linkage to HIV care at government health clinics, and systematic TB symptom screening. The Tuberculosis Reduction through Expanded Anti-retroviral Treatment and Screening (TREATS) study aimed to measure the impact of delivering the PopART intervention on TB outcomes, in communities with high HIV and TB prevalence.<br /><b>Methods and findings</b><br />The study population of the HPTN 071 (PopART) trial included individuals aged ≥15 years living in 21 urban and peri-urban communities in Zambia and South Africa, with a total population of approximately 1 million and an adult HIV prevalence of around 15% at the time of the trial. Two sputum samples for TB testing were provided to CHiPs by individuals who reported ≥1 TB suggestive symptom (a cough for ≥2 weeks, unintentional weight loss ≥1.5 kg in the last month, or current night sweats) or that a household member was currently on TB treatment. Antiretroviral therapy (ART) was offered universally at clinics in arm A and according to local guidelines in arms B and C. The TREATS study was conducted in the same 21 communities as the HPTN 071 (PopART) trial between 2017 and 2022, and TB prevalence was a co-primary endpoint of the TREATS study. The primary comparison was between the PopART intervention (arms A and B combined) and the standard-of-care (arm C). During 2019 to 2021, a TB prevalence survey was conducted among randomly selected individuals aged ≥15 years (approximately 1,750 per community in arms A and B, approximately 3,500 in arm C). Participants were screened on TB symptoms and chest X-ray, with diagnostic testing using Xpert-Ultra followed by culture for individuals who screened positive. Sputum eligibility was determined by the presence of a cough for ≥2 weeks, or ≥2 of 5 \"TB suggestive\" symptoms (cough, weight loss for ≥4 weeks, night sweats, chest pain, and fever for ≥2 weeks), or chest X-ray CAD4TBv5 score ≥50, or no available X-ray results. TB prevalence was compared between trial arms using standard methods for cluster-randomised trials, with adjustment for age, sex, and HIV status, and multiple imputation was used for missing data on prevalent TB. Among 83,092 individuals who were eligible for the survey, 49,556 (59.6%) participated, 8,083 (16.3%) screened positive, 90.8% (7,336/8,083) provided 2 sputum samples for Xpert-Ultra testing, and 308 (4.2%) required culture confirmation. Overall, estimated TB prevalence was 0.92% (457/49,556). The geometric means of 7 community-level prevalence estimates were 0.91%, 0.70%, and 0.69% in arms A, B, and C, respectively, with no evidence of a difference comparing arms A and B combined with arm C (adjusted prevalence ratio 1.14, 95% confidence interval, CI [0.67, 1.95], p = 0.60). TB prevalence was higher among people living with HIV than HIV-negative individuals, with an age-sex-community adjusted odds ratio of 2.29 [95% CI 1.54, 3.41] in Zambian communities and 1.61 [95% CI 1.13, 2.30] in South African communities. The primary limitations are that the study was powered to detect only large reductions in TB prevalence in the intervention arm compared with standard-of-care, and the between-community variation in TB prevalence was larger than anticipated.<br /><b>Conclusions</b><br />There was no evidence that the PopART intervention reduced TB prevalence. Systematic screening for TB that is based on symptom screening alone may not be sufficient to achieve a large reduction in TB prevalence over a period of several years. Including chest X-ray screening alongside TB symptom screening could substantially increase the sensitivity of systematic screening for TB.<br /><b>Trial registration</b><br />The TREATS study was registered with ClinicalTrials.gov Identifier: NCT03739736 on November 14, 2018. The HPTN 071 (PopART) trial was registered at ClinicalTrials.gov under number NCT01900977 on July 17, 2013.<br /><br />Copyright: © 2023 Klinkenberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Sep 2023; 20:e1004278</small></div>

<div><h4>Access to publicly funded weight management services in England using routine data from primary and secondary care (2007-2020): An observational cohort study.</h4><i>Coulman KD, Margelyte R, Jones T, Blazeby JM, ... Redaniel MT, Judge A</i><br /><b>Background</b><br />Adults living with overweight/obesity are eligible for publicly funded weight management (WM) programmes according to national guidance. People with the most severe and complex obesity are eligible for bariatric surgery. Primary care plays a key role in identifying overweight/obesity and referring to WM interventions. This study aimed to (1) describe the primary care population in England who (a) are referred for WM interventions and (b) undergo bariatric surgery and (2) determine the patient and GP practice characteristics associated with both.<br /><b>Methods and findings</b><br />An observational cohort study was undertaken using routinely collected primary care data in England from the Clinical Practice Research Datalink linked with Hospital Episode Statistics. During the study period (January 2007 to June 2020), 1,811,587 adults met the inclusion criteria of a recording of overweight/obesity in primary care, of which 54.62% were female and 20.10% aged 45 to 54. Only 56,783 (3.13%) were referred to WM, and 3,701 (1.09% of those with severe and complex obesity) underwent bariatric surgery. Multivariable Poisson regression examined the associations of demographic, clinical, and regional characteristics on the likelihood of WM referral and bariatric surgery. Higher body mass index (BMI) and practice region had the strongest associations with both outcomes. People with BMI ≥40 kg/m2 were more than 6 times as likely to be referred for WM (10.05% of individuals) than BMI 25.0 to 29.9 kg/m2 (1.34%) (rate ratio (RR) 6.19, 95% confidence interval (CI) [5.99,6.40], p < 0.001). They were more than 5 times as likely to undergo bariatric surgery (3.98%) than BMI 35.0 to 40.0 kg/m2 with a comorbidity (0.53%) (RR 5.52, 95% CI [5.07,6.02], p < 0.001). Patients from practices in the West Midlands were the most likely to have a WM referral (5.40%) (RR 2.17, 95% CI [2.10,2.24], p < 0.001, compared with the North West, 2.89%), and practices from the East of England least likely (1.04%) (RR 0.43, 95% CI [0.41,0.46], p < 0.001, compared with North West). Patients from practices in London were the most likely to undergo bariatric surgery (2.15%), and practices in the North West the least likely (0.68%) (RR 3.29, 95% CI [2.88,3.76], p < 0.001, London compared with North West). Longer duration since diagnosis with severe and complex obesity (e.g., 1.67% of individuals diagnosed in 2007 versus 0.34% in 2015, RR 0.20, 95% CI [0.12,0.32], p < 0.001), and increasing comorbidities (e.g., 2.26% of individuals with 6+ comorbidities versus 1.39% with none (RR 8.79, 95% CI [7.16,10.79], p < 0.001) were also strongly associated with bariatric surgery. The main limitation is the reliance on overweight/obesity being recorded within primary care records to identify the study population.<br /><b>Conclusions</b><br />Between 2007 and 2020, a very small percentage of the primary care population eligible for WM referral or bariatric surgery according to national guidance received either. Higher BMI and GP practice region had the strongest associations with both. Regional inequalities may reflect differences in commissioning and provision of WM services across the country. Multi-stakeholder qualitative research is ongoing to understand the barriers to accessing WM services and potential solutions. Together with population-wide prevention strategies, improved access to WM interventions is needed to reduce obesity levels.<br /><br />Copyright: © 2023 Coulman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Sep 2023; 20:e1004282</small></div>

<div><h4>Evaluating socioeconomic inequalities in influenza vaccine uptake during the COVID-19 pandemic: A cohort study in Greater Manchester, England.</h4><i>Watkinson RE, Williams R, Gillibrand S, Munford L, Sutton M</i><br /><b>Background</b><br />There are known socioeconomic inequalities in annual seasonal influenza (flu) vaccine uptake. The Coronavirus Disease 2019 (COVID-19) pandemic was associated with multiple factors that may have affected flu vaccine uptake, including widespread disruption to healthcare services, changes to flu vaccination eligibility and delivery, and increased public awareness and debate about vaccination due to high-profile COVID-19 vaccination campaigns. However, to the best of our knowledge, no existing studies have investigated the consequences for inequalities in flu vaccine uptake, so we aimed to investigate whether socioeconomic inequalities in flu vaccine uptake have widened since the onset of the COVID-19 pandemic.<br /><b>Methods and findings</b><br />We used deidentified data from electronic health records for a large city region (Greater Manchester, population 2.8 million), focusing on 3 age groups eligible for National Health Service (NHS) flu vaccination: preschool children (age 2 to 3 years), primary school children (age 4 to 9 years), and older adults (age 65 years plus). The sample population varied between 418,790 (2015/16) and 758,483 (2021/22) across each vaccination season. We estimated age-adjusted neighbourhood-level income deprivation-related inequalities in flu vaccine uptake using Cox proportional hazards models and the slope index of inequality (SII), comparing 7 flu vaccination seasons (2015/16 to 2021/22). Among older adults, the SII (i.e., the gap in uptake between the least and most income-deprived areas) doubled over the 7 seasons from 8.48 (95% CI [7.91,9.04]) percentage points to 16.91 (95% CI [16.46,17.36]) percentage points, with approximately 80% of this increase occurring during the pandemic. Before the pandemic, income-related uptake gaps were wider among children, ranging from 15.59 (95% CI [14.52,16.67]) percentage points to 20.07 (95% CI [18.94,21.20]) percentage points across age groups and vaccination seasons. Among preschool children, the uptake gap increased in 2020/21 to 25.25 (95% CI [24.04,26.45]) percentage points, before decreasing to 20.86 (95% CI [19.65,22.05]) percentage points in 2021/22. Among primary school children, inequalities increased in both pandemic years to reach 30.27 (95% CI [29.58,30.95]) percentage points in 2021/22. Although vaccine uptake increased during the pandemic, disproportionately larger increases in uptake in less deprived areas created wider inequalities in all age groups. The main limitation of our approach is the use of a local dataset, which may limit generalisability to other geographical settings.<br /><b>Conclusions</b><br />The COVID-19 pandemic led to increased inequalities in flu vaccine uptake, likely due to changes in demand for vaccination, new delivery models, and disruptions to healthcare and schooling. It will be important to investigate the causes of these increased inequalities and to examine whether these increased inequalities also occurred in the uptake of other routine vaccinations. These new wider inequalities in flu vaccine uptake may exacerbate inequalities in flu-related morbidity and mortality.<br /><br />Copyright: © 2023 Watkinson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Sep 2023; 20:e1004289</small></div>