2026-03-31
Christina Vogel, Sarah Crozier, Preeti Dhuria, Joanne Lord, Graham Moon, Wendy Lawrence, Janet Cade, Kylie Ball, Cyrus Cooper, Janis Baird
by Christina Vogel, Sarah Crozier, Preeti Dhuria, Joanne Lord, Graham Moon, Wendy Lawrence, Janet Cade, Kylie Ball, Cyrus Cooper, Janis Baird Background Previous product placement trials have been underpowered and limited in outcomes. This study assessed effects of positioning an expanded fruit and vegetable section near entrances on store-level sales, household-level purchasing and waste, and dietary behaviours. Methods and findings This prospective matched controlled cluster trial (NIHR 17/44/46) involved 36 stores (18 intervention and 18 control) of a discount supermarket chain in England. The study took place between March 2018 and May 2022, and the intervention was implemented for six months. Control stores were matched on store sales, customer profiles and neighbourhood deprivation. Women customers aged 18–60 years, with loyalty cards, who shopped at intervention ( n = 280) or control ( n = 300) stores agreed to participate. The primary outcome was household purchasing of fresh fruit and vegetables. Secondary outcomes included: i) differences in household purchasing by educational attainment, ii) store sales of fresh fruit and vegetables, iii) dietary quality score for woman, and iv) child aged 2−6 years (if relevant), and v) household fruit and vegetable waste. The proportion of households purchasing fruit and vegetables in intervention compared to control stores was very similar at baseline (−0.1% (95%CI −6.1%, 6.0%)). After 3 months of exposure to the intervention, the proportion was 0.6% (95%CI −5.6%, 6.7%; p = 0.83) and after 6 months the proportion was 3.3% (95%CI −2.5%, 9.2%; p = 0.23). Interrupted time series analyses showed differences in intervention compared to predicted store-level sales of fruit and vegetables were 0.32SDs (95%CI 0.11, 0.53; p = 0.002) at intervention implementation, equivalent to ~2,525 (95% CI 775, 4,115) extra portions per store, per week. The differences were 0.23SDs (95%CI −0.05, 0.52; p = 0.10) at 3 months and 0.18SDs (−0.16, 0.52); p = 0.29) at 6 months post-intervention. Not being able to randomise stores potentially biases the results through unmeasured confounding effects and findings related to intervention dose were not prespecified but determined from process evaluation findings investigating intervention implementation. Conclusions This study was conducted during the COVID-19 pandemic and cost-of-living crisis when population level fruit and vegetable sales and intake declined and recruitment to research was challenging. Despite these circumstances, the results of this study show that positioning produce sections near supermarket entrances may improve the nutrition profile of store sales, household purchasing and women’s dietary quality. Trial registration NCT03573973.
DOI: 10.1371/journal.pmed.10045752026-03-27
John L. Gittleman
by John L. Gittleman Long recognized as a breakthrough approach, One Health has been slow and piecemeal to infiltrate medical fields. Growing evidence suggests that it’s time for change by taking on a new patient—the environment. Long recognized as a breakthrough synthetic approach, One Health has been slow and piecemeal to infiltrate medical fields. In this Perspective, John Gittleman argues that it’s time for change by taking on a new patient - the environment.
DOI: 10.1371/journal.pmed.10050422026-03-26
Binh Nguyen, Katherine B. Owen, Mengyun Luo, Wendy Brown, Gregore I. Mielke, Philip J. Clare, Ding Ding
by Binh Nguyen, Katherine B. Owen, Mengyun Luo, Wendy Brown, Gregore I. Mielke, Philip J. Clare, Ding Ding Background Long-term causal evidence comparing different physical activity patterns and mortality outcomes is needed. Using observational data to emulate an RCT, this study compared different physical activity patterns over 15 years in relation to mortality from all causes, cardiovascular disease (CVD) and cancer in mid-aged Australian women. Methods and findings A target trial emulation framework was used to emulate an RCT, based on data collected every 3 years (nine surveys between 1996 and 2019) from 11,169 women in the Australian Longitudinal Study on Women’s Health (ALSWH; 1946−51 cohort). Two emulated interventions were compared against consistent non-adherence (control) to WHO moderate-to-vigorous physical activity (MVPA) recommendations during the 15-year ‘exposure period’: (1) consistent adherence to recommendations (at least 150 min/week) over 15 years (2001−2016; women were 50−55–65−70 years); and (2) starting to meet the recommendations at age 55, 60, or 65 years. Analyses were adjusted for sociodemographic and health variables using marginal structural models with the assumptions of conditional exchangeability, positivity, consistency, and no interference. Mortality outcomes that occurred between surveys 4−9 (women were 53−58 to 68−73 years), were ascertained from Australian death registries. Comparing consistent adherence to MVPA recommendations with consistent non-adherence, there was evidence (Bayes factor [BF] = 5.71) for a protective effect for all-cause mortality (risk ratio [RR]: 0.50, 99.5% CI [0.27, 0.94]; risk difference [RD]: −5.2%, 99.5% CI [−10.5%, 0.1%]). Findings for CVD (BF = 2.05; RR: 0.50, 99.5% CI [0.19, 1.30]; RD: −2.1%, 99.5% CI [−5.3%, 1.1%]) and cancer mortality (BF = 2.26; RR: 0.35, 99.5% CI [0.10, 1.17]; RD: −3.3%, 99.5% CI [−8.4%, 1.9%]) were more uncertain and less conclusive, as were those for an effect of starting to meet MVPA recommendations in the mid-fifties on mortality outcomes. The main study limitations included reliance of self-reported physical activity and that findings may not be generalisable to all mid-aged Australian women. Conclusions Based on findings from this target trial emulation, women should be encouraged to meet physical activity recommendations throughout mid-age to derive mortality benefits.
DOI: 10.1371/journal.pmed.10049762026-03-24
Jonathan P. Evans, Joanna McLaughlin, Jonathan T. Evans
by Jonathan P. Evans, Joanna McLaughlin, Jonathan T. Evans Joint replacement surgery transforms lives for patients with higher body mass index (BMI). Strong evidence shows safe outcomes and meaningful benefit, yet access remains restricted by BMI alone, an approach that risks stigma, inequity, and avoidable harm. In this Perspective, Jonathan Evans and colleagues discuss why restricting access to joint replacement surgery based on BMI alone is not supported by evidence, and highlight how such restrictions risk exacerbating stigma, inequity and avoidable harm to those who would benefit from surgery.
DOI: 10.1371/journal.pmed.10050032026-03-24
Pyry N. Sipilä, Kaarina Korhonen, Joni V. Lindbohm, Mika Kivimäki, Pekka Martikainen
by Pyry N. Sipilä, Kaarina Korhonen, Joni V. Lindbohm, Mika Kivimäki, Pekka Martikainen Background Severe infections have been linked to an increased risk of dementia, but both conditions often coexist with other illnesses that may confound this association. Using nationwide Finnish health registry data, we examined the role of noninfectious mental and physical illnesses in the association between severe infections and dementia. Methods and findings This register-based study included 62,555 individuals aged 65 or older in Finland in 2016 who were diagnosed with late-onset dementia between 2017 and 2020 and 312,772 dementia-free controls matched for year of birth, sex, and the follow-up period. Analyses were adjusted for education, marital status, employment, and area of residence, with age and sex accounted for through the matched conditional design and analysis. Applying a 1-year lag period, we identified 29 hospital-treated diseases that occurred 1–21 years before dementia diagnosis in cases (or index date in controls), had a prevalence of ≥ 1% prior to dementia, and were robustly associated with increased dementia risk (confounder-adjusted rate ratio ≥ 1.20, p p p p p Conclusions This nationwide Finnish study identified several mental and physical diseases that are associated with an increased risk of dementia and showed that the increased incidence of dementia among individuals with severe infections is not attributable to these comorbid conditions. These results support the role of severe infections as independent risk factors for dementia.
DOI: 10.1371/journal.pmed.10046882026-03-17
Ann M. Weber, Gary L. Darmstadt
by Ann M. Weber, Gary L. Darmstadt Benchmarking life expectancy against what is achievable reveals how sex disadvantage shifts by age, place, and time, and reframes inequality as unrealized potential due to social and structural constraints rather than differences in biology. In this Perspective article, Ann Weber and Gary Darmstadt discuss how benchmarking life expectancy against what is achievable reveals how sex disadvantage shifts by age, place, and time, and reframes inequality as unrealized potential due to social and structural constraints rather than differences in biology.
DOI: 10.1371/journal.pmed.10049872026-03-17
Yulu Zheng, Jae Jeong Yang, Deepak K. Gupta, David M. Herrington, Bing Yu, Ngoc Quynh H. Nguyen, Rui Pinto, Ioanna Tzoulaki, Hui Cai, Qiuyin Cai, Loren Lipworth, Xiao-Ou Shu, Wei Zheng, Danxia Yu
by Yulu Zheng, Jae Jeong Yang, Deepak K. Gupta, David M. Herrington, Bing Yu, Ngoc Quynh H. Nguyen, Rui Pinto, Ioanna Tzoulaki, Hui Cai, Qiuyin Cai, Loren Lipworth, Xiao-Ou Shu, Wei Zheng, Danxia Yu Background Despite growing evidence linking gut microbiota and microbial metabolites to human cardiometabolic health, few studies have systematically examined associations between circulating microbial metabolites and incident coronary heart disease (CHD). Methods and findings We conducted a multi-stage metabolomics study involving five prospective cohorts. Discovery involved untargeted plasma metabolite profiling of 896 incident cases and 896 age-/sex-/race-matched controls (~300 pairs per race: Black, White, Asian) from the Southern Community Cohort Study (SCCS; baseline: 2002–2009) and the Shanghai Women’s Health Study and Shanghai Men’s Health Study (SWHS/SMHS; baseline: 1996–2000 and 2002–2006). In-silico validation was conducted in the Atherosclerosis Risk in Communities Study (ARIC; N = 3,539; 663 cases; baseline: 1987–1989) and Multi-Ethnic Study of Atherosclerosis (MESA; N = 3,860; 446 cases; baseline: 2000–2002). Lastly, a quantitative assay was developed and applied to a new set of 864 cases and 864 age-/sex-/race-matched controls (~260−340 pairs per race) from the SCCS and SWHS/SMHS. Conditional logistic regression estimated odds ratios (ORs) of incident CHD per standard deviation (SD) metabolite increase in discovery and quantitative stages with a nested case-control design. Cox regression was used in ARIC and MESA with a cohort design. Similar covariates were adjusted across stages, including age, sex (if applicable), race (if applicable), education, income, smoking status, alcohol consumption, physical activity, diet quality, and body mass index (BMI). The mean (SD) time between enrollment and CHD diagnosis was 5.6 (3.8), 6.9 (4.4), 15.0 (7.4), and 8.0 (4.9) years in the SCCS, SWHS/SMHS, ARIC, and MESA, respectively. The discovery stage identified 73 circulating microbiota-related metabolites associated with incident CHD (false discovery rate p trans- 4-hydroxyproline, and 3-hydroxybutyrate; OR per SD ranged from 1.18 to 1.27 after adjustment for sociodemographics, lifestyles, and BMI. The targeted assay measured eight other promising microbial metabolites, four of which were significant: trimethylamine N-oxide, phenylacetyl-L-glutamine, 4-hydroxyhippuric acid, and indolepropionate. Most associations were consistent across participant subgroups by demographics, lifestyles, metabolic disease history, family CHD history, and follow-up time, although some potential effect modifications were found by race, age, obesity status, and follow-up time. The main limitations of the study are the observational design and the inability to validate all significant metabolites due to differences in metabolomic assay coverage across the three stages. Conclusions We identified and validated circulating gut microbial metabolites associated with incident CHD across diverse populations. Our findings offer novel epidemiological evidence on the importance of gut microbial metabolism in CHD development and highlight specific metabolites to prioritize for mechanistic investigation, biomarker validation, and therapeutic development.
DOI: 10.1371/journal.pmed.10047502026-03-13
George Davey Smith, Gibran Hemani, Shah Ebrahim
by George Davey Smith, Gibran Hemani, Shah Ebrahim The explosion of Mendelian Randomization (MR) submissions of dubious quality to journals globally is well recognized. Contributing to this deluge of publications may be the poor understanding among practitioners, reviewers, and editors of gene-environment equivalence, the fundamental principle of MR. In this Perspective, George Davey Smith and colleagues outline how and why gene-environment equivalence, the fundamental principle of Mendelian Randomization (MR), must be properly applied and critically considered in MR studies.
DOI: 10.1371/journal.pmed.10050132026-03-10
David B. Page, Michael Simanonok, Douglas A. Hanes, Alan Su
by David B. Page, Michael Simanonok, Douglas A. Hanes, Alan Su Digitally automated spatial profiling of immune-tumor cell interactions using multispectral immunofluorescence holds promise as a biomarker to predict outcomes in early-stage breast cancer, but prospective validation and harmonization with existing biomarkers is necessary before clinical adoption. In this Perspective, David Page and colleagues discuss how spatially profiling immune-tumor cell interactions using multispectral immunofluorescence analyses holds promise as a biomarker to predict outcomes in early-stage breast cancer.
DOI: 10.1371/journal.pmed.10049792026-03-06
Shih-Chieh Shao, Daniel Hsiang-Te Tsai, Albert Tzu-Ming Chuang, Kuan-Hung Liu, Edward Chia-Cheng Lai
by Shih-Chieh Shao, Daniel Hsiang-Te Tsai, Albert Tzu-Ming Chuang, Kuan-Hung Liu, Edward Chia-Cheng Lai Background Recent studies have suggested potential effects on magnesium homeostasis associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). We sought to determine whether these effects lead to a reduced risk of hypomagnesemia among adults with type 2 diabetes in clinical practice. Methods and findings We conducted a target trial emulation study using the multi-institutional cohort data from the TriNetX Global Collaborative Network. We compared 1:1 propensity score-matched patients with type 2 diabetes newly initiating SGLT2 inhibitors versus dipeptidyl peptidase-4 (DPP4) inhibitors ( n = 718,798), GLP-1 RAs versus DPP4 inhibitors ( n = 623,390), and SGLT2 inhibitors versus GLP-1 RAs ( n = 702,808) from 2016 to 2024. Propensity scores were estimated using logistic regression models that included baseline covariates such as age, sex, race, comorbidities, and medication and laboratory data. In each comparison, patients receiving DPP4 inhibitors were considered the active-comparator group. The primary outcome was incident hypomagnesemia, defined by clinical diagnosis or serum magnesium p p p Conclusions Treatment with SGLT2 inhibitors and GLP-1 RAs was associated with a lower risk of hypomagnesemia, compared with DPP4 inhibitors. These findings suggest that SGLT2 inhibitors and GLP-1 RAs may be preferable options for patients at risk of hypomagnesemia.
DOI: 10.1371/journal.pmed.10049682026-03-02
Alexandra Tosun, on behalf of the PLOS Medicine Staff Editors
by Alexandra Tosun, on behalf of the PLOS Medicine Staff Editors Despite affecting 190 million women worldwide, endometriosis remains underdiagnosed, under-researched, and underfunded. Tackling awareness gaps, diagnostic delays, and inadequate treatment requires earlier education, increased funding, and recognition of endometriosis as a systemic disease—redefining pain, equity, and investment in women’s health. In recognition of Endometriosis Awareness Month, this Editorial by Alexandra Tosun discusses why raising awareness and education of endometriosis, as well as increasing funding and research for this systemic condition, are imperative to redefining pain, equity, and investment in women’s health.
DOI: 10.1371/journal.pmed.1004981