PLOS Medicine recently published

by Naveed Sattar, Martin K. Rutter

Naveed Sattar and Martin K Rutter discuss the contributory role of obesity in the development and progression of cardiovascular disease, and prospects for tackling the obesity epidemic.

by Yafei Si, Lei Guo, Shu Chen, Xinyu Zhang, Xiaochen Dai, Daniel Wang, Yunguo Liu, Bach Xuan Tran, Paul Michael Pronyk, Shenglan Tang

Background

The Sustainable Development Goals (SDGs) articulate an ambitious global agenda and set of targets to achieve by 2030. Among the health-related SDGs, many formidable challenges remain in settings like the Association of Southeast Asian Nations (ASEAN) which face wide-ranging social, economic and health inequalities. In advance of the 2030 horizon, charting the trajectory of the health SDGs is critical for informing policy and programmatic course corrections to advance health and well-being among ASEAN’s 10 member countries with its 667 million people.

Methods and findings

We used estimates from the Global Burden of Disease (GBD) Study 2021 and surveillance data to identify 27 health-related SDG indicators. The indicators were classified into 7 thematic areas: (i) nutrition, (ii) maternal, child and reproductive health (MCH), (iii) infectious diseases, (iv) non-communicable diseases (NCDs), (v) environmental health, (vi) universal health coverage (UHC), and (vii) road injuries. We developed an attainment index ranging from 0 to 100 for each SDG indicator by referencing the SDG targets and projected their progress to 2030.We find an overall positive progress towards the health-related SDG targets in ASEAN from 1990 to 2030. At the aggregate level by 2030, 2 member countries, Singapore and Brunei, are projected to achieve their targets (attainment score ≥ 90). At a wider regional level, ASEAN is projected to make substantial progress in nutrition, MCH, and UHC, with a majority of countries projected to come close to or achieve their targets. However, progress is projected to be slower in the areas of reducing the incidence of infectious disease (i.e., HIV and AIDs, hepatitis B, TB, and neglected tropical diseases), NCD-related mortality and its risk factors (i.e., harmful alcohol use and smoking), environment-related mortality and its risk factors (i.e., unsafe water and poor hygiene, and air pollution), and road injuries. Substantial disparities are identified in the region, with Singapore, Brunei, Malaysia and Thailand generally performing better than elsewhere.A limitation of our study was its reliance on historical trends which may not fully capture future political, social, or technological changes.

Conclusions

As a regional bloc, ASEAN faces persistent challenges in achieving health-related SDG targets by 2030, with unequal progress between countries. Moreover, epidemiological transitions and worsening environmental threats further compound potential gains. At the country level, efforts to enhance health system financing, quality and equity will need to be coupled with wider approaches that address structural drivers of disease. Furthermore, coordinated regional efforts will be essential to effectively respond to emerging threats posed by pollution and environmental risks.

by Natasha L. Hezelgrave, Natalie Suff, Paul Seed, Vicky Robinson, Jenny Carter, Helena Watson, Alexandra Ridout, Anna L. David, Susana Pereira, Fatemeh Hoveyda, Joanna Girling, Latha Vinayakarao, Rachel M. Tribe, Andrew H. Shennan, The SuPPoRT Collaborating Team

by Teng-Li Lin, Yi-Hsuan Fan, Kuo-Sheng Fan, Chao-Kuei Juan, Yi-Ju Chen, Chun-Ying Wu

Background

Psoriasis is associated with various cardiovascular diseases (CVDs). The aim of this study was to compare the risk of CVD in patients with psoriasis who were prescribed biologics or oral therapies, and to assess the association between different classes of biologics and CVD risk.

Methods and Findings

This retrospective cohort study utilized the TriNetX Global Collaborative Network (2014–2025). Patients with psoriasis newly prescribed biologics (BIO-cohort) and those newly initiating oral anti-psoriatic drugs without biologic exposure (Non-BIO-cohort) were enrolled. A propensity score-matched analysis was conducted, accounting for age, sex, race, comorbidities, body mass index, serum lipid profile, and inflammatory marker levels. Cardiovascular risk was compared between the BIO- and Non-BIO-cohorts using Cox regression to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). After matching, each cohort comprised 12,732 patients, with approximately 50% being female, a mean age of 57 years, and 55% identifying as White. The 5-year cumulative incidence of any CVDs was significantly lower in the BIO-cohort (10.68%; 95% CI [10.03%, 11.36%]) than in the Non-BIO-cohort (16.17%; 95% CI: [15.34%, 17.05%]) (p < 0.001). The BIO-cohort had attenuated risks of any CVDs (HR 0.621; 95% CI [0.571, 0.676]), cerebrovascular diseases (HR 0.616; 95% CI [0.519, 0.731]), arrhythmias (HR 0.632; 95% CI [0.565, 0.706]), inflammatory heart diseases (HR 0.566; 95% CI [0.360, 0.891]), ischemic heart diseases (HR 0.579; 95% CI [0.465, 0.721]), heart failure (HR 0.637; 95% CI [0.521, 0.780]), non-ischemic cardiomyopathy (HR 0.654; 95% CI [0.466, 0.918]), thrombotic disorders (HR 0.570; 95% CI [0.444, 0.733]), peripheral arterial occlusive diseases (HR 0.501; 95% CI [0.383, 0.656]), and major adverse cardiac events (HR 0.697; 95% CI [0.614, 0.792]). Receiving only anti-tumor necrosis factor (TNF)-α (HR 0.886; 95% CI [0.807, 0.973]), anti-interleukin (IL)-17 (HR 0.724; 95% CI [0.599, 0.875]), or anti-IL-23 (HR 0.739; 95% CI [0.598, 0.914]) was associated with reduced risks of any CVDs, whereas no significant association was observed for only anti-IL-12/23 (HR 0.915; 95% CI [0.742, 1.128]). This risk reduction remained consistent across various subgroups, including age (≤45 or >45 years), sex (male or female), regions of research data (the United States, Europe, Middle East and Africa, and Asia-Pacific), and comorbidities (psoriatic arthritis, hypertension, diabetes, hyperlipidemia, overweight or obesity). Eight sensitivity analyses, such as extending the washout period or tightening medication definitions, validated our findings. The main limitation of our study is the observational design, which can only establish associations, not causation.

Conclusions

Patients with psoriasis prescribed biologics exhibited a lower risk of CVDs versus those on oral therapy. Anti-TNF-α, anti-IL-17, and anti-IL-23 were associated with decreased cardiovascular hazards, while anti-IL-12/23 was not.

by Global Health & Population Project on Access to Care for Cardiometabolic Diseases (HPACC)

Background

Diabetes mellitus, particularly type 2 diabetes, is a growing health concern in low- and middle-income countries (LMICs). The potential impact of newer diabetes medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, on insulin dosage and health outcomes in these settings is not well understood.

Methods and findings

We developed a microsimulation model to estimate the impact of treating patients with type 2 diabetes who use insulin with GLP-1 receptor agonists or SGLT-2 inhibitors in LMICs. The model utilized data from the Global Health and Population Project on Access to Care for Cardiometabolic Diseases (HPACC) dataset, encompassing surveys from 79 countries and clinical trial data to estimate insulin dose reduction. We incorporated weight-based insulin dosing formulas and hazard ratios for severe hypoglycemia, cardiovascular and renal outcomes, side effects of new therapies, and mortality. The primary outcome was the change in insulin dosage, and secondary outcomes were disability-adjusted life years (DALYs) lost per 1,000 person-years by diabetes complication (micro- and macro-vascular).Our results indicate that the addition of GLP-1 receptor agonists or SGLT-2 inhibitors could reduce insulin dosage by 8.2 IU/day (IQR: 6.9, 9.5) and 5.3 IU/day (IQR: 4.5, 6.2), respectively. The median DALYs lost per 1,000 person-years decreased from 2.20 (IQR: 1.49, 4.02) to 1.01 (IQR: 0.61, 1.86) with GLP-1 receptor agonists and 1.25 (IQR: 0.81, 2.29) with SGLT-2 inhibitors. Primary benefits arose from weight loss, decreased cardiorenal disease, and decreased mortality, with smaller DALY benefits from the prevention of severe hypoglycemia. Key limitations include the inability to differentiate between type 1 and type 2 diabetes in some datasets and reliance on assumptions from clinical trials conducted primarily in high-income countries.

Conclusions

The introduction of GLP-1 receptor agonists and SGLT-2 inhibitors for managing type 2 diabetes in LMICs could significantly reduce insulin dosage and associated health risks, leading to improved outcomes and reduced disability. These findings suggest that expanding access to these newer diabetes medications in LMICs could have substantial public health benefits.

by Chun-Hsien Lin, Meng Lee, Bruce Ovbiagele, David S. Liebeskind, Borja Sanz-Cuesta, Jeffrey L. Saver

Background

Endovascular thrombectomy (EVT) is the standard treatment for acute ischemic stroke due to internal carotid artery (ICA) or middle cerebral artery (MCA) M1 occlusion with a small ischemic core. However, the effect of EVT on acute stroke with a large ischemic core remains unclear. This study aimed to evaluate the association of EVT plus medical care versus medical care alone with outcomes in patients with acute stroke and a large ischemic core due to ICA or MCA M1 occlusion.

Methods and findings

PubMed, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1, 2000 to September 25, 2024. There were no language restrictions. Randomized controlled trials (RCTs) of patients with acute stroke and a large ischemic core that compared EVT plus medical care versus medical care alone were evaluated. We computed the random-effects estimate based on the inverse variance method. Risk ratio (RR) with 95% confidence interval (CI) was used to measure outcomes of EVT plus medical care versus medical care alone. The primary outcome was functional independence, defined as modified Rankin Scale (mRS) of 0–2 at 90 days post-stroke; and the lead secondary outcome was reduced disability, defined as ordinal shift of mRS. Safety outcomes were requiring constant care or death (mRS 5–6), death, and early symptomatic intracranial hemorrhage (sICH). Grading of Recommendations Assessment, Development and Evaluations (GRADE) was used to evaluate summaries of evidence for the outcomes. We included six RCTs comprising 1870 patients (826 females [44.2%]) with acute stroke and a larger moderate or large ischemic core due to ICA or MCA M1 occlusion. All patients were nondisabled before stroke. Pooled results showed that at 90 days post-stroke, EVT plus medical care, compared with medical care alone, was associated with greater functional independence (RR 2.53, 95% CI [1.95, 3.29]; p  < 0.001; number needed to treat [NNT], 9, 95% CI [6,15]) and reduced disability (common odds ratio 1.63, 95% CI [1.38, 1.93]; p < 0.001; NNT, 4 [minimum possible NNT, 2; maximum possible NNT, 6]). EVT plus medical care, compared with medical care alone, was associated with a lower risk of requiring constant care or death (RR 0.74, 95% CI [0.66, 0.84]; p  <  0.001; NNT, 7, 95% CI [6,11]). EVT plus medical care, compared with medical care alone, was associated with a nonsignificantly higher proportion of patients with early symptomatic intracranial hemorrhage (RR 1.65, 95% CI [1.00, 2.70]; p  =  0.05). The rates of death were not significantly different between the EVT plus medical care and medical care alone groups (RR 0.86, 95% CI [0.72, 1.02]; p  =  0.08). Main limitations include variability in imaging definitions of large core and inclusion of both larger moderate and large cores in the analysis.

Conclusions

Among patients with acute stroke and a larger moderate or large ischemic core due to ICA or MCA M1 occlusion who were nondisabled before stroke, EVT plus medical care, compared with medical care alone, may be associated with improved functional independence, reduced disability, and reduced rates of severe disability or death at 90 days post-stroke.PROSPERO registration number: CRD42024514605

by Anh Tran, Mahmoud Zureik, Jeanne Sibiude, Sara Miranda, Jérôme Drouin, Lise Marty, Alain Weill, Rosemary Dray-Spira, Xavier Duval, Sarah Tubiana

Background

While macrolides are among the frequently prescribed antibiotics for pregnant women, evidence of their fetal safety remains conflicting. This study aimed to evaluate the risk of major congenital malformations (MCM) after first-trimester exposure to macrolides compared with amoxicillin, focusing on specific MCM subtypes.

Methods and findings

This nationwide cohort study used data from the Mother-Child EPI-MERES Register nested in the French Health Data System (SNDS). Pregnancies linked with their singleton live-born infants from January 1, 2010, and December 31, 2020, were included. The macrolide exposure group comprised pregnancies with one or more prescriptions filled for systemic macrolides (erythromycin, spiramycin, roxithromycin, josamycin, clarithromycin, and azithromycin) during the first trimester. The comparator group comprised pregnancies exposed to amoxicillin during the first trimester. Adjusted relative risks (aRR) and 95% CI were estimated by log-binomial regression for any MCM overall and individual MCMs with a prevalence of at least one per 10,000 live-born infants in the macrolide exposure group. Among 7,644,579 eligible pregnancies, 140,708 exposed to macrolides and 592,652 exposed to amoxicillin were included. After adjustment for measured confounders, macrolide exposure during the first trimester was not associated with any MCM overall (aRR 1.00, 95% CI 0.96 to 1.05) compared with amoxicillin. Specifically, no increased risk was found for most individual MCMs. However, an increase in the risk for spina bifida (aRR 1.82, 95% CI 1.22 to 2.71) and syndactyly (aRR 1.65, 95% CI 1.06 to 2.58) was observed. The adjusted risk difference per 10,000 live-born infants was 1.15 (95% CI 0.26 to 2.05) for spina bifida and 0.87 (95% CI 0.01 to 1.72) for syndactyly. Sensitivity analyses consistently yielded elevated point estimates for these two MCMs, despite wide confidence intervals and small numbers of events. Residual confounding by indication is possible.

Conclusions

The findings indicate that macrolide exposure during the first trimester is not strongly associated with an increased risk for most individual MCMs, which is reassuring. However, an increased risk of spina bifida and syndactyly remains possible. Future studies are required to investigate these observations further as evidence continues to grow.

by Milou M. F. Schuurbiers, Christopher G. Smith, Koen J. Hartemink, Robert C. Rintoul, Davina Gale, Kim Monkhorst, Bas L. R. Mandos, Anna L. Paterson, Daan van den Broek, Nitzan Rosenfeld, Michel M. van den Heuvel, On Behalf of the LEMA Study Group and the LUCID Study Group

Background

Despite treatment with curative intent, many patients with localized non-small cell lung cancer (NSCLC) develop recurrence. The current challenge is to identify high-risk patients to guide adjuvant treatment. Identification of residual disease by detection of circulating tumor DNA (ctDNA) may allow more accurate clinical decision-making, but its reliability in NSCLC is not established. We aimed to build on previous data to validate a tissue-informed personalized ctDNA assay, to predict recurrence in patients with early-stage disease.

Methods and findings

Tumor tissue and plasma was collected from patients with stage 0–III NSCLC enrolled to LEMA (Lung cancer Early Molecular Assessment trial, NCT02894853). Serial plasma was collected before and after definitive treatment, with the latter including key timeframes of interest (1–3 days post-treatment, between 14 and 122 days after treatment end, and ≥14 days after treatment end). Somatic mutations identified by tumor exome sequencing were used to design patient-specific assays, to analyze ctDNA. Results were compared and combined with an independent dataset (LUCID; LUng Cancer CIrculating Tumour Dna study, NCT04153526). In LEMA, 130 patients (57% male; median age 66 years (range 44–82); 69% adenocarcinoma, 22% squamous cell carcinoma (SCC); 3%/49%/19%/29% with stage 0/I/II/III) were treated with curative intent. Tumor tissue originated from surgical resection or diagnostic biopsy in 118 and 12 patients respectively. LUCID included 88 patients (51% male; median age 72 years (range 44–88); 63% adenocarcinoma, 31% SCC; 49%/28%/23% with stage I/II/III). Before treatment, ctDNA was detected in 48% LEMA and 51% LUCID patients. Sensitivity, specificity, positive and negative predictive value of ctDNA detection post-treatment (≥1 positive sample ≥14 days after treatment end) to predict recurrence were 61%, 97%, 92% and 84% for LEMA and 64%, 96%, 90% and 83% for LUCID. In the combined cohort, ctDNA detection after treatment was associated with shorter recurrence-free survival (hazard ratio (HR) 11.4 (95% confidence interval (CI) [7.0,18.7]; p < 0.001)) and overall survival (HR 8.1 (95% CI [4.6,14.2]; p < 0.001)), accounting for guarantee-time bias. Of note, a key limitation of this work was the irregular sample collection schedules, during routine follow-up visits, of both studies.

Conclusions

ctDNA detection predicted recurrence in independent retrospective cohorts with notable reproducibility, including near-identical detection rates and predictive values, confirming its ability to differentiate patients at high- versus low risk of recurrence. Our results support the potential of tissue-informed ctDNA analysis as a decision-support tool for adjuvant therapy in NSCLC.

by Zhiwei Guo, Ke Wang, Xiang Huang, Kun Li, Guojun Ouyang, Xu Yang, Jiayu Tan, Haihong Shi, Liangping Luo, Min Zhang, Bowei Han, Xiangming Zhai, Jinhai Deng, Richard Beatson, Yingsong Wu, Fang Yang, Xuexi Yang, Jia Tang

Background

Preterm birth (PTB) occurs in approximately 11% of all births worldwide, resulting in significant morbidity and mortality for both mothers and their offspring. Identifying pregnancies at risk of preterm birth during early pregnancy may help improve interventions and reduce its incidence. Plasma cell-free DNA (cfDNA), derived from placenta and other maternal tissues, serves as a dynamic indicator of biological processes and pathological changes in pregnancy. These properties establish cfDNA as a valuable biomarker for investigating pregnancy complications, including PTB.

Methods and findings

To date, there are few methods available for PTB prediction that have been developed with large sample sizes, high-throughput screening, and validated in independent cohorts. To address this gap, we established a large-scale, multi-center case-control study involving 2,590 pregnancies (2,072 full-term and 518 preterm) from three independent hospitals to develop a spontaneous preterm birth classifier. We performed whole-genome sequencing on cfDNA, focusing on promoter profiling (read depth of promoter regions spanning from −1 to +1 kb around transcriptional start sites). Using four machine learning models and two feature selection algorithms, we developed classifiers for predicting preterm birth. Among these, the classifier based on the support vector machine model, named PTerm (Promoter profiling classifier for preterm prediction), exhibited the highest area under the curve (AUC) value of 0.878 (0.852–0.904) following leave-one-out cross-validation. Additionally, PTerm exhibited strong performance in three independent validation cohorts, achieving an overall AUC of 0.849 (0.831–0.866).

Conclusions

In summary, PTerm demonstrated high accuracy in predicting preterm birth. Additionally, it can be utilized with current non-invasive prenatal test data without changing its procedures or increasing detection cost, making it easily adaptable for preclinical tests.

by Sally Hopewell, An-Wen Chan, Gary S. Collins, Asbjørn Hróbjartsson, David Moher, Kenneth F. Schulz, Ruth Tunn, Rakesh Aggarwal, Michael Berkwits, Jesse A. Berlin, Nita Bhandari, Nancy J. Butcher, Marion K. Campbell, Runcie C. W. Chidebe, Diana Elbourne, Andrew Farmer, Dean A. Fergusson, Robert M. Golub, Steven N. Goodman, Tammy C. Hoffmann, John P. A. Ioannidis, Brennan C. Kahan, Rachel L. Knowles, Sarah E. Lamb, Steff Lewis, Elizabeth Loder, Martin Offringa, Philippe Ravaud, Dawn P. Richards, Frank W. Rockhold, David L. Schriger, Nandi L. Siegried, Sophie Staniszewska, Rod S. Taylor, Lehana Thabane, David Torgerson, Sunita Vohra, Ian R. White, Isabelle Boutron

Background

Well designed and properly executed randomised trials are considered the most reliable evidence on the benefits of healthcare interventions. However, there is overwhelming evidence that the quality of reporting is not optimal. The CONSORT (Consolidated Standards of Reporting Trials) statement was designed to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996, then updated in 2001 and 2010. Here, we present the updated CONSORT 2025 statement, which aims to account for recent methodological advancements and feedback from end users.

Methods

We conducted a scoping review of the literature and developed a project-specific database of empirical and theoretical evidence related to CONSORT, to generate a list of potential changes to the checklist. The list was enriched with recommendations provided by the lead authors of existing CONSORT extensions (Harms, Outcomes, Non-pharmacological Treatment), other related reporting guidelines (TIDieR) and recommendations from other sources (e.g., personal communications). The list of potential changes to the checklist was assessed in a large, international, online, three-round Delphi survey involving 317 participants and discussed at a two-day online expert consensus meeting of 30 invited international experts.

Results

We have made substantive changes to the CONSORT checklist. We added seven new checklist items, revised three items, deleted one item, and integrated several items from key CONSORT extensions. We also restructured the CONSORT checklist, with a new section on open science. The CONSORT 2025 statement consists of a 30-item checklist of essential items that should be included when reporting the results of a randomised trial and a diagram for documenting the flow of participants through the trial. To facilitate implementation of CONSORT 2025, we have also developed an expanded version of the CONSORT 2025 checklist, with bullet points eliciting critical elements of each item.

Conclusions

Authors, editors, reviewers, and other potential users should use CONSORT 2025 when writing and evaluating manuscripts of randomised trials to ensure that trial reports are clear and transparent.

by Ming Jun Kuck, Eef Hogervorst

Ming Jun Kuck and Eef Hogervorst consider the data on the safety and potential cognitive effects in later life of midlife menopausal hormone treatment in women.

by David Horner, Jens Richardt Møllegaard Jepsen, Bo Chawes, Rebecca Vinding, Julie B. Rosenberg, Parisa Mohammadzadeh, Yang Luo, Birgitte Fagerlund, Trine Flensborg-Madsen, Thomas Ragnar Wood, Janine F. Felix, Louise Monnerup, Birte Y. Glenthøj, Klaus Bønnelykke, Bjørn H. Ebdrup, Jakob Stokholm, Morten Arendt Rasmussen

Background

Early life is a critical period for neurodevelopment, where factors such as maternal nutrition and breastfeeding duration significantly impact the growth of head circumference and cognitive development in children. Our study aimed to explore the associations between maternal dietary patterns during pregnancy, duration of breastfeeding, and their impacts on child head circumference and cognitive outcomes.

Methods and findings

Our study utilised data from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort, which enrolled 700 mother–child pairs between 2008 and 2010 with 86% clinical follow-up at age 10. Pregnancy dietary patterns, described as ‘Varied’ and ‘Western,’ were derived from food frequency questionnaires and used to model quantitative metabolite scores via sparse partial least squares modelling of blood metabolome data. Cognitive development was assessed using the Bayley Scales of Infant Development at 2.5 years and the Wechsler Intelligence Scale for Children at age 10. Head circumference was measured from 20 weeks gestation to 10 years, and calibrated using related anthropometric measures. Growth trajectories were evaluated using linear mixed models and latent class trajectory models. Parental and child genetic influences for cognition and head circumference were controlled by including polygenic risk scores derived from genomic data. We found that a Western dietary pattern during pregnancy was associated with lower cognitive scores at age 2.5 (β −1.24 [−2.16, −0.32], p = 0.008) and reduced head circumference growth (p-interaction < 0.0001). We found that a Varied dietary pattern during pregnancy was associated with higher estimated intelligence quotient (IQ) at age 10 (β 1.29 [0.27, 2.3], p = 0.014). Additionally, head circumference growth was associated with higher cognitive scores at age 10 (β 3.40 [1.21, 5.60], p = 0.002), and it partly mediates the association between the Varied dietary pattern and estimated IQ (proportion mediated 13.5% [0.01, 0.71], p = 0.034). Extended breastfeeding duration was also independently associated with increased head circumference growth (p-interaction < 0.0001). These patterns and correlations were consistent even after adjusting for potential confounders and accounting for genetic influences.

Conclusions

Our findings reveal that a Western dietary pattern during pregnancy is associated with lower cognitive scores at age 2.5 and decreased head circumference growth, suggesting potential adverse impacts on early neurodevelopment. Conversely, a Varied dietary pattern is linked with a higher estimated IQ at age 10, with head circumference growth contributing to this positive outcome. These findings highlight the critical role of maternal nutrition during pregnancy, and duration of breastfeeding, in promoting optimal neurodevelopmental outcomes. Effective public health strategies should therefore focus on enhancing maternal dietary practices to support better cognitive and physical development in children.

by Marie Payen de la Garanderie, Anaïs Hasenbohler, Nicolas Dechamp, Guillaume Javaux, Fabien Szabo de Edelenyi, Cédric Agaësse, Alexandre De Sa, Laurent Bourhis, Raphaël Porcher, Fabrice Pierre, Xavier Coumoul, Emmanuelle Kesse-Guyot, Benjamin Allès, Léopold K. Fezeu, Emmanuel Cosson, Sopio Tatulashvili, Inge Huybrechts, Serge Hercberg, Mélanie Deschasaux-Tanguy, Benoit Chassaing, Héloïse Rytter, Bernard Srour, Mathilde Touvier

Background

Mixtures of food additives are daily consumed worldwide by billions of people. So far, safety assessments have been performed substance by substance due to lack of data on the effect of multiexposure to combinations of additives. Our objective was to identify most common food additive mixtures, and investigate their associations with type 2 diabetes incidence in a large prospective cohort.

Methods and Findings

Participants (n = 108,643, mean follow-up =  7.7 years (standard deviation (SD) =  4.6), age =  42.5 years (SD =  14.6), 79.2% women) were adults from the French NutriNet-Santé cohort (2009–2023). Dietary intakes were assessed using repeated 24h-dietary records, including industrial food brands. Exposure to food additives was evaluated through multiple food composition databases and laboratory assays. Mixtures were identified through nonnegative matrix factorization (NMF), and associations with type 2 diabetes incidence were assessed using Cox models adjusted for potential socio-demographic, anthropometric, lifestyle and dietary confounders. A total of 1,131 participants were diagnosed with type 2 diabetes. Two out of the five identified food additive mixtures were associated with higher type 2 diabetes incidence: the first mixture included modified starches, pectin, guar gum, carrageenan, polyphosphates, potassium sorbates, curcumin, and xanthan gum (hazard ratio (HR)per an increment of 1SD of the NMF mixture score = 1.08 [1.02, 1.15], p = 0.006), and the other mixture included citric acid, sodium citrates, phosphoric acid, sulphite ammonia caramel, acesulfame-K, aspartame, sucralose, arabic gum, malic acid, carnauba wax, paprika extract, anthocyanins, guar gum, and pectin (HR = 1.13 [1.08,1.18], p < 0.001). No association was detected for the three remaining mixtures: HR =  0.98 [0.91, 1.06], p = 0.67; HR =  1.02 [0.94, 1.10], p = 0.68; and HR =  0.99 [0.92, 1.07], p = 0.78. Several synergistic and antagonist interactions between food additives were detected in exploratory analyses. Residual confounding as well as exposure or outcome misclassifications cannot be entirely ruled out and causality cannot be established based on this single observational study.

Conclusions

This study revealed positive associations between exposure to two widely consumed food additive mixtures and higher type 2 diabetes incidence. Further experimental research is needed to depict underlying mechanisms, including potential synergistic/antagonist effects. These findings suggest that a combination of food additives may be of interest to consider in safety assessments, and they support public health recommendations to limit nonessential additives.

Trial Registration

The NutriNet-Santé cohort is registered at clinicaltrials.gov (NCT03335644). https://clinicaltrials.gov/study/NCT03335644.

by Heather Wightman, Elaine Butterly, Lili Wei, Ryan McChrystal, Naveed Sattar, Amanda Adler, David Phillippo, Sofia Dias, Nicky Welton, Andrew Clegg, Miles Witham, Kenneth Rockwood, David A. McAllister, Peter Hanlon

Background

The representation of frailty in type 2 diabetes trials is unclear. This study used individual participant data from trials of newer glucose-lowering therapies to quantify frailty and assess the association between frailty and efficacy and adverse events.

Methods and findings

We analysed IPD from 34 trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) receptor agonists, and dipeptidyl peptidase 4 (DDP4) inhibitors. Frailty was quantified using a cumulative deficit frailty index (FI). For each trial, we quantified the distribution of frailty; assessed interactions between frailty and treatment efficacy (HbA1c and major adverse cardiovascular events [MACE], pooled using random-effects network meta-analysis); and associations between frailty and withdrawal, adverse events, and hypoglycaemic episodes. Trial participants numbered 25,208. Mean age across the included trials ranged from 53.8 to 74.2 years. Using a cut-off of FI > 0.2 to indicate frailty, median prevalence was 9.5% (IQR 2.4%–15.4%). Applying a higher threshold of FI > 0.3, median prevalence was 0.5% (IQR 0.1%–1.5%). Prevalence was higher in trials of older people and people with renal impairment however, even in these higher risk populations, people with FI > 0.4 were generally absent. For SGLT2 inhibitors and GLP1 receptor agonists, there was a small attenuation in efficacy on HbA1c with increasing frailty (0.08%-point and 0.14%-point smaller reduction, respectively, per 0.1-point increase in FI), below the level of clinical significance. Findings for the effect of treatment on MACE (and whether this varied by frailty) had high uncertainty, with few events occurring in trial follow-up. A 0.1-point increase in the FI was associated with more all-cause adverse events regardless of treatment allocation (incidence rate ratio, IRR 1.44, 95% CI 1.35–1.54, p < 0.0001), adverse events judged to the possibly or probably related to treatment (1.36, 1.23, to 1.49, p < 0.0001), serious adverse events (2.09, 1.85, to 2.36, p < 0.0001), hypoglycaemia (1.21, 1.06, to 1.38, p = 0.012), baseline risk of MACE (hazard ratio 3.01, 2.48, to 3.67, p < 0.0001) and with withdrawal from the trial (odds ratio 1.41, 1.27, to 1.57, p < 0.0001). The main limitation was that the large cardiovascular outcome trials did not include data on functional status and so we were unable to assess frailty in these larger trials.

Conclusions

Frailty was uncommon in these trials, and participants with a high degree of frailty were rarely included. Frailty is associated very modest attenuation of treatment efficacy for glycaemic outcomes and with greater incidence of both adverse events and MACE independent of treatment allocation. While these findings are compatible with calls to relax HbA1c-based targets in people living with frailty, they also highlight the need for inclusion of people living with frailty in trials. This would require changes to trial processes to facilitate the explicit assessment of frailty and support the participation of people living with frailty. Such changes are important as the absolute balance of risks and benefits remains uncertain among those with higher degrees of frailty, who are largely excluded from trials.

by Christine Laine, Dianne Babski, Vivienne C. Bachelet, Till W. Bärnighausen, Christopher Baethge, Kirsten Bibbins-Domingo, Frank Frizelle, Laragh Gollogly, Sabine Kleinert, Elizabeth Loder, João Monteiro, Eric J. Rubin, Peush Sahni, Christina C. Wee, Jin-Hong Yoo, Lilia Zakhama

In this Editorial, representatives of the International Committee of Medical Editors discuss the need for multi-stakeholder involvement to recognize and counter the actions of predatory journals.

by Lin Geng, Lilith K. Whittles, Borame L. Dickens, Martin T. W. Chio, Yihao Chen, Rayner Kay Jin Tan, Azra Ghani, Jue Tao Lim

by Reina Tonegawa-Kuji, Yuan Hou, Bo Hu, Noah Lorincz-Comi, Andrew A. Pieper, Babak Tousi, James B. Leverenz, Feixiong Cheng

Background

While recently U.S. FDA-approved anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs) offer new treatment approaches for patients suffering from Alzheimer’s disease (AD), these medications also carry potential safety concerns and uncertainty about their efficacy for improving cognitive function. This study presents an updated meta-analysis of cognitive outcomes and side effects of anti-Aβ mAbs from phase III randomized controlled trials (RCTs) in patients with sporadic AD.

Methods and Findings

Phase III randomized, placebo-controlled blinded trials evaluating the efficacy and safety of anti-Aβ mAbs in patients with AD were identified through a search in clinicaltrials.gov, PubMed and Embase on January 14th, 2024. The retrieved studies were further screened from January 15th, 2024, to February 14th, 2024. We included studies that had been published in any language. Quality of trials was assessed using the Jadad score and publication bias was assessed using Egger’s test and Funnel plot. Primary outcomes were mean changes from baseline to post-treatment in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) and AD Assessment Scale-Cognitive Subscale (ADAS-Cog) scores, and secondary outcomes were adverse events, including amyloid-related imaging abnormalities with edema (ARIA-E), and ARIA with hemorrhage (ARIA-H). Random-effects meta-analysis and meta-regression analyses were conducted. The literature search identified 13 phase III RCTs, which included 18,826 patients with mild cognitive impairment or dementia due to AD. Compared with placebo, treatment with mAbs significantly improved cognitive performance on CDR-SB (mean difference −0.25, 95% confidence interval [CI] [−0.38, −0.11]) and ADAS-Cog (standardized mean difference −0.09, 95% CI [−0.12, −0.06]), in which a negative change indicates improvement for both scores. Meta-regression analysis suggested that trials enrolling patients with early-stage AD were associated with better efficacy. Elevated risk of ARIA-E (risk ratio [RR] 9.79, 95% CI [5.32,18.01]), ARIA-H (RR 1.94, 95% CI [1.47,2.57]), and headaches (RR 1.21, 95% CI [1.10,1.32]) were noted. Statistical heterogeneity was relatively high for ARIA-E and ARIA-H, leading to wide confidence intervals and considerable variability in effect sizes, though meta-regression was conducted to address this. Furthermore, differences in trial designs introduce limitations in cross-trial comparisons.

Conclusions

Anti-Aβ mAb therapy slows cognitive decline, but with small effect sizes, and raises potential concerns about ARIA and headaches.

by Melese Siyoum, Rahel Nardos, Biniyam Sirak, Theresa Spitznagle, Wondwosen Teklesilasie, Ayalew Astatkie

Background

Pelvic organ prolapse (POP) is a common condition that can significantly impact a woman’s quality of life. Pelvic floor muscle training (PFMT) is recommended as a first-line conservative treatment for prolapse, but evidence on its effectiveness from low-resource settings is limited. This study aimed to assess the effect of midwife-led PFMT on prolapse symptoms and health-related quality of life (HRQoL) among women with mild-to-moderate POP in Ethiopia.

Methods and findings

A community-based, parallel-groups, two-arm cluster-randomized controlled trial was conducted in Dale and Wonsho districts of Sidama Region, Ethiopia. Women with symptomatic POP stages I–III were randomized by cluster to receive either midwife-led PFMT plus lifestyle counseling (intervention group) or lifestyle counseling alone (control group). The participants and counselors knew what the women were receiving, but they were not aware of the other group. The outcome assessors, who collected data at the end of intervention, were blinded to the participants’ treatment allocation. The primary outcomes were changes in prolapse symptom score (POP-SS) and prolapse quality of life (P-QoL). Mixed-effects generalized linear model was used to determine the effect of PFMT on prolapse symptoms and P-QoL at 99% confidence level. Adjusted β coefficients were used as effect measures. The level of significance was adjusted for multiple comparisons.A total of 187 women were randomized to intervention (n = 86) from four clusters and control (n = 101) arms from another four clusters. At sixth months, the intervention group showed significantly greater improvements both in prolapse symptoms and P-QoL. The mean change difference in POP-SS was −4.11 (99% CI [−5.38, −2.83]; p <  0.001). Similarly, the mean change difference was: −8.86 (99% CI [−13.84, −3.89]; p < 0.001) in physical domain of P-QoL; −11.18 (99% CI [−15.03, −7.32]; p < 0.001) in psychological domain of P-QoL, and −9.01 (99% CI [−10.49, −5.54]; p < 0.001) in personal relationship domain of P-QoL. A significantly higher proportion (83.72%) of women in the intervention group perceived their condition as “better” after the intervention as compared to 41.58% in the control group. Women with earlier stages of prolapse (stages I and II) experienced higher benefits compared to those in stage III.

Conclusions

A midwife-led PFMT combined with lifestyle counseling significantly improves prolapse symptoms and quality of life in mild-to-moderate POP. This strategy can be integrated into the existing maternal and reproductive health programs to address POP in low-income settings where access to trained specialist is limited.

Trial registration

The trial was registered at the Pan African Clinical Trial Registry (https://pactr.samrc.ac.za) database, with the registration number PACTR202302505126575 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=24311).