PLoS Med. [JOURNAL]
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200 papers
Correction: Natural cycle versus hormone replacement therapy as endometrial preparation in ovulatory women undergoing frozen-thawed embryo transfer: The COMPETE open-label randomized controlled trial.
PLOS Medicine Staff
PLoS Med · 2025 Dec · PMID 41364624 · Full text
[This corrects the article DOI: 10.1371/journal.pmed.1004630.].
[This corrects the article DOI: 10.1371/journal.pmed.1004630.].
Impact of combined hormonal contraceptives and metformin on metabolic syndrome in women with hyperandrogenic polycystic ovary syndrome and obesity: The COMET-PCOS randomized clinical trial.
Dokras A, Coutifaris C, Remaley AT … +6 more , Mehta NN, Playford MP, Kunselman AR, Stetter CC, Dodson WC, Legro RS
PLoS Med · 2025 Dec · PMID 41359669 · Full text
BACKGROUND: The risk-to-benefit ratio of using combined oral contraceptive pills (COCPs) and/or metformin for comprehensive management of polycystic ovary syndrome (PCOS) in women with obesity is unclear. As there is a l...
BACKGROUND: The risk-to-benefit ratio of using combined oral contraceptive pills (COCPs) and/or metformin for comprehensive management of polycystic ovary syndrome (PCOS) in women with obesity is unclear. As there is a lack of robust evidence on the impact of these first-line medications on cardiovascular disease (CVD) risk, we compared the effect of COCPs, metformin or both on prevalence of metabolic syndrome (MetS) in participants with hyperandrogenic PCOS and hypothesized that COCPs would increase prevalence of MetS while metformin would decrease prevalence of MetS. METHODS AND FINDINGS: We conducted a multicenter, double-blind, double-dummy, randomized trial (COMET-PCOS) in participants between ages ≥18 and ≤40 years and body mass index (BMI) ≥25 kg/m2 and ≤ 48 kg/m2 with hyperandrogenic PCOS (defined by the Rotterdam criteria). Participants were randomized 1:1:1 to 24 weeks of low-dose COCPs (20 μg ethinyl estradiol/0.15 mg desogestrol), metforminXR (2,000 mg), or both (Combined). The primary outcome, assessed by intention-to-treat analysis, was the effect of the different treatment groups on the prevalence of MetS at the end of study. The analytical model included site, race, and the presence or absence of MetS at the screening visit as covariates. The secondary outcomes included changes in each component of MetS (TG, HDL-C, BP, WC, and fasting glucose levels) over the study period. Of the 240 participants randomly assigned, 20 out of 79 in the COCP group, 16 out of 81 in the metformin group, and 17 out of 80 in the combined group dropped out of the study. A total of 169 participants (70.4%) completed the trial between January 2018 and June 2023 (mean age: 29.5 years; mean BMI: 35.6 kg/m2; 70% were White and 23% were Black). The overall prevalence of MetS was 31% at baseline and comparable across groups. At the end of the study, the prevalence of MetS was 26.2% (17/65) in the metformin group, 28.6% (17/59) in the Combined group, and 28.8% (17/59) in COCP group with no significant difference in trend of MetS prevalence between groups (adjusted p = 0.26). Waist circumference (mean change (MC) -2.23 cm; 95% CI [-3.98, -0.49]; p = 0.01), BMI (MC -0.49 kg/m2; 95% CI [-0.88, -0.10]; p = 0.01), and android fat mass measured by DXA (MC -167 g; 95% CI [-264, -71[; p < 0.001) decreased in the COCP group over the study period whilst there was no statistically significant changes in these parameters in the metformin only group when compared to baseline.. In the metformin and Combined groups, the majority of participants (>64%) reported diarrhea, while 24.1% in the COCP group reported uterine bleeding. The main methodologic limitation of the study is the potential lack of power to detect differences in secondary outcomes. CONCLUSIONS: In participants with hyperandrogenic PCOS and overweight/obesity, low-dose COCPs effectively managed PCOS symptoms without increasing prevalence of MetS. Our findings challenge the current practice of using metformin alone or with COCPs for lowering cardiometabolic risk. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT03229057.
Ultrasensitive quantification of serum IFN-α and IFN-γ in systemic lupus erythematosus: A cross-sectional observational study.
González-Gay MÁ, Gómez-Bernal F, Quevedo-Abeledo JC … +11 more , Almeida-Santiago C, Heras-Recuero E, Torres-Roselló A, de Vera-González A, Tejera-Segura B, García-Barrera E, Blázquez-Sánchez T, Villar LM, Ocejo-Vinyals JG, Largo R, Ferraz-Amaro I
PLoS Med · 2025 Dec · PMID 41348830 · Full text
BACKGROUND: Interferon (IFN) has been implicated in the pathogenesis of patients with systemic lupus erythematosus (SLE). However, its measurement in serum has been limited by low circulating levels that fall below the d...
BACKGROUND: Interferon (IFN) has been implicated in the pathogenesis of patients with systemic lupus erythematosus (SLE). However, its measurement in serum has been limited by low circulating levels that fall below the detection threshold of standard laboratory assays. In this study, we measured serum levels of IFN-alpha (IFN-α) and IFN-gamma (IFN-γ) using a novel ultrasensitive assay. We then aimed to analyze the relationship between these IFN levels and a broad spectrum of disease characteristics, including indices of disease activity and remission, and autoantibodies profiles. METHODS AND FINDINGS: From an initial cohort of 400 patients, a total of 313 patients with SLE were recruited in this cross-sectional study from September 2023 to February 2024. A comprehensive characterization of the patients was performed, including autoantibody profiles and indices of disease activity (SLE-DAS, SLEDAI-2K, and LLDAS), damage (SLICC-DI), and remission (DORIS). IFN-α and IFN-γ serum levels were measured using Simoa (Single Molecule Array) technique. A multivariable linear regression analysis was performed to examine the associations between the disease characteristics and circulating IFN-α and IFN-γ as the dependent variables. Besides, the diagnostic capacity of serum IFN levels to discriminate between high and low disease activity was studied using area under the curve analysis and determination of optimal cutoff points. Serum levels of IFN-α and IFN-γ showed a significant, albeit weak, correlation (Pearson's r = 0.369, p < 0.001). Both IFNs exhibited minimal associations with demographic characteristics (such as age, sex, and body mass index) and traditional cardiovascular risk factors (including hypertension, diabetes, dyslipidemia, smoking status, obesity, and metabolic syndrome). After multivariable adjustment, IFN-α-but not IFN-γ-was significantly and positively associated with acute-phase reactants (C-reactive protein and interleukin-6), disease activity indices (SLEDAI-2K, beta coefficient: 0.20 [95% confidence interval 0.09, 0.32] log pg/ml, p < 0.001 and SLE-DAS, beta coefficient: 0.15 [95% confidence interval 0.05, 0.25] log pg/ml, p = 0.003) and the presence of antinuclear antibodies. In contrast, remission (as defined by DORIS) and low disease activity (LLDAS) were negatively and significantly associated with IFN-α levels after adjustment for covariates. However, when attempts were made to define IFN cutoff values to discriminate between active and inactive disease or remission, they exhibited a poor balance between sensitivity and specificity. The cross-sectional design of this study limits our ability to infer causality and raises the possibility of reverse causation. CONCLUSIONS: In this study, we observed that IFN-α, but not IFN-γ, significantly associates with inflammation, indices of disease activity and remission, and autoantibody status in SLE. Investigating the potential of IFN-α as a biomarker for treatment response and long-term outcomes is warranted.
Wildfire-related PM2.5 and respiratory transmitted disease among Chinese children and adolescents from 2008 to 2019: A retrospective study.
Chen L, Xu R, Xie J … +20 more , Xing Y, Wen B, Wu Y, Su B, Geng M, Ren X, Zhang Y, Liu J, Song X, Qin Y, Wang R, Jiang J, Guo T, Yuan W, Ma Y, Dong Y, Song Y, Ma J, Li S, Guo Y
PLoS Med · 2025 Dec · PMID 41348817 · Full text
BACKGROUND: Exposure to fine particles (PM2.5) from wildfires is known to cause deaths and chronic diseases, but its effect on respiratory infections, especially in children and adolescents, is not well characterized. We...
BACKGROUND: Exposure to fine particles (PM2.5) from wildfires is known to cause deaths and chronic diseases, but its effect on respiratory infections, especially in children and adolescents, is not well characterized. We aimed to comprehensively assess the association between short-term exposure to wildfire-related PM2.5 and the incidence and mortality of respiratory transmitted diseases in children and adolescents. METHODS AND FINDINGS: Data on daily counts of incident and mortality cases of respiratory transmitted diseases in persons aged 4-24 years old were collected from China Information System for Disease Control and Prevention, covering 501 cities from 2008 to 2019. Daily concentrations of wildfire-related PM2.5 were estimated using machine learning and chemical transport models at a 0.25°×0.25° spatial resolution. We used time-stratified case-crossover design with conditional logistic regression to estimate the association between short-term exposures to wildfire-related PM2.5 and incidence and mortality of respiratory transmitted diseases, adjusting for temperature, relative humidity, precipitation, and total PM2.5. There were 6,089,271 incident cases and 1,034 mortality cases of 10 respiratory transmitted diseases included in our analyses. Each 5 μg/m3 increase in the lag 0-28-day (average of current day and previous 28 days) for wildfire-related PM2.5 was associated with a 6.8% (95%CI: 5.0%, 8.7%) increase in the daily incidence rate of respiratory transmitted diseases, which is greater than that of a 1.2% (1.0%, 1.4%) increase associated with the same increase of non-wildfire-related PM2.5. A 5 μg/m3 increase in wildfire-related PM2.5 was associated with a 28.6% (21.0%, 36.8%), 5.2% (2.3%, 8.3%), 12.6% (9.5%, 15.8%), and 13.6% (5.6%, 22.2%) increase in the incidence of seasonal influenza, scarlet fever, rubella, and measles, respectively. Although wildfire-related PM2.5 constitutes only 2.7% of the total PM2.5, it contributes significantly to respiratory transmitted diseases, accounting for 10.8% of all PM2.5-associated cases. In areas where the annual concentration of wildfire-related PM2.5 is lower than 1.5 μg/m3, the proportion of cases associated with wildfire-related PM2.5 reached 29.7%. Study limitations include potential exposure misclassification from using city-average wildfire PM2.5 as a proxy for individual exposure and an inability to adjust for some potential confounders. CONCLUSIONS: Short-term exposure to wildfire-related PM2.5 was associated with increased incidence of respiratory transmitted diseases, surpassing the impact observed with non-wildfire-related PM2.5. This phenomenon is not restricted to regions with high pollutant concentrations; even populations residing in areas with lower concentrations of wildfire-related PM2.5 are at an increased risk of these respiratory conditions. Consequently, there emerges a pressing global imperative to confront the escalating challenges presented by climate change and the intensifying menace of wildfires.
Social and health system factors associated with maternal mortality in Eastern and Western China: Population health estimates using provincial-level data.
Zeng X, Yang D, Li S … +4 more , Hua X, Wang Y, Zhang J, Liu Z
PLoS Med · 2025 Dec · PMID 41343599 · Full text
BACKGROUND: Globally, maternal mortality is off track in achieving the Sustainable Development Goals by 2030. Over the past two decades, China has dramatically reduced maternal mortality in more developed (eastern) and l...
BACKGROUND: Globally, maternal mortality is off track in achieving the Sustainable Development Goals by 2030. Over the past two decades, China has dramatically reduced maternal mortality in more developed (eastern) and less developed (western) regions. An understanding of the social and health system factors associated with maternal mortality in China may be helpful for countries attempting to meet the 2030 targets and beyond. METHODS AND FINDINGS: We analyzed provincial-level data on maternal mortality and social and health system factors from the National Health Statistics Yearbooks and China Statistical Yearbooks from 2004 to 2020. We investigated the factors associated with maternal mortality before and after 2013, the year that a historic national program, Reducing Maternal Mortality and Eliminating Neonatal Tetanus, came to an end. Bayesian kernel machine regression was employed to analyze social and health system factors (urbanization rate, per capita disposable income, average years of schooling, number of health technical personnel in maternal and child healthcare, number of hospital beds for obstetrics and gynecology, local fiscal expenditure on healthcare, prenatal booking rate, antenatal care rate, and hospital delivery rate) as a mixture and identify the factors with larger posterior inclusion probability and a higher value of the exposure-response relationship for the total and cause-specific maternal mortality. In the East, an increase in hospital delivery rate correlated with the decrease in total maternal mortality [posterior mean and standard deviation (SD): -14.8(1.5)] before 2013, and the urbanization rate was negatively associated with total maternal mortality [posterior mean and SD: -3.9(0.6)] after 2013. Hospital delivery, urbanization, local fiscal expenditure on healthcare, and antenatal care were the factors associated with reduced cause-specific maternal mortality in the East. In the West, an increase in antenatal care rate was associated with reduced total maternal mortality, with the posterior mean and SD of -33.8(6.8) and -11.5(4.1) before and after 2013, respectively. Hospital delivery and antenatal care were the factors associated with reduced cause-specific maternal mortality in the West. The main limitation of this study was the data constraints in the national statistics. CONCLUSIONS: Coverage of maternal care, health financing, and urbanization were the factors associated with the substantial reduction in maternal deaths in Eastern and Western China during 2004-2020. The improvement of the quantity and quality of antenatal care and hospital delivery may be a viable policy priority in less developed regions worldwide.
Setting the standard for high-quality studies using open health datasets.
Cunha A, de Bruijn S, Farrell A … +3 more , Lumbard H, Tosun A, Routledge D
PLoS Med · 2025 Dec · PMID 41343539 · Full text
Large open health datasets present unique opportunities for studies that when well-designed, conducted, and reported, can offer valuable contributions to health and medicine. However, recent years have seen a concerning...
Large open health datasets present unique opportunities for studies that when well-designed, conducted, and reported, can offer valuable contributions to health and medicine. However, recent years have seen a concerning proliferation of analyses lacking robust or novel findings. In this Editorial, we provide guidance to authors for conducting and reporting high-quality secondary analyses using these datasets.
Association of hydralazine use with risk of hematologic neoplasms in patients with hypertension: A nationwide population-based cohort study in Taiwan.
Wang LT, Chien WC, Ma KS … +4 more , Chung CH, Chen YC, Tsai WC, Yang BH
PLoS Med · 2025 Dec · PMID 41343491 · Full text
BACKGROUND: Onco-hypertension recognizes well-controlled blood pressure as a favorable prognostic factor for survival in patients with hypertension and solid tumors, including hematologic neoplasms. However, it remains u...
BACKGROUND: Onco-hypertension recognizes well-controlled blood pressure as a favorable prognostic factor for survival in patients with hypertension and solid tumors, including hematologic neoplasms. However, it remains unknown whether continuous use of hydralazine-an antihypertensive agent (AHA) with notable anti-neoplastic activity-is associated with a lower risk of hematologic neoplasms compared to other AHAs. METHOD AND FINDINGS: Utilizing Taiwan's National Health Insurance Research Database, we conducted a 16-year follow-up study (2000-2015) involving 375,107 patients with hypertension treated with an AHA for ≥180 days. The patients with hypertension were divided into two groups based on hydralazine prescription duration: an exposure group (hydralazine ≥180 days; n = 59,786) and a reference group (hydralazine <180 days; n = 239,144) after 1:4 matching for sex, age, and index date with the exposure group. Both groups were well-matched, with a mean age of approximately 60.8 years and 52.19% male. We assess the association between hydralazine use and the risk of hematologic neoplasms using Kaplan-Meier analysis and multivariable Cox proportional hazards regression, with models adjusted for concomitant medications possessing potential anti-neoplastic properties. The 16-year cumulative incidence of hematologic neoplasms was lower in the exposure group (105.58 per 100,000 person-years) than in the reference group (160.33). Accounting for death as competing risk, the exposure group exhibited an adjusted subdistribution hazard ratio (adjusted sHR) of 0.789 (95% confidence interval [0.667,0.913]; P < .001) for hematologic neoplasms compared to the reference group. Subgroup analyses demonstrated that the association with a lower risk was strongest in the longest prescription duration category. For example, for patients with prescription durations of ≥668 days, the adjusted sHR was 0.448 (95% CI [0.366,0.555]; P < .001) for other malignant neoplasms of lymphoid and histiocytic tissue, 0.552 (95% CI [0.453,0.683]; P < .001) for multiple myeloma and immunoproliferative neoplasms, and 0.555 (95% CI [0.457,0.689]; P < .001) for myeloid leukemia. The main limitation was the potential for residual confounding due to the unavailability of lifestyle and laboratory data in the administrative database. CONCLUSIONS: In this study, we observed that long-term hydralazine use in patients with hypertension was associated with a lower, duration-dependent risk of hematologic neoplasms. These findings warrant prospective studies to confirm this association and its potential clinical implications.
Hospital-based care for hallucinogens and risk of mania and bipolar disorder: A population-based cohort study.
Myran DT, MacDonald-Spracklin R, Pugliese M … +4 more , Gibb M, Fiedorowicz JG, Kaster TS, Solmi M
PLoS Med · 2025 Dec · PMID 41329646 · Full text
BACKGROUND: Hallucinogen use for both recreational and medical purposes is rapidly increasing globally, raising concerns about potential adverse effects. This study examined the risk of incident mania or bipolar disorder...
BACKGROUND: Hallucinogen use for both recreational and medical purposes is rapidly increasing globally, raising concerns about potential adverse effects. This study examined the risk of incident mania or bipolar disorder (BD) diagnosis associated with having an emergency department (ED) visit or hospitalization involving hallucinogens. METHODS AND FINDINGS: We used a population-based cohort study of all individuals aged 14-65 years with no baseline history of BD and registered in the Ontario Health Insurance Plan in Ontario, Canada, between 2008-2022. Incident mania (primary outcome) and incident BD (secondary outcome) were compared between individuals with acute care (an ED visit or hospitalization) involving hallucinogens and the general population using overlap propensity score weighted Cox proportional hazard models. Models were adjusted for age, sex, rural residence, income quintile, recent documentation of homelessness, and healthcare encounters for mental health or other substance use in the past five years. The study included 9,311,844 individuals of which 7,285 (0.08%) had acute care involving hallucinogens. Within 3-years of acute care involving hallucinogens, 1.43% (n = 104) of individuals had an incident episode of mania requiring acute care compared to 0.06% (n = 41) of individuals in the age-sex matched general population, a 25-fold increase in risk. After weighting, acute care for hallucinogens was associated with a 6-fold (weighted Hazard Ratio [HR] 5.97, 95% CI 3.29, 10.82) increase in risk of incident mania relative to individuals without hallucinogen acute care who had otherwise similar demographic and mental health histories. Associated increases were also observed for risk of an incident diagnosis of BD (HR 3.75 95%CI 2.49, 5.65, absolute proportion 2.50% versus 0.11%). The main limitation of the study is the risk associated with the exposure examined in this study may not generalize to the majority of people who use hallucinogens who do not require acute care. CONCLUSIONS: These findings suggest the need for ongoing caution regarding hallucinogen use in individuals at risk of bipolar disorder. They also have potential implications for clinical practice, research, and public health policy, including substance regulation and targeted education for high-risk groups in the context of rising hallucinogen use.
Treatment and prevention of HIV/AIDS: Unfinished business.
Fauci AS, Folkers GK
PLoS Med · 2025 Dec · PMID 41325318 · Full text
Since the inception of World AIDS Day in 1988, advances with antiretroviral drugs have revolutionized the landscape of HIV/AIDS treatment and prevention. In 2025, we reflect on progress made, highlight promising therapeu...
Since the inception of World AIDS Day in 1988, advances with antiretroviral drugs have revolutionized the landscape of HIV/AIDS treatment and prevention. In 2025, we reflect on progress made, highlight promising therapeutic developments, and look ahead to what is needed to end the AIDS epidemic.
The association between implant design, age, sex and the rate of major reoperation in patients undergoing primary total hip replacement: A retrospective study of UK National Joint Registry and Hospital Episodes Statistics data.
Lamb JN, Sayers A, Wilkinson JM … +2 more , Pandit H, Whitehouse MR
PLoS Med · 2025 Nov · PMID 41296797 · Full text
BACKGROUND: Implant revision is an operation with exchange of implants, and is used as a standard outcome after total hip replacement (THR), but may not fully represent the patient experience after a THR. Major reoperati...
BACKGROUND: Implant revision is an operation with exchange of implants, and is used as a standard outcome after total hip replacement (THR), but may not fully represent the patient experience after a THR. Major reoperation (hereafter referred to as 'reoperation') without revision of implants can also lead to increased patient morbidity and mortality, and most commonly occurs when the femur fractures around an implant (postoperative periprosthetic femoral fractures; POPFF) and is treated with fixation and the implant is left in place. Reliance on revision metrics that do not capture these reoperations has led to large-scale underreporting of reoperations in THR, and is likely to have affected implant performance estimates, which have guided national policy and implant selection. It is important to include these additional reoperations when estimating treatment success to guide innovation and clinical practice. We aimed to estimate the incidence of reoperation following primary THR. METHODS AND FINDINGS: We performed a large national cohort study on a mandatory, prospective database, the National Joint Registry, linked to Hospital Episode Statistics. All linkable primary THRs using recently available implants, with highest safety ratings between 01/01/2010 and 31/12/2020, were included. Major reoperation was defined as the first revision for any cause or fixation of POPFF and was identified using a combination of procedural and diagnosis codes. We identified 372,967 THRs representing 2,127,464 prostheses years at risk with a median follow-up time of 5.39 years (range 0 to 12.1 years). A total of 8,043 reoperations were identified that had been surgically treated by revision for any cause or fixation of POPFF. The incidence of reoperation was 3.78% (95% confidence interval [CI 3.70%, 3.86%]) per 1,000 prostheses years in comparison to 3.00% (95% CI [2.93%, 3.07%]) per 1,000 prostheses years when using conventional revision only outcomes. Cumulative incidence of major reoperation at 10 years was 3.1% (95% CI [3.0%, 3.1%]). Cumulative reoperation estimates were stratified by age and sex. In men aged 68 years and older, collared cementless stems performed better than cemented stems and in women aged 75 years and older, the relationship was reversed. Residual differences in patient characteristics may affect the accuracy of the estimates. CONCLUSIONS: Treatment failure after THR has been underrepresented by revision-only estimates. Major reoperation rates in older men were lowest with cementless collared stems, and in older women, reoperation rates were lowest with cemented polished taper stems made of stainless steel. These results prompt a review of the current implant guidance for hip replacements in older patients. LEVEL OF EVIDENCE: III (Retrospective cohort study).
Global Burden of Disease 2023: Challenges and opportunities for a growing collaboration.
Bhutta ZA
PLoS Med · 2025 Nov · PMID 41296779 · Full text
The Global Burden of Disease 2023 represents the most comprehensive iteration of its kind since first reported in 1993. Despite improved health monitoring, data acquisition, and analytical methods, its expansion creates...
The Global Burden of Disease 2023 represents the most comprehensive iteration of its kind since first reported in 1993. Despite improved health monitoring, data acquisition, and analytical methods, its expansion creates new challenges and opportunities for improving its accuracy, completeness, external validity, and policy relevance.
The impact of adherence on colorectal cancer screening cost-effectiveness: A modeling study.
Xie J, Dong X, Luo Z … +13 more , Wang C, Zheng Y, Chen X, Guo Z, Shi X, Wang F, Cao W, Xu Y, Wang L, Wu W, Hang D, Du L, Li N
PLoS Med · 2025 Nov · PMID 41296753 · Full text
BACKGROUND: Adherence to colorectal cancer (CRC) screening remains suboptimal in many countries, reducing its cost-effectiveness. This study aimed to evaluate how multistage uptake rates influence the health benefit and...
BACKGROUND: Adherence to colorectal cancer (CRC) screening remains suboptimal in many countries, reducing its cost-effectiveness. This study aimed to evaluate how multistage uptake rates influence the health benefit and cost-effectiveness of various CRC screening strategies in the Chinese population, incorporating both traditional and emerging screening methods. METHODS AND FINDINGS: We developed a multistate Markov model (CRC-SIM) to evaluate the impact of multistep uptake on CRC screening. A hypothetical cohort of 100,000 individuals aged 40 was simulated and followed until 79 or death. Two-step screening strategies were modeled: initial screening followed by colonoscopy after a positive result. Traditional initial screening methods include: questionnaire-based risk assessment, fecal immunochemical test (FIT), and questionnaire combined with FIT; Non-invasive biomarker-based initial strategies include a hypothetical test meeting the minimum standards of China National Medical Products Administration (NMPAmin), multitarget stool DNA (mt-sDNA) test, and blood-based strategies. All strategies were modeled as one-time screenings, with outcomes projected for CRC cases, deaths, quality-adjusted life years (QALYs), and lifetime costs. Incremental cost-effectiveness ratios (ICERs) were calculated, and a cost-effectiveness heatmap was conducted to assess the impact of multistep uptake (modeled in 10% steps) on economic outcomes. All strategies reduced CRC cases, deaths and increased QALYs compared to no screening, with biomarker-based strategies outperforming the traditional methods at the same uptake level (e.g., questionnaire combined with FIT prevented 224 (95% confidence interval (CI) [157, 292]) CRC cases and 151 (95% CI [109, 195]) deaths, whereas NMPAmin prevented 312 (95% CI [257, 360]) cases and 210 (95% CI [175, 241]) deaths at 100% uptake). The cost-effectiveness heatmap indicated that each 10% increase in initial and follow-up colonoscopy uptake improved ICERs in a non-linear pattern. The questionnaire combined with FIT was the most cost-effective strategy (ICER = $2,413 per QALY gained). Non-invasive biomarker-based tests were not cost-effective compared with the combined questionnaire and FIT strategy under current assumptions of test costs and identical uptake rate. Threshold analysis showed that non-invasive biomarker-based screening would become cost-effective if test costs fell below $131.7 or colonoscopy uptake increased to at least 70% for NMPAmin and 50% for blood-based tests and mt-sDNA. Limitations include the assumption of a one-time screening scenario; future iterations of the model and merging evidence in repeated screening will address these limitations. CONCLUSION: Improving screening participation could enhance health benefits and cost-efficiency in CRC screening. Questionnaire-based risk assessment combined with FIT was a cost-effective strategy in China, whereas non-invasive biomarker-based methods require cost reduction and higher uptake to justify adoption. These findings provide evidence for policymakers to optimize CRC screening programs.
Towards insulin independence in type 1 diabetes: Prospects for prevention and cure.
Sydney GI, Perdigoto AL, Herold KC
PLoS Med · 2025 Nov · PMID 41289263 · Full text
The discovery of insulin transformed type 1 diabetes from an acutely lethal illness to a chronic disease that is managed with insulin dependence. Now, exciting developments in preventive treatments and stem cell-based th...
The discovery of insulin transformed type 1 diabetes from an acutely lethal illness to a chronic disease that is managed with insulin dependence. Now, exciting developments in preventive treatments and stem cell-based therapies bring the prospects of arresting the disease and achieving insulin independence for type 1 diabetics closer to reality.
Impact of first-trimester ultrasound on early detection of major fetal anomalies: Nationwide population-based study of over 1 million pregnancies.
Karim JN, Broughan JM, Aldridge N … +4 more , Pandya P, McHugh A, Papageorghiou AT, ACCEPTS study group
PLoS Med · 2025 Nov · PMID 41289226 · Full text
BACKGROUND: Major fetal anomalies are an important cause of perinatal morbidity and mortality. While routine second-trimester ultrasound screening around 20 weeks is the current standard, advances in imaging have enabled...
BACKGROUND: Major fetal anomalies are an important cause of perinatal morbidity and mortality. While routine second-trimester ultrasound screening around 20 weeks is the current standard, advances in imaging have enabled earlier anatomical assessment in the first trimester. Despite increasing practice of early screening in England, there is no national policy recommending first-trimester anatomical evaluation, and little is known about its impact on detection rates at population level. Our aim was to examine if different policies of fetal anatomical ultrasound practice have an impact on earlier diagnosis of major fetal anomalies. METHODS AND FINDINGS: We conducted a nationwide, population-based study linking data from a national survey of first-trimester ultrasound protocols in all NHS maternity units in England with congenital anomaly registration data from the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS) for pregnancies between April 2017 and March 2019. NHS trusts were classified into four protocol groups: no anatomical assessment, basic, advanced, and extended anatomical protocols. We evaluated the proportion of 14 predefined major congenital anomalies detected prior to 16 weeks' gestation across these groups. A total of 1,030,224 pregnancies were included from 110 NHS trusts (84% response rate), with 5,895 fetuses affected by one of the anomalies of interest. First-trimester anatomical assessment was routinely conducted in 75% of trusts, though the scope varied. Overall, 32.7% (95% CI 31.5-33.9) of anomalies were detected before 16 weeks, with detection rates increasing stepwise by protocol detail: 27.7% (95% CI 25.4-30.0) in trusts with no protocol to 40.4% (95% CI 37.3-43.4) in those with extended protocols (p < 0.0001 for trend). Conditions such as acrania, exomphalos, and gastroschisis were commonly detected early regardless of protocol, whereas for anomalies such as spina bifida, limb reduction defects, and major cardiac malformations, detection was significantly higher in centers employing detailed first-trimester anatomical protocols. Due to data access restrictions and confidentiality considerations, analyses were conducted at the level of protocol group rather than individual hospitals. Hospital-level characteristics, including sonographer expertise and patient population risk, could not be adjusted for and may act as confounders. CONCLUSIONS: More detailed first-trimester anatomical screening protocols are associated with significantly higher early detection rates of major fetal anomalies. While current practices vary considerably across England, this study provides population-level evidence suggesting that systematic first-trimester screening could improve the timeliness of anomaly detection. These findings support the consideration of standardized national guidance to reduce inequity and enhance prenatal care.
From dependence to self-reliance: The future of the global tuberculosis response.
Heitkamp P, Chijioke-Akaniro O, Pai M
PLoS Med · 2025 Nov · PMID 41270107 · Full text
Just as tuberculosis services were recovering after the COVID-19 pandemic disruptions, abrupt funding cuts by G7 nations are putting progress at risk. These trends, while perilous, also reveal a turning point toward a mo...
Just as tuberculosis services were recovering after the COVID-19 pandemic disruptions, abrupt funding cuts by G7 nations are putting progress at risk. These trends, while perilous, also reveal a turning point toward a more equitable, resilient, and self-reliant TB response, led by high-burden countries.
The association of body mass index with patient outcomes after shoulder replacement surgery: Population-based cohort study using linked national data from the United Kingdom and Denmark.
Valsamis EM, Larsen JB, Sayers A … +7 more , Jones T, Gwilym SE, Kjær-Kristensen P, Thillemann TM, Mechlenburg I, Whitehouse MR, Rees JL
PLoS Med · 2025 Nov · PMID 41264572 · Full text
BACKGROUND: There is growing evidence that access to joint replacement surgery is being restricted based on body mass index (BMI) despite any formal recommendations. Our aim was to investigate the association between BMI...
BACKGROUND: There is growing evidence that access to joint replacement surgery is being restricted based on body mass index (BMI) despite any formal recommendations. Our aim was to investigate the association between BMI and patient outcomes after elective primary shoulder replacement surgery to inform future commissioning and national guidance. METHODS AND FINDINGS: In this population-based cohort study, patients aged 18-100 years having elective primary shoulder replacement surgery were identified using linked national joint registry and hospital data from public and private hospitals in the United Kingdom (2018-22) and Denmark (2006-21). The main outcome measure was mortality within 365 days of surgery. Secondary outcome measures included mortality within 90 days, serious adverse events within 90 days, and revision surgery within 4.5 years of surgery. The association between BMI and patient outcomes was assessed using flexible parametric survival models and logistic regression models, adjusting for age, sex, deprivation, main surgical indication and American Society of Anaesthesiologists (ASA) score. 15,320 and 5,446 shoulder replacement procedures from within the United Kingdom and Denmark, respectively, met the inclusion criteria. In the United Kingdom, the average age was 72.2 years, 68.3% were female and the average BMI was 29.4 kg/m2. In Denmark, the average age was 70.5 years, 65.3% were female and the average BMI was 28.0 kg/m2. There was a decreased risk of 365-day mortality in obese (BMI 40 kg/m2) patients (hazard ratio (HR) 0.40 [95%CI 0.21, 0.73]) and an increased risk in underweight (BMI < 18.5 kg/m2) patients (HR 1.18 [95%CI 1.06, 1.32]), compared to patients with BMI 21.75 kg/m2. Underweight patients had an increased risk of 90-day mortality (HR 1.69 [95%CI 1.14, 2.52]), 90-day serious adverse events (odds ratio 1.36 [95%CI 1.05, 1.77]) and revision surgery (HR 1.70 [95%CI 1.25, 2.33]). Increasing BMI was not associated with a significantly increased risk of any secondary outcome. The main limitation of this study was the high proportion of missing BMI data and the small case numbers for the underweight study population (n = 131[UK], 70[Denmark]). CONCLUSIONS: Increasing BMI was associated with lower 365-day mortality, and no poorer outcomes after elective primary shoulder replacement surgery. This surgery is safe and effective in obese patients and access to shoulder replacements should not be restricted based on BMI alone. Clinicians and hospitals should be aware that underweight patients appear more at risk of mortality, serious adverse events and revision surgery after shoulder replacement.
Trends in assisted dying among patients with psychiatric disorders and dementia in Belgium: A health registry study.
Wels J, Hamarat N
PLoS Med · 2025 Nov · PMID 41259405 · Full text
BACKGROUND: Assisted dying and euthanasia (ADE) for patients with psychiatric disorders or dementia have increased in jurisdictions where the practice is legal. In this study, we examine trends in euthanasia cases involv...
BACKGROUND: Assisted dying and euthanasia (ADE) for patients with psychiatric disorders or dementia have increased in jurisdictions where the practice is legal. In this study, we examine trends in euthanasia cases involving patients with these conditions in Belgium, where the law makes a distinction based on whether a patient's death is not expected in the foreseeable future (>12 months)-a common situation in cases of dementia or psychiatric disorders. METHODS AND FINDINGS: We use data on all cases of euthanasia reported to the Federal Commission for the Control and Evaluation of Euthanasia from 2002 (when the legislation was introduced) to 2023 (N = 33,592). Psychiatric disorders and dementia represent 1.27% and 0.92% of all cases, respectively. Using time-series zero-inflated negative binomial regression, we model trends by first examining interactions between euthanasia reasons and year, then extending to three-way interactions with patients' characteristics. The model calculates change in count and is replicated with an offset to account for demographic changes and generate rates. Our results show that euthanasia for psychiatric disorders and dementia showed distinct trends over time. Although slightly increasing, euthanasia for psychiatric disorders followed trends similar to the other types of euthanasia (count = 1.00 [95%CI: 0.98; 1.03]-rate = 1.02 [95%CI: 0.99; 1.04]), while euthanasia cases for dementia increased faster than other types of euthanasia (count = 1.03 [95%CI: 1.00; 1.06]-rate = 1.04 [95%CI: 1.01;1.07]). Trends in euthanasia for dementia and psychiatric disorders coincide with demographic changes. While euthanasia rates for psychiatric disorders were initially higher among women, the rate among men has been increasing over time. Regional trends show higher overall euthanasia rates in the Dutch-speaking population, but with faster increases in the French-speaking population. A key limitation of this study is the lack of information on patients' socio-economic profiles. CONCLUSIONS: In Belgium, between 2002 and 2023, there are distinct trends for euthanasia for non-terminal illnesses. Euthanasia for psychiatric disorders followed similar trends as euthanasia for terminal illnesses, whereas euthanasia cases involving cognitive conditions increased at a faster rate. Furthermore, there were gender and regional differences, which diminished over time.
Association between cigarette smoking status, intensity, and cessation duration with long-term incidence of nine cardiovascular and mortality outcomes: The Cross-Cohort Collaboration (CCC).
Tasdighi E, Yao Z, Dardari ZA … +30 more , Jha KK, Osuji N, Rajan T, Boakye E, Matsushita K, Simonsick EM, Lima JAC, Lloyd-Jones DM, Cohen DL, Appel LJ, Khera A, Hall ME, Rodriguez CJ, Judd S, Cole SA, Ramachandran VS, Benjamin EJ, Lotufo PA, Bittencourt MS, El Khoudary SR, Thurston RC, Derby CA, Psaty BM, Eaton CB, LaMonte MJ, Cawthon PM, Orwoll ES, Bhatnagar A, DeFilippis AP, Blaha MJ
PLoS Med · 2025 Nov · PMID 41252354 · Full text
BACKGROUND: Uncertainties persist regarding the precise shape of the smoking-outcome curves across various cardiovascular and mortality endpoints. This study aims to elucidate the relationships among smoking burden, inte...
BACKGROUND: Uncertainties persist regarding the precise shape of the smoking-outcome curves across various cardiovascular and mortality endpoints. This study aims to elucidate the relationships among smoking burden, intensity, and cessation duration across multiple cardiovascular outcomes. METHODS AND FINDINGS: Cox proportional hazard models were constructed to evaluate the association between pack-years, cigarettes per day (CPD), and years since cessation with cardiovascular outcomes in participants from 22 prospective cohort studies within the Cross-Cohort Collaboration Tobacco Working Group. We evaluated myocardial infarction (MI), stroke, coronary heart disease (CHD; MI, coronary revascularization, or coronary death), cardiovascular disease (CVD; stroke or cardiovascular death), heart failure (HF), atrial fibrillation (AFib), CHD mortality, CVD mortality, and all-cause mortality. Median follow-up varied across outcomes, with 14.4 years for MI (17,570 events), 19.3 years for CHD (30,625 events), 18.6 years for CVD (54,078 events), and approximately 19.4-19.9 years for mortality outcomes (CHD mortality: 17,429 events; CVD mortality: 33,120 events; all-cause mortality: 125,044 events). Spline terms were used to investigate the nonlinear association of continuous smoking/cessation measures with the examined outcomes. Models were adjusted for demographic, socioeconomic, and other cardiovascular risk factors. The study included 323,826 adults (148,635 non-mortality and 176,396 mortality outcomes with 25 and 16 million person-years at risk, respectively). Compared to never-smokers, current smokers had significantly increased risks for CVD (hazard ratio (HR) 1.74, 95% confidence intervals (CIs) [1.66,1.83] in men; HR 2.07, 95% CI [2.00,2.14] in women) and all-cause mortality (HR 2.17, 95% CI [2.09,2.25] in men; HR 2.43, 95% CI [2.38,2.48] in women; all p < 0.001). Compared with never-smokers, participants with 2-5 CPD demonstrated substantially elevated cardiovascular risks, with HR ranging from 1.26 (95% CI [1.09,1.45], p = 0.002) for AFib to 1.57 (95% CI [1.39,1.78], p < 0.001) for HF. Smoking 2-5 CPD was associated with increased CVD mortality (HR 1.57, 95% CI [1.41,1.75]), and all-cause mortality (HR 1.60, 95% CI [1.52,1.69]; both p < 0.001). Smoking 11-15 CPD conferred a higher risk of CVD (HR 1.87, 95% CI [1.69,2.06]) and all-cause mortality (HR 2.30, 95% CI [2.14,2.47]; both p < 0.001). The increased risk associated with the evaluated outcomes was steeper for the initial 20 pack-years and 20 CPD, respectively, compared to further smoking exposure. The most substantial reduction in risk across all outcomes was observed within the first 10 years after smoking cessation. However, the progressive risk reduction continues over extended time periods, with former smokers demonstrating over 80% lower relative risk than those of current smokers within 20 years of cessation. Limitations include potential exposure misclassification due to reliance on single baseline self-reported smoking measurements with extended follow-up periods, which may underestimate true risk associations, and lack of data on other tobacco products and electronic nicotine delivery systems, preventing analysis of dual- and poly-use patterns. CONCLUSION: Lower-intensity smoking is associated with cardiovascular risk and the primary public health message for current smokers should be early cessation, rather than reducing the amount of smoking. Cessation provides substantial immediate risk reduction, although risk continues to decrease significantly for the following two decades.
Diagnostic accuracy of the WHO tuberculosis treatment decision algorithms for children with presumptive tuberculosis: An individual participant data meta-analysis.
Olbrich L, Larsson L, Dunbar R … +25 more , Dodd PJ, Palmer M, Huyen Ton Nu Nguyet M, d'Elbée M, Hesseling AC, Heinrich N, Zar HJ, Ntinginya NE, Khosa C, Nliwasa M, Verghese VP, Bonnet M, Wobudeya E, Nduna B, Moh R, Mwanga-Amumpere J, Mustapha A, Breton G, Taguebue JV, Borand L, Chabala C, Marcy O, Seddon JA, van der Zalm MM, Decide-TB Study Group, the RaPaed-TB Consortium, the Umoya Study Group, and the TB Speed Consortium
PLoS Med · 2025 Nov · PMID 41252347 · Full text
INTRODUCTION: In 2023, almost 200,000 children under 15 years died from tuberculosis, most without appropriate treatment. Treatment decision algorithms (TDAs), developed to facilitate rapid anti-tuberculosis treatment in...
INTRODUCTION: In 2023, almost 200,000 children under 15 years died from tuberculosis, most without appropriate treatment. Treatment decision algorithms (TDAs), developed to facilitate rapid anti-tuberculosis treatment initiation in children, were recommended by the World Health Organization (WHO) in 2022, conditional on validation in different cohorts and settings. We performed a retrospective external evaluation of WHO TDAs using an individual participant dataset (IPD). METHODS AND FINDINGS: The IPD comprised four paediatric cohorts, restricted to children with presumptive pulmonary TB < 10 years, and including children in high-risk groups (children living with HIV "CLHIV", children with severe acute malnutrition "SAM", and children <2 years). All children in the IPD were retrospectively evaluated using both TDA A (an algorithm including chest X-ray) and TDA B (without chest X-ray), excluding the triage step. The diagnostic accuracy against a composite reference standard (confirmed and unconfirmed tuberculosis versus unlikely tuberculosis) was determined and reported as sensitivities and specificities. Of 1,886 children included (RaPaed-TB: n = 740, Umoya: n = 474, TB-Speed HIV: n = 204, TB-Speed Decentralisation: n = 468), the median age was 2.9 years (interquartile range [IQR]:1.3,5.5), 741 (39.3%) were <2 years, 382 (20.3%) were CLHIV, and 284 (15.1%) had SAM. 281 (14.9%) had confirmed tuberculosis, 672 (35.6%) were classified as unconfirmed tuberculosis (clinically diagnosed, microbiological investigations negative), and 933 (49.5%) as unlikely tuberculosis. For TDAs A and B, algorithm sensitivity was 84.3% (95% CI: 74.8, 90.6) and 90.6% (95% CI: 83.8, 94.7), respectively, with a specificity of 50.6% (95% CI: 30.4, 70.7) and 30.8% (95% CI: 21.5, 42.0), respectively. For TDA A, estimated sensitivity in children in high-risk groups was lower than those with low-risk (83.0%, 95% CI: 79.4%, 86.1%; versus 88.0%, 95% CI: 84.8%, 90.6%), while having a gain in specificity (50.0%, 95% CI: 44.9%, 55.1%; versus 36.6%, 95% CI: 32.7%, 40.7%). Trends were similar for TDA B. As for limitations, most diagnostic tuberculosis studies in children, including two of those included in the IPD, are performed at secondary or tertiary hospitals with higher levels of healthcare and thus the target population might differ somewhat from the IPD, potentially limiting the generalisability of our results. CONCLUSIONS: This retrospective external evaluation of WHO TDAs in a large IPD shows high sensitivity but sub-optimal specificity for both TDAs, in line with the meta-analyses that generated the algorithms. Prospective studies that evaluate the entire TDA, including triage step are needed. Additionally, the integration of novel diagnostic tools within the TDAs should aim to enhance the accuracy, especially the specificity.
How can middle-income countries successfully transition away from international health aid?
Ogbuoji O, Bharali I, Nonvignon J … +1 more , Yamey G
PLoS Med · 2025 Nov · PMID 41196882 · Full text
Recent research has examined factors contributing to the successful transition of middle-income countries away from international health aid. Three factors are especially important: effective leadership, using domestic r...
Recent research has examined factors contributing to the successful transition of middle-income countries away from international health aid. Three factors are especially important: effective leadership, using domestic resources to close the financing gap created by loss of aid, and realigning country systems to new sources of domestic funding.
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