PLoS Medicine最新文献

Background: Sex hormones have been implicated in leukemogenesis, but evidence regarding hormonal contraceptive use and leukemia risk remains limited and primarily based on older formulations. Given the widespread use of contemporary hormonal contraceptives, clarification of this potential association is needed. This study examines the association between contemporary hormonal contraceptives and leukemia risk.

Methods and findings: In a nationwide cohort design, we assessed associations between the use of contemporary hormonal contraceptives and the risk of leukemia based on a cohort of all women aged 15-49 years residing in Denmark from 1995 to 2021 with no previous cancer, hysterectomy, oophorectomy, or sterilization. Information on hormonal contraception use, leukemia diagnoses, and potential confounders (age, calendar year, education) was obtained from nationwide registries. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals [CIs] were estimated for any leukemia, and specific types of leukemia, associated with any hormonal contraceptive use, current and recent use, and previous use, type of product used, duration, and time since last use. Among 1,957,490 pre-menopausal women followed for 24.5 million person-years (median 12.5 years, interquartile range: 5.9,20.5), 671 were diagnosed with leukemia. The incidence rate for leukemia among current and recent users was similar to that among women who had never used hormonal contraception: IRR 0.95 (95% CI [0.78,1.16]; p = 0.62). No association with different durations of use was found: 0-5 years; IRR 0.93 (95% CI [0.75,1.14]; p = 0.48), >5-10 years; IRR 1.16 (95% CI [0.84,1.61]; p = 0.37), >10 years; IRR 0.67 (95% CI [0.33,1.37]; p = 0.27); nor for time since last use: 0-5 years; IRR 1.01 (95% CI [0.78,1.29]; p = 0.96), >5-10 years; IRR 1.05 (95% CI [0.76,1.45]; p = 0.75), >10 years; IRR 0.88 (95% CI [0.60,1.29]; p = 0.52). Also, the IRRs for leukemia with use of different hormonal contraceptive types (e.g., combined products; IRR 0.91 (95% CI [0.73,1.14]; p = 0.42) and progestin-only products; IRR 1.05 (95% CI [0.78,1.40]; p = 0.75)), as well as for product-specific durations of use, were for the majority close to 1. The IRRs were similar for different types of leukemia. Main study limitations include small case numbers in some analyses; therefore, additional large-scale studies are warranted to reliably exclude weak associations.

Conclusions: Contemporary hormonal contraceptives were not associated with leukemia, independent of product used, duration of use, time since last use, and type of leukemia. While estimates were imprecise for some subgroups, the overall findings do not support an association.

Climate change is accelerating the frequency and severity of extreme weather events and increasingly threatening human health and life, particularly in low- and middle-income countries. Research on the effectiveness of climate adaptation interventions for human health, as well as their desirability, implementation, and financial viability, are urgently required.

Background: Vaginal cervical cerclage and progesterone are established treatments for prevention of pregnancy loss and prematurity. There is limited data to assess the effect of these treatments in combination. The objective of this study was to investigate the association between progesterone and no progesterone treatment on pregnancy outcomes in women at high risk of preterm birth who had received a vaginal cervical cerclage.

Methods and findings: This is a secondary post-hoc analysis of women recruited to the C-STICH randomised controlled trial, which recruited in 75 obstetric units in the UK between 2015 and 2021. In the C-STICH trial, women with a singleton pregnancy, receiving a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were randomised to cerclage with braided or monofilament suture, with a primary outcome of pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life. In this secondary analysis, the primary outcome was pregnancy loss, defined as miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life. Secondary maternal outcomes included miscarriage and previable neonatal death; stillbirth; gestational age at delivery; preterm pre labour rupture of membranes, and sepsis. Secondary neonatal outcomes included early/late neonatal death and sepsis. For each outcome, regression models were fitted adjusting for prespecified prognostic variables. From the 2,048 women recruited to C-STICH, 1943 (95%) women had a vaginal cerclage placed and available progesterone data. Of these, 834 (43%) women received progesterone and 1,109 (57%) did not receive progesterone. In women with primary outcome data available, in our predefined analysis pregnancy loss occurred in 49 (5.9%) of 832 women who received progesterone and 91 (8.3%) of 1,103 women who did not receive progesterone (adjusted* risk ratio 0.70 (95% confidence interval (CI) [0.50, 0.99]); adjusted risk difference -0.02 (95% CI [-0.04, -0.001], *adjusted for indication, obstetric history, surgical technique, and maternal age). Further exploratory analysis excluding women who had termination of pregnancy for foetal anomaly demonstrated a nonsignificant reduction in the risk of pregnancy loss. Key limitations of this study include a nonrandomised trial design and unknown confounding relating to variation in progesterone use.

Conclusion: In women with a vaginal cervical cerclage and concomitant progesterone there appears to be an association with a reduced risk of pregnancy loss. This combination therapy may be an important opportunity to further reduce the risk of pregnancy loss in this high-risk cohort.

[This corrects the article DOI: 10.1371/journal.pmed.1003636.].

Anti-amyloid drugs modestly slow Alzheimer's disease progression, albeit with uncertainty of sustained benefit, particularly as they cause paradoxical acceleration of brain volume changes. Here, we examine explanations for these volume changes and argue for transparent release of clinical trial data.

Background: Maternal respiratory syncytial virus (RSV) vaccine, RSV prefusion F protein vaccine (RSVpreF (Abrysvo)), was found to be safe and efficacious in the MATISSE trial. However, post-hoc stratified analyses identified an excess of preterm births in the intervention arm in two upper-middle-income countries, most prominently in South Africa. This study weighs the potential benefits and risks in mortality associated with maternal RSV vaccination in South Africa, assuming the increased risk of preterm births observed in the trial was caused by vaccination.

Methods and findings: We compared the estimated RSV-associated infant deaths averted by vaccination (benefits) and neonatal mortality potentially associated with vaccine-associated risk in preterm birth (risks) in South Africa. The benefit model estimated the South African RSV disease burden in 2011-2016 and waning vaccine protection during infancy. The risk model estimated excess neonatal mortality using gestational age (GA)-specific mortality data from the Drakenstein Child Health Study and the GA-specific birth distribution in South Africa in the MATISSE trial, but did not incorporate the mortality risk found in the MATISSE vaccine trial in which no excess deaths occurred. The benefit model estimated that vaccination would reduce RSV-associated infant deaths by 31 (95% credible interval (Crl): 27, 35) per 100,000 live births born to vaccinated mothers in South Africa. Using the number of infants born to mothers vaccinated at 24-36 GA weeks in the MATISSE trial, if the association in South Africa between vaccination and preterm birth is actually causal, the risk model suggested that neonatal deaths would increase by 44 (95%CrI: -43, 210), totaling 1.4 (95%CrI: -1.4, 6.9) excess neonatal deaths for every infant RSV death prevented. When this was changed to the number of infants born to mothers vaccinated at 27-36 GA weeks in the MATISSE trial, the predicted risks dropped and in 97% of the simulations the benefits outweighed the risks. The outcome was sensitive to the GA window that we used to determine which infants to include in the analysis. The study was limited by only considering mortality associated with RSV disease and preterm birth.

Conclusions: If RSVpreF increases preterm birth risk, and if this increases neonatal mortality, then the benefit-risk analysis failed to show that the direct benefits of vaccination in reducing RSV-associated infant mortality would substantially outweigh the risks of preterm birth-associated neonatal mortality in South Africa with vaccination from 24 GA to 36 GA weeks. There was large uncertainty in the analyses due to small numbers of preterm births. With vaccination from 27 GA weeks, the benefit-risk analysis favored vaccination. RSVpreF vaccination has the potential to be safe and effective when used from the third trimester.

Glucagon-like peptide-1 (GLP-1)-based medications, such as semaglutide and tirzepatide, have transformed obesity care. However, rising use brings concerns about side effects, long-term outcomes, and unregulated products. Ensuring safe access requires oversight, monitoring, and coordinated clinical care.

Background: Approximately 20% of patients with stage II colorectal cancer (CRC) experience tumor relapse despite standard surgical treatment. Histopathological analysis holds promise for postsurgical risk stratification and guiding adjuvant chemotherapy (ACT) decisions. The aim of this study was to use deep learning to extract explainable tissue biomarkers from whole-slide images.

Methods and findings: In this retrospective cohort study, we developed and validated SurvFinder, an interpretable deep learning framework designed to autonomously identify tissue-based risk biomarkers from hematoxylin and eosin (H&E)-stained slides. The framework aims to support individualized risk stratification and explore associations with treatment outcomes. The present study included 6,950 H&E slides from 1,604 patients with stage II CRC across four independent cohorts in China. Patients were enrolled from 2012 to 2018 and followed for a minimum of 24 months. The primary outcome of the study was relapse-free survival (RFS). Our analyses identified tertiary lymphoid structures (TLSs) as critical prognostic features in stage II CRC. The multi-view integration of TLS characteristics by SurvFinder consistently demonstrated superior predictive and prognostic accuracy across four multicenter datasets (AUROC with 95% confidence interval [CI]: 0.827 [0.789,0.864], 0.805 [0.749,0.860], 0.805 [0.748,0.861], and 0.712 [0.621,0.804]), surpassing traditional clinical prognostic parameters (hazard ratio [HR]: 8.23, 95% CI: 5.43-12.47; p < 0.001). Using explainable AI (XAI) methods, we ensured model transparency and identified key TLS features-such as their location at the tumor periphery and their maturity state-as significant factors influencing prognosis and the efficacy of adjuvant therapy. The retrospective design without prospective validation and real-world clinical deployment is the main limitation of this study.

Conclusions: Together, these results highlight the potential utility of deep learning-based histopathological analysis for automated risk stratification in stage II CRC. In particular, our findings support the relevance of TLSs as a histological biomarker with potential implications for personalizing ACT decisions.