PLOS Medicine

BackgroundThe multicentre WOMAN trial showed that tranexamic acid reduces postpartum haemorrhage (PPH) deaths. Several studies have recommended adjusting for clustering at the country and centre level to improve power and reduce bias in the standard errors. We reanalysed data from the WOMAN trial, adjusting for these centre effects. MethodsThe WOMAN trial recruited 20,060 women with clinically diagnosed PPH from 193 centres in 21 countries. The intervention was intravenous tranexamic acid versus matching placebo and the outcome was death from bleeding within 42 days of randomisation. We reanalysed data for the 14,928 women treated within 3 hours of birth for whom tranexamic acid provided the most benefit. We used random effects logistic regression to calculate the effect of tranexamic acid taking into account variation in risk of death and treatment effectiveness by country and centre. We calculated intraclass correlations (ICCs) to quantify between country and between centre within country variation. Results216 (1.4%) women died from bleeding. Using a univariable analysis without adjusting for centre effects, we found tranexamic acid reduced the odds of death from bleeding by 31% (OR=0.69 95% CI: 0.52-0.90, p=0.007). Adjusting for baseline covariates (age, systolic blood pressure (SBP) and SBP2) but not country or centre yielded a 36% odds reduction (OR=0.64 95% CI: 0.48-0.85 p=0.002). Adjustment for baseline covariates, country and centre yielded a 37% odds reduction (OR=0.63 95% CI: 0.48-0.85 p=0.002). We found substantial between country and centre variation in outcomes but not treatment effectiveness. The ICC for outcome was 14% for country and 19% for centre within country. ConclusionsAdjusting for country and centre effects made negligible differences to the magnitude of the treatment effect estimate or its associated p-value. Consistent with other studies of large clinical trials for medicines with binary outcomes, we found considerable between country and centre variation in outcomes but not in relative treatment effectiveness. Despite substantial ICCs for the outcome, adjusting for country and centre effects had minimal impact on our results. Trial registrationclinicalTrials.gov:NCT00872469 (March 2009)

We estimated the number needed to vaccinate (NNV) with an M72/AS01E-like vaccine to prevent one tuberculosis case in U.S. high-risk groups. Targeted vaccination of Mycobacterium tuberculosis-infected persons yielded NNVs of 217 (persons with HIV) to 2,486 (U.S.-born), within the range of established adult vaccines.

Background: Intrauterine contraceptives (IUCs) are effective, but effects on genital inflammation among women living with HIV (WLHIV) by antiretroviral therapy (ART) use are unclear. We evaluated the longitudinal effects of copper IUC (C IUC) and the levonorgestrel intrauterine system (LNG IUS) on cervicovaginal cytokine profiles in a secondary analysis of a randomized trial (NCT01721798, 2013 to 2016). Methods: Cervicovaginal secretions were collected from 100 WLHIV (non ART users; ART users) randomized 1:1 to C IUC or LNG IUS. Twenty eight cytokines were measured prior to insertion and 3 and 6 months post insertion. Cytokine concentrations at each follow up visit were compared with baseline, using participant fixed effects models stratified by ART status. Results: At enrolment, non ART users had higher average concentrations of most cytokines (21/28) than women using ART. Among non-ART users, IUC use was not associated with cytokine increases; only MCP1 increased significantly at 3 months among C IUC users (log10 geometric mean ratio 0.77, 95%CI 0.38 to 1.17), while none increased with LNG IUS use. Among ART users, C IUC insertion resulted in broad and sustained cytokine increases at both 3 (16/28) and 6 months (15/28). At month 3, the largest increases in log10 geometric mean were observed for IL6 (1.04, 0.72 to 1.36), RANTES (0.97, 0.54 to 1.40), MCP1 (0.71, 0.46 to 0.96), MIP1; (0.66, 0.37 to 0.94), and GCSF (0.63, 0.36 to 0.89), which was maintained until month 6. Cytokine changes following LNG IUS insertion were minimal (IL5, month 3). Conclusions: Among ART users, C IUC is associated with increases in cervicovaginal cytokines, across functional classes. This supports LNG IUS as a less inflammatory option for WLHIV to minimize genital immune activation.

Background: U.S. POINTER reported a modest structured-versus-self-guided difference in the annual rate of global cognitive change. However, the clinical and economic implications of this incremental standardized cognitive-slope benefit for delaying progression from cognitively normal status to mild cognitive impairment or dementia remain uncertain. Objectives: To translate the U.S. POINTER cognitive-slope benefit into clinically interpretable progression outcomes in ADNI, A4, and LEARN, and to summarize scenario-based economic implications in ADNI subgroups. Design: External-cohort translation analysis using two complementary analytic frameworks: an early-change landmark Cox model targeting Month 24 with a prespecified fallback window and a joint longitudinal-survival model. Setting: ADNI, A4, and LEARN. Participants: Cognitively normal participants. Landmark analytic samples included 399 ADNI participants with 61 events, 124 A4 participants with 37 events, and 394 LEARN participants with 45 events. Joint-model samples included 486 ADNI participants with 86 events, 1,064 A4 participants with 410 events, and 505 LEARN participants with 87 events. Intervention: No multidomain lifestyle intervention was administered in ADNI, A4, or LEARN. ADNI and LEARN were observational longitudinal cohorts, whereas A4 was a randomized solanezumab trial; the present analysis did not estimate solanezumab treatment effects. We evaluated a counterfactual +0.029 SD/year improvement in cohort-specific mPACC slope, corresponding to the structured-versus-self-guided cognitive-slope difference reported in U.S. POINTER. Measurements: The clinical outcome was sustained progression to mild cognitive impairment or dementia. Main translated measures were hazard ratios (HRs), 5-year risk differences (RDs), number needed to treat (NNT), and restricted mean survival time (RMST) differences. ADNI subgroup economic summaries used incremental 2-year delivery-cost scenarios and prespecified willingness-to-pay thresholds for prevented progression events and MCI-free years. Results: Landmark analyses yielded small translated effects. For the +0.029 SD/year slope shift, HRs were 0.972 (95% CI, 0.949-0.989) in ADNI, 0.998 (0.989-1.005) in A4, and 0.996 (0.990-1.003) in LEARN, with corresponding 5-year RDs of 0.31 percentage points (95% CI, 0.12-0.57), 0.06 (-0.13 to 0.27), and 0.08 (-0.05 to 0.20). Joint models produced larger effects, with HRs of 0.831 (95% CrI, 0.776-0.879), 0.917 (0.907-0.927), and 0.833 (0.746-0.907), and 5-year RDs of 1.26 percentage points (0.90-1.68), 3.04 (2.65-3.43), and 2.25 (1.24-3.45), respectively. Corresponding NNT values were 79.1, 32.9, and 44.5, and RMST gains were 0.297, 1.242, and 0.617 months. In exploratory ADNI subgroup analyses, the small joint-model APOE-{varepsilon}4+ & A{beta}+ subgroup (61 participants, 22 events) showed the largest translated clinical effect, with HR 0.775 (95% CrI, 0.597-0.919), RD 2.65 percentage points (0.93-4.82), NNT 37.7, and RMST gain 0.723 months. In an exploratory threshold exercise, assuming an incremental 2-year delivery cost of $400 per participant for a structured intervention relative to a self-guided/reference intervention and a willingness-to-pay threshold of $100,000 per prevented progression event, the largest threshold-based net monetary benefit was observed in the APOE-{varepsilon}4+ & A{beta}+ joint-model subgroup (+$2,250/person). On an MCI-free-year basis under the same incremental-cost assumption, this subgroup also had the largest threshold-based net monetary benefit (+$5,622/person). These values should be interpreted as scenario-dependent thresholds rather than empirical cost-effectiveness estimates. Conclusions: A U.S. POINTER-referenced structured-versus-self-guided cognitive-slope increment translated into directionally consistent reductions in predicted progression risk across ADNI, A4, and LEARN. The absolute clinical delay was generally modest and varied with cohort risk structure, biomarker/genotype enrichment, and analytic framework. Exploratory economic-threshold results suggested more favorable margins in higher-risk ADNI subgroups under low incremental-cost and high willingness-to-pay assumptions, but these findings should be interpreted as hypothesis-generating translation estimates rather than empirical cost-effectiveness evidence.

BackgroundHIV-related stigma remains a primary barrier to the elimination of the HIV epidemic worldwide. No studies have examined long-term changes in the distribution of stigmatizing attitudes within populations. MethodsWe conducted a whole-population, open cohort study of adults in 8 villages in rural southwestern Uganda, with 5 biennial surveys spanning 2014-2024 (N=1,776 at baseline; 869 participated in all waves). We measured individual negative attitudes toward people with HIV ("public stigma") and perceptions of negative attitudes among others ("perceived stigma") using parallel 15-item scales. We estimated mean stigma scores, computed inequality measures at each wave, and decomposed inequality by sociodemographic characteristics. Leveraging the cohort design, we estimated intraclass correlation coefficients and rank-order stability over time. ResultsBoth public and perceived stigma declined substantially from baseline to endline and became concentrated in an increasingly smaller subgroup of the population. Theil decomposition failed to identify any stratifying variables that explained more than 3% of this variation: nearly all the inequality in HIV stigma occurred within population subgroups rather than between them. In longitudinal analyses, public stigma showed trait-like properties (intraclass correlation coefficient=0.35; 95% CI, 0.31-0.38) and meaningful rank-order stability (baseline-to-endline r=0.41). Perceived stigma showed no rank-order stability, no appreciable between-person variance, and universal convergence to low levels regardless of baseline. ConclusionsBoth public and perceived HIV stigma declined substantially in this rural Ugandan population, but remaining public stigma has become concentrated within a persistent minority. Sociodemographic profiling to target individuals who carry persistently negative attitudes toward people with HIV is unlikely to succeed.

Background: The isolation of many HIV broadly neutralizing antibodies (bnAbs) from people living with HIV (PLWH) and rigorous characterization of their ontogeny has promoted the goal of reverse engineering their natural development as a strategy for achieving an effective preventive HIV vaccine. We previously described the developmental process of CH103, a CD4-binding site (CD4bs)-specific monoclonal antibody, and the associated evolution of HIV Envelopes (Envs) within the person (CH505) from whom it was isolated. A series of monomeric gp120 protein subunit immunogens representing the transmitted founder (TF) and Envs that evolved during infection and optimally reacted with lineage members at each step of the CH103 clone maturation path were evaluated in this placebo controlled randomized vaccine trial to test for the first time in humans the concept of whether sequential immunization with gp120 monomeric proteins can recapitulate the development of CD4bs B-cell clonal lineages, including CH103. Methods: HIV Vaccine Trials Network 115 (HVTN 115) was a randomized placebo-controlled vaccine trial at US clinical research sites. We tested the safety and immunogenicity of CH505TF gp120 + GLA-SE (Part A), and then the ability of sequential CH505 gp120 proteins (corresponding to CH505s weeks 53 and 78 Envs) + GLA-SE immunizations to induce CD4bs-specific neutralizing antibodies (Part B). We assessed binding and neutralizing antibody responses, antibody dependent cellular cytotoxicity, antibody dependent cellular phagocytosis, T-cell responses and B-cell phenotyping. Results: We enrolled 42 participants between October 2017 and May 2018 for Part A, and 65 participants from December 2020 to October 2022 for Part B. Immunization with the CH505 gp120 proteins adjuvanted with GLA-SE was well tolerated and induced CD4bs-specific B cells and Env-specific plasma antibodies. The plasma neutralizing antibody response was limited to primarily tier 1 autologous and heterologous HIV-1 strains. Blood-derived B-cell repertoire analyses identified CD4bs antibodies that preferentially bound to open-occluded trimeric Envs that exist in an intermediate state between prefusion-closed to CD4-bound open confirmations, consistent with tier 1 HIV neutralizing activity. Conclusions: Together, these results suggest that the low-affinity CH505TF gp120 monomer elicited CD4bs antibodies in the sera and B-cell repertoires of humans. However, our findings also indicate that gp120 monomers are insufficient to induce detectable bnAb precursors to epitopes on native Env trimers. Nonetheless, our data provide a benchmark for comparison with ongoing clinical trials testing high-affinity CH505 Env trimers for induction of CD4bs bnAb precursors.

Background. Nascent findings suggest that people with attention-deficit/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk. Methods. We used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported. Findings. At baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive. Interpretation. In the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group. Funding. This paper received no direct funding. GDB is supported by the UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).

Background Lifestyle interventions can increase the probability of remission of prediabetes to normal glucose tolerance, but their economic value remains unclear. We assessed the within-trial and lifetime-horizon modeled cost-effectiveness of intensive and conventional lifestyle interventions in risk-stratified participants with prediabetes. Methods A health economic evaluation was conducted alongside the 12-month multicenter PLIS trial (n=1,105). High-risk participants were randomized to intensive (HR-INT) or conventional (HR-CONV); low-risk participants to conventional lifestyle intervention (LR-CONV) or control (only short single consultation; LR-CTRL) with risk stratification based on insulin secretion, insulin sensitivity, and liver fat content. Within-trial analyses estimated incremental costs per additional remission to normoglycemia and per quality-adjusted life year (QALY). Lifetime cost-effectiveness was modelled using a four-state Markov Model. Findings At 12 months, HR-INT and LR-CONV increased remission compared with their respective comparators. The incremental cost per additional remission was {euro}7,081 (95% CI: dominated-47,277) for HR-INT and {euro}4,278 (1,312-11,793) for LR-CONV from a health insurance perspective. A willingness-to-pay of {euro}22,000 (HR-INT) and {euro}7,500 (LR-CONV) per additional remission corresponded to 90% probability of cost-effectiveness. Neither intervention was cost-effective in terms of QALYs gained within the 12-months period. Lifetime modelling suggested that both HR-INT and LR-CONV are not only cost-effective, but also cost-saving, relative to HR-CONV and LR-CTRL, respectively. Also in the probabilistic sensitivity analysis, most simulations indicated dominance (71.7% for HR and 88% for LR). Interpretation Based on short-term economic evaluation, the interventions assessed were cost-effective regarding additional participants with remission, not for incremental QALYs gained. Lifetime modelling suggests cost savings for both risk groups. Targeting populations with lifestyle interventions to achieve prediabetes remission seems to generate good value for money in the long term.

Abstract Introduction The ARRIVE trial first demonstrated that elective induction of labour (IOL) at 39 weeks in low-risk pregnancies reduced the likelihood of caesarean section (CS) without compromising perinatal safety; however, the generalizability of these findings remains debated, leading to uncertainty in clinical practice. The LIRIC trial aims to evaluate whether 39-week elective IOL reduces CS rates compared with expectant management, while exploring its impact on infant neurodevelopment and multi-omics profiles. Methods and analysis This is a single-centre, open-label, randomized controlled trial in China. A total of 1,074 low-risk pregnant women (nulliparous or multiparous) will be randomly assigned (1:1 ratio) to either 39-week IOL or expectant management. The primary outcome is the caesarean section (CS) rate. Secondary outcomes include a composite of severe neonatal morbidity and perinatal mortality and infant neurodevelopmental scores (Bayley-4 and ASQ-3), among others. Data analysis will follow the Intention-to-Treat (ITT) principle. Biospecimen will be collected for metagenomic and metabolomic analyses, with results to be reported separately. Ethics and dissemination The protocol has been approved by the Ethics Committee of Women's Hospital, School of Medicine, Zhejiang University. Informed consent will be obtained from all participants. Results will be disseminated via peer-reviewed journals, and standardized infant developmental reports will be provided to participants to enhance study benefit. Trial registration number NCT07082530.

Background Fertility rates in Australia have been declining over recent decades, reaching a record low total fertility rate of 1.48 births per woman in 2024. Concurrently, vasectomy remains widely accessible and increasingly normalised as a permanent contraceptive option. Despite extensive commentary on falling birth rates, no contemporary Australian study has examined vasectomy rates relative to birth rates over time. We aimed to compare population level vasectomy and birth rates across Australian jurisdictions and age groups. Study design Nationwide retrospective time-series study. Retrospective population-based study using Medicare Benefits Schedule item 37623 to identify vasectomy procedures performed between July 2015 and December 2024. Rates were calculated per 100,000 male population using quarterly Australian Bureau of Statistics (ABS) population estimates and summarised as rolling 12-month averages. Birth rates were derived using matched ABS data for women across equivalent age strata (18-24, 25-34, 35-44 years). Results: Vasectomy rates increased nationally from 32 per 100,000 in 2016 to 55 per 100,000 in 2023 before declining modestly in 2024. Birth rates declined from 5,200 to 3,800 per 100,000 over the same period. Trends were consistent across states and age groups, with the greatest vasectomy uptake in men aged 35-44 years. Conclusion: Australia is undergoing a demographic shift characterised by rising vasectomy uptake and declining fertility. While vasectomy rates remain lower than birth rates, their convergence signals changing reproductive intentions and contraceptive behaviours. Ongoing monitoring of permanent and long-acting contraception is essential to understand evolving population dynamics and inform reproductive health policy.

ImportanceChildren with Down syndrome (DS), a genetic condition associated with neuromotor impairments, walk [~]1 year later than typically developing peers. Treadmill training is the most successful known intervention for accelerating walking onset in DS. Overground stepping with mobility devices better mimics critical properties of real-world walking, but it is unknown how overground stepping develops in pre-walking infants with DS. ObjectiveWe aimed to characterize the developmental trajectory of stepping quantity and quality in supported overground stepping compared to supported treadmill stepping. We also measured infants ability to self-propel in the walker. Finally, we assessed caregivers perspectives on both devices. DesignWe tested infants at 10, 13, 16, and/or 19 months of age. SettingThis study occurred in a university laboratory in the United States. ParticipantsWe tested 31 pre-walking infants with Down syndrome across 69 sessions. ExposureAt each session, infants completed four trials per task (treadmill and walker) and a test of self-propulsion in the walker. Main Outcomes and MeasuresWe measured step quantity (overall step rate and alternating step rate), step quality (percentage of steps that were alternating, forward, and flat-landing), the ability to self-propel the walker, and caregiver perspectives on both devices. ResultsStep quantity increased with age and varied by task--infants took more steps per minute in the walker compared to the treadmill. Moreover, steps were of equal or higher quality in the walker. By 16 months, about half of infants could self-propel. Caregivers viewed both devices favorably, though the majority preferred the walker for home and/or community use. ConclusionsOverground walkers promote more stepping than a treadmill in pre-walking infants with DS, with stepping of similar or higher quality. Caregivers feel positively about overground walkers. RelevanceOverground stepping using a suspension walker shows promise as an intervention for pre-walking infants with Down syndrome.

Background: Isoniazid resistance is the most common form of drug-resistant tuberculosis (TB) globally. However, WHO-recommended molecular tests available to most TB patients worldwide detect rifampin resistance only, risking under-treatment of isoniazid-resistant, rifampin-susceptible TB (HR-TB) and subsequent emergence of rifampin resistance. Methods: This prospective study (2020-2024) aimed to collect and archive sputum specimens from all adults diagnosed with rifampin-susceptible pulmonary TB in Ho Chi Minh City, Vietnam. Cases were participants who developed rifampin-resistant recurrence; controls had rifampin-susceptible recurrence or no recurrence. Whole-genome sequencing of paired isolates distinguished acquired rifampin resistance from reinfection. The effect of pre-existing isoniazid resistance on rifampin resistance acquisition was estimated using inverse probability of treatment weighting, and the projected epidemiological impact of routine HR-TB testing was modelled. Results: 42,843 people were diagnosed with TB during the study period, from whom we archived 33,843 sputum samples. We enrolled 1,241 participants, 873 (70.4%) of whom had analysable data. 51/873 (5.8%) acquired rifampin resistance, of whom 49/51 (96.1%) had undetected isoniazid resistance. The weighted risk of acquired rifampin resistance was 2.98% (95% CI 2.08-4.50) with undetected isoniazid resistance, versus 0.03% (0.00-0.08) without (risk ratio105.42 (33.43-309.69)). Modelling projected that universal HR-TB diagnosis and treatment would reduce RR-TB incidence by 46% (35-61) over 10 years in Vietnam, with reductions of 26% (12-43) projected even where HR-TB prevalence was as low as 5%. Conclusions: Undetected, under-treated HR-TB confers a 100 fold increased risk of acquiring rifampin resistance. Routine isoniazid susceptibility testing combined with effective HR-TB treatment could substantially reduce the burden of RR-TB.

Background Tobacco smoking during pregnancy increases the risk of preterm birth, small for gestational age (SGA), stillbirth, and longer-term adverse health outcomes. Globally, reducing smoking in pregnancy is a key public health priority, yet the organisation, accessibility, and effectiveness of cessation support varies substantially between countries and healthcare systems. Differences in policy implementation, resource allocation, and integration of cessation services into antenatal care influence uptake and success rates across diverse settings. In England, pregnant women are entitled to free smoking cessation support, however, service delivery varies across regions with mixed efficacy. While tobacco smoking is more prevalent in deprived communities, there is limited understanding of how, why, for whom, and under what circumstances these services are most effective, particularly in areas of social deprivation, such as the North East and Yorkshire. Objective To conduct a realist evaluation to understand how smoking cessation services support pregnant women in areas of social deprivation to stop smoking and reduce adverse perinatal outcomes. Methods This multi-site realist evaluation will be conducted across three NHS maternity services in West Yorkshire, England. The study comprises four iterative stages: (1) development of initial programme theories through realist-informed literature scoping and stakeholder consultation; (2) case study data collection including qualitative interviews with pregnant women (approximately 15-30) and staff (approximately 15-30); (3) analysis of routine anonymised maternity and neonatal electronic data collected over a one-year period; and (4) realist analysis to refine context-mechanism-outcome (CMO) configurations. Qualitative data will be analysed using realist logic supported by NVivo software. Quantitative data will be analysed using descriptive and inferential statistics to explore associations between smoking cessation engagement and perinatal outcomes. Ethics and dissemination Ethical approval was obtained through the UK Health Research Authority and a Research Ethics Committee prior to study commencement (IRAS 364173; REC reference number 26/SC/0020). Findings will inform recommendations to improve smoking cessation support for pregnant women in deprived areas. Results will be disseminated through peer-reviewed publications, conference presentations, and stakeholder engagement.

Background: Lipoprotein(a) (Lp[a]) is a genetically determined causal and independent cardiovascular risk factor and Lp(a) targeted therapies are being developed. However, evidence on the safety of substantial Lp(a) lowering during pregnancy is limited. We evaluated the impact of Lp(a) lowering on adverse pregnancy and perinatal outcomes (APPOs) using human genetic evidence. Material and Methods: We applied a drug-target Mendelian randomization (MR) approach using genetic variants associated with Lp(a) in the UK Biobank at the LPA locus to proxy pharmacological Lp(a) lowering. Summary-level APPO data were obtained from the MR-PREG collaboration, comprising up to 714,899 women across multiple studies. Twenty APPOs were included. Sensitivity analyses included adjustment for fetal genotype, alternative Lp(a) datasets, leave-one-study-out analyses, and exploration of Lp(a) genetic scores and individuals homozygous for LPA loss-of-function variants in the UK Biobank. Results: Across 20 APPOs, MR estimates showed no strong evidence of causal effects, with no associations surviving false discovery rate P-value correction. Most estimates were close to null, including gestational hypertension, gestational diabetes, preeclampsia, miscarriage and neonatal intensive care unit admission. Some associations were slightly larger in magnitude but with wide confidence intervals: gestational age (mean difference 0.04 weeks, 95% CI 0.02-0.06 per 210nmol/L reduction in Lp[a]) and congenital malformation (OR 0.82, 95% CI: 0.72-0.94) in the protective direction of effect, and higher odds of stillbirth (OR 1.09, 95% CI: 1.00-1.19) and low Apgar at 1 minute (OR 1.11, 95% CI: 0.99-1.24). Sensitivity analyses consistently supported the primary findings, with no evidence of increased maternal nor offspring risk in analyses adjusting for maternal-fetal genotype, across alternative exposure datasets, or in leave-one-study-out tests. Individual-level analyses of Lp(a) genetic score and LPA loss-of-function variants showed no associations, although power was limited. Conclusion: These findings suggest that substantial lowering of Lp(a) is unlikely to increase APPO risk, although modest effects, particularly for rare outcomes, cannot be excluded.

Lower cognitive ability measured in childhood or late adolescence has been consistently associated with higher mortality risk across adulthood. However, this evidence largely relies on single assessments, leaving it unclear to what extent mortality risk reflects cognitive differences established early in life versus developmental divergence during adolescence - a period of substantial neurocognitive plasticity. Using two nationally representative Swedish cohorts comprising 9,412 males born in 1948 and 1953, we linked cognitive ability assessed in primary school at age 13 years and military conscription at age 18 years to all-cause and cause-specific mortality recorded in nationwide registers through 2025. We decomposed late-adolescent cognitive ability into childhood cognitive level and adolescent cognitive change and evaluated their independent associations with mortality. Childhood cognitive level (HR = 0.81; 95% CI, 0.78-0.85) and adolescent cognitive change (HR = 0.84; 95% CI, 0.79-0.89) independently predicted lower mortality risk, also after adjustment for parental education. Childhood cognitive level and adolescent cognitive change showed partially distinct cause-specific patterns. Childhood cognitive level was most strongly associated with mortality from intrinsic causes, whereas adolescent cognitive change showed relatively stronger associations with external causes, particularly accidental deaths. Although adolescent cognitive change was associated with psychosocial factors including education and psychiatric diagnosis at conscription, its association with mortality persisted after adjustment for these factors. These findings suggest that cognitive development during adolescence carries independent prognostic information regarding long-term survival beyond cognitive level established by late childhood, highlighting adolescence as a consequential period for lifelong health.

Background: Physical activity is a well-established modifiable risk factor for depression and anxiety. However, whether vigorous intermittent lifestyle physical activity (VILPA), defined as short, sporadic bouts embedded in daily life, confers mental health benefits remains unclear. We aimed to examine the associations of accelerometer-measured VILPA with risks of incident depression and anxiety among non-exercising adults. Methods: This prospective cohort study included 19,962 non-exercising adults (mean age 62.3 years) from the UK Biobank, free of depression and anxiety at baseline (2013-2015), with 7-day wrist-worn accelerometry data. Cox proportional hazards models and restricted cubic splines were used to examine associations between average daily duration of VILPA bouts lasting up to 1 or 2 minutes and these outcomes. Findings: Over an average follow-up of 7.8 years, 469 participants developed depression and 536 developed anxiety. Approximately 94.6% of participants engaged in VILPA bouts lasting up to 1 minute. Daily VILPA duration exhibited L-shaped associations with both depression and anxiety. Compared with participants who accumulated no VILPA, the whole-sample median daily VILPA duration for bouts lasting up to 1 minute, 4.1 minutes, was associated with a hazard ratio of 0.70 (95% confidence interval [CI]: 0.56-0.88) for depression and 0.79 (95% CI: 0.64-0.97) for anxiety. Findings were similar for VILPA bouts lasting up to 2 minutes. Interpretation: Among non-exercisers, even small amounts of VILPA were associated with substantially lower risks of depression and anxiety, highlighting the potential of high-intensity incidental physical activity as a feasible strategy for preventing depression and anxiety, particularly among individuals unable or unwilling to engage in structured exercise.

Background Community-wide active case-finding (ACF) is being increasingly implemented as a tuberculosis (TB) elimination intervention. However, conventional site selection strategies may result in low yields from screening. We evaluated whether an artificial intelligence (AI) software guided targeting strategy could improve detection of TB during screening activities (called camps) relative to routine approaches to site selection in the programmatic setting in Pakistan. Methods We conducted a stepped-wedge cluster-randomised trial embedded within Global Fund supported ACF activities implemented by Pakistan s National TB Program and private sector partners. Thirty mobile X-ray van teams operating in 68 districts were randomly assigned to transition from routine site selection approaches (based on field-staff experience and historical data) to an AI-guided targeting strategy, using the software MATCH-AI. We assessed the effect of the intervention on the primary outcome, Camp Positivity Yield, defined as the number of individuals diagnosed with bacteriologically confirmed TB per camp, using generalised linear mixed models. The primary analysis was by intention to treat. Camps conducted within a 5-km radius of the AI selected locations were included in a validated per-protocol analysis. We conducted several district-level subgroup analyses. This trial is registered, number NCT06017843. Findings Between August 2023 and September 2024, 3,936 screening camps were conducted (2,046 control, 1,890 intervention), screening 269,254 individuals. In the intention-to-treat analysis, Camp Positivity Yield was 7% higher in the intervention group relative to the control group, however this difference was not statistically significant (adjusted risk ratio [RR] 1.07, 95% CI: 0.94 -1.22). In the validated per-protocol analysis, Camp Positivity Yield was 32% higher in the intervention group relative to the control group (adjusted RR 1.32, 95% CI: 1.12-1.54). Yields were highest in districts that had moderate baseline yields of 0.5-1% per population screened prior to the trial (adjusted RR: 1.57, 95% CI: 1.13 - 2.18) and in rural districts (adjusted RR 1.43, 95% CI: 1.23 -1.65). Interpretation The use of an AI-guided targeting strategy significantly increased detection of bacteriologically confirmed TB during active case-finding in the validated per-protocol analysis, relative to conventional site-selection approaches employed by field-staff. This software may be considered as a supportive tool to improve the efficiency of community-based TB case-finding interventions in other high burden countries.

Background: The Vaccine Safety Datalink (VSD) detected a statistical signal for ischemic events (ischemic stroke or transient ischemic attack) following bivalent mRNA COVID-19 vaccination through prospective surveillance during 2022-2023. Although multiple studies from other surveillance systems and countries reported no increased risk, important methodological limitations remained. This U.S. study addressed those limitations by evaluating the ischemic stroke risk following bivalent mRNA COVID-19 vaccination, influenza vaccination, and their same-day coadministration using event-dependent self-controlled case series (SCCS) design. Methods: Study outcomes included first-ever ischemic stroke (primary outcome), first-in-1-year ischemic stroke (secondary outcome), and ischemic events (exploratory outcomes), identified using ICD-10-CM codes in inpatient and emergency department settings during September 1, 2022-March 31, 2023, among individuals aged>=12 years across eight VSD sites. Analyses were conducted separately for Pfizer-BioNTech and Moderna bivalent vaccines, with relative incidences (RI) and 95% confidence intervals (CI) estimated for 1-21-day and 1-42-day risk intervals, using person-time outside these intervals as the control period. Subgroup analyses were performed by age group (12-64, >65 years) and history of documented SARS-CoV-2 infection. Results: A total of 6,510 first-ever ischemic strokes were identified among more than 6.8 million participants. Among recipients of Pfizer-BioNTech bivalent COVID-19 and influenza vaccines, no statistically significant increased risk of first-ever ischemic stroke was observed following bivalent COVID-19 vaccination (RI=0.94; 95% CI: 0.63-1.41), influenza vaccination (RI=0.95; 95% CI: 0.82-1.10), or same-day coadministration (RI=1.15; 95% CI: 0.88-1.49) within 1-21-day risk intervals; findings were similar for 1-42-day intervals. Comparable null results were observed for Moderna vaccines and across all subgroups, secondary, and exploratory outcomes. Conclusion: No increased risk of ischemic stroke was found following bivalent mRNA COVID-19 vaccination, influenza vaccination, or their coadministration in this multi-site SCCS study. These findings are consistent with previous studies and underscore the importance of continued vaccine safety monitoring.

Background: Microbiota dysbiosis of the skin has been implicated in ulcer formation. Individuals with diabetes remain at high risk for diabetic foot ulcers (DFUs) even after ulcer healing. Topical chlorhexidine gluconate (CHG) is a broad-spectrum antiseptic commonly used to reduce microbial burden. In a prior randomized clinical trial comparing daily CHG foot treatment with soap-and-water treatment, no statistically significant reduction in new DFUs was observed, prompting evaluation of whether CHG produced durable changes in the skin microbiota. Objective: To compare changes in foot skin microbiota (including bacterial bioburden, diversity, and community composition) associated with daily CHG versus soap-and-water use over one year in people with diabetes and prior foot complications. Methods: In a single-center, double-blind, placebo-controlled randomized trial, 87 participants were randomized to daily CHG wipes or soap-and-water wipes for 12 months. Foot swabs were collected at baseline, 3 and 12 months, and 4 weeks post-treatment. Bacterial bioburden was quantified. Microbiota composition was assessed using 16S rRNA and ITS amplicon sequencing. Key Results: CHG treatment significantly reduced bacterial bioburden, increased microbial diversity, and altered community composition, including sustained reductions in Staphylococcus abundance. Several microbiota changes persisted more than 4 weeks after treatment cessation. Soap-and-water treatment showed similar but smaller and largely nonsignificant trends. Conclusions: Daily CHG use durably modifies foot skin microbiota in high-risk individuals with diabetes. However, this alone may be insufficient to prevent new foot complications, highlighting the need for additional interventions. These findings have implications for long-term CHG use in populations at risk for staphylococcal infections.

Background: Observational studies have consistently reported associations between social media use (SMU) and poorer mental health outcomes; however, such designs cannot establish causality. This study synthesised evidence from randomized experiments to estimate the effects of restricting SMU on mental health outcomes. Methods: A systematic search was conducted across MEDLINE, Embase, PsycINFO, and Cochrane CENTRAL to identify experimental trials evaluating interventions that constrained SMU for at least 24 hours and included an unconstrained control condition. Multilevel random-effects meta-analyses were used to synthesise effect estimates. Prespecified meta-regressions explored study-level moderators, and population-level impact fractions were estimated relative to global SMU prevalence. Results: From 7,784 screened records, 37 reports representing 35 distinct studies were included (pooled N = 7,160). Most interventions lasted one to three weeks and targeted college-aged youth. Pooled estimates favoured SMU constraints across outcomes, with magnitude and precision varying by domain. Confidence intervals were entirely above zero, consistent with a beneficial response for depressive symptoms (g = 0.22; 95% CI, 0.12 to 0.32), perceived stress (g = 0.15; 95% CI, 0.01 to 0.29), anxiety symptoms (g = 0.19; 95% CI, 0.05 to 0.34), fear of missing out/nomophobia (g = 0.14; 95% CI, 0.04 to 0.24), and well-being (g = 0.36; 95% CI, 0.10 to 0.63). Heterogeneity was substantial for several outcomes (I2 > 75%). In bivariate meta-regressions, higher baseline SMU was associated with larger effects for anxiety symptoms ({beta} = 0.13; 95% CI, 0.03 to 0.22), and longer interventions were associated with larger effects for depressive symptoms ({beta} = 0.16; 95% CI, 0.02 to 0.30). Inferences revealed that a short-term reduction in SMU globally could plausibly mitigate 17.5% and 15.4% of depressive and anxiety symptom cases, respectively. Conclusions: Experimental design-based evidence supports the causal case for an effect of SMU on mental health, with constraints producing improvements across multiple outcomes and no evidence of harm. Population-level inferences suggest that even individually modest effects may translate into meaningful public health benefits given the high prevalence of SMU exposure. These findings suggest that reducing SMU may represent a low-intensity, low-cost, scalable strategy to support mental health and improve well-being.