PNAS Nexus

Inappropriate antibiotic use presents a major global health challenge, particularly in low-resource settings where access to quality care is limited but antibiotics remain relatively unrestricted. This study estimates the causal effect of frontline primary care quality on inappropriate community antibiotic use, combining detailed community-based data from approximately 100 rural villages in rural China with an instrumental variable (IV) approach embedded within a double/debiased machine learning (DML) framework. We linked objective measures of village doctor clinical practice quality, measured through unannounced standardized patient visits, to household-level antibiotic use data collected from the same villages. To identify the causal effect, we constructed multiple candidate instruments from extensive provider characteristics and used an ensemble of machine learning algorithms within a flexible DML-IV framework to approximate an optimal instrument, addressing a many-weak-instruments problem. We found that improving village provider clinical practice quality reduced both antibiotic receipt during healthcare encounters for common diseases and household antibiotic storage for future self-medication. Our findings suggest that strengthening frontline primary care quality can meaningfully reduce inappropriate community antibiotic use without restricting access to essential treatment. More broadly, this study illustrates how causal machine learning can strengthen conventional causal estimation in complex observational settings in global health economics research.

Improvements in data availability, sharing, and integration, together with the development of explainable artificial intelligence (XAI) techniques, are advancing precision medicine for pediatric cancer by facilitating diagnosis, biomarker discovery, and drug development. Data sharing commons and initiatives like the Childhood Cancer Data Initiative (CCDI) provide access to pediatric-specific genomic and clinical data cohorts and improve data availability for pediatric cancer research. Based on CCDI, a scalable AI platform, Graph Artificial Intelligence for Pediatric Oncology (GAIPO), integrates various data modalities from bulk and single-cell omics data to clinical information. Such multi-modal data facilitates the training and development of advanced XAI models for pediatric cancers. We then developed an end-to-end multi-modality framework, PCGS, for pediatric cancer by incorporating omics-specific representation learning via GNN models with cross-attention fusion and multi-objective learning for downstream tasks such as classification, clustering, and survival analysis. This framework outperforms previous supervised multi-omics integration baseline approaches based on glioma and Wilms tumor cohorts and enables GNN model explainability via Shapley value-based feature attribution approaches to explain the contributions of gene-level features across various biomedical tasks, including classification and survival. Given specific background samples (e.g., age groups, sex, grades) as baselines, this explainable GNN model estimates and ranks the importance scores for input features from each omics modality. It identifies background-specific key features for biomarker discovery, risk group identification, and survival analysis in glioma and Wilms tumor, with potential applicability to other pediatric cancers.

Contact inhibition of proliferation (CIP) enables epithelial tissues to self-regulate growth and maintain tissue homeostasis. However, how cell-level mechanical contact, tissue-scale structural order, and proliferation kinetics interplay remains a fundamental open question in living matter physics. Here, we present a particle-based model of a confluent epithelial monolayer governed by overdamped dynamics, where individual cells interact via a two-dimensional hard core- soft shoulder potential. By comparing structural evolution during quasistatic densification with previously reported experimental division kinetics, we find that the dynamics of proliferation arrest mimics the onset of direct steric contacts between the hard cores of the shell. Identifying hard core contacts as the physical driver of CIP, we couple our mechanical model with a stochastic Monte Carlo division scheme in which the instantaneous division rate decreases to zero from an intrinsic value as the number of hard core contact increases to six from zero. We demonstrate that for high intrinsic division rates, the cellular densification outpaces mechanical relaxation. This kinetic mismatch drives premature hard-core contact formation, shifts the onset of jamming and contact inhibition to lower packing fractions, and induces increasingly disordered transient configurations before the tissue universally converges to a hexagonal close-packed limit. Our model's predicted division kinetics and structural order evolution are consistent with epithelial monolayer experiments, both reported and our own. This minimal physical framework links single-cell steric contact mechanics directly to tissue-scale growth regulation and structural evolution.

Background Childhood respiratory mortality in China has fallen by over 90% in three decades alongside sustained national warming, yet national long-run evidence on temperature and child respiratory mortality is lacking. Methods We linked Global Burden of Disease (GBD) 2021 mortality estimates for China - lower respiratory infections (LRI), ages 0-19, and asthma, ages 0-24, 1990-2021 - with C-LSAT 0.5 deg gridded temperature data (1990-2019), aggregated nationally and to five climate zones. Four annual indicators (mean temperature, diurnal temperature range, seasonal amplitude, interannual variability) entered regressions of log mortality rates with Newey-West standard errors. A bootstrapped (500 resamples) quadratic model probed the minimum mortality temperature (MMT), with PM2.5-adjusted analyses and future-exposure, permutation, and detrended falsification tests. Results LRI deaths fell by 96.3% (330,194 in 1990 to 12,098 in 2021; 95% uncertainty interval 9,669-14,891) and asthma deaths by 94.9% (3,287 to 167), while mean temperature rose 0.364 deg C per decade and diurnal temperature range narrowed 0.092 deg C per decade. Baseline coefficients were large (mean temperature -1.696, SE 0.174; diurnal temperature range +2.408, SE 0.336; seasonal amplitude -0.162, SE 0.082; interannual variability +2.924, SE 1.514, per 1 deg C in log rate), but the future-exposure test failed and detrending nullified every coefficient: the associations are trend-level, and short-cycle causal effects are not identifiable. Nor was the national MMT identifiable - observed temperature support spans only 6.66-8.13 deg C, and the nominal turning point of 35.84 deg C is an extrapolation artifact (quadratic term p = 0.963). Within the observed range, warming and declining mortality moved in the same direction. Conclusions The 96% decline in childhood respiratory mortality cannot be attributed to warming. China sits on the low-temperature side of the optimum, and the marginal direction of future warming requires stronger designs to establish. The falsification framework offers a discipline for climate-health inference in China.

Wastewater-based epidemiology (WBE) has emerged as a powerful population-level surveillance tool, but its coverage is structurally concentrated in in-network urban areas, potentially leaving rural populations underrepresented. Routine human movement between sewered (in-network) and unsewered (off-network) areas may, however, cause wastewater treatment plant (WWTP) measurements to reflect infectious disease dynamics beyond sewer boundaries. We evaluated this hypothesis using daily clinical COVID-19 testing data (January 2021-April 2022) across New York State excluding New York City (NYC). We disaggregated weekly cases and tests into in-network (WWTP catchment area) and off-network (outside WWTP catchment area) components applied to two geographic frameworks: administrative counties (N = 53 mixed-coverage) and mobility-defined communities identified through Walktrap community detection applied to census tract-level movement networks (N = 32 mixed-coverage). In/off-network COVID-19 trends were strongly correlated under both frameworks. County-level statewide aggregate correlations were high (incidence r = 0.994, positivity r = 0.996), as were individual county correlations (median r = 0.909 and 0.932, respectively). Mobility-defined community-level statewide correlations were similarly strong (r = 0.990 and 0.992), with comparable unit-level medians (r = 0.877 and 0.894). The mobility-defined community framework provided better population balance between in-network and off-network strata (87.5% vs. 69.8% in balanced range) and a higher floor on representativeness (minimum r = 0.440 vs. 0.177). Population size was the dominant predictor of in-network/off-network alignment at both scales; wastewater infrastructure density and off-network signal variability provided additional explanatory power at the mobility-defined community level. WWTPs broadly represent COVID-19 dynamics in surrounding off-network populations, supporting their use as sentinel surveillance sites. Representativeness weakens in smaller, more rural communities, and mobility-defined communities provide a complementary framework for identifying where this occurs.

Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection is associated with accelerated liver disease, but whether coinfection is associated with newly documented social determinants of health (SDoH) is unclear. We conducted a retrospective cohort study using TriNetX across 110 U.S. healthcare organizations (2010-2026). We propensity score matched adults with HIV/HBV to adults with HIV or HBV monoinfection. We organized newly documented SDoH indicators using a dynamic individual-level framework with four clinically recognized domains of social disadvantage: material vulnerability, healthcare access and engagement, interpersonal adversity, and psychosocial vulnerability. Matched cohorts included 10,071 HIV/HBV-HIV pairs and 9,659 HIV/HBV-HBV pairs (mean age, 47 years; 79% male; 66% non-White; median follow-up, 3.3 years). Over 178,900 person-years, HIV/HBV was associated with higher risk of the primary SDoH composite compared with HIV (11.5% vs 9.7%; incidence rate, 2.50 vs 1.97 per 100 person-years; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.15-1.37) and HBV (11.0% vs 6.4%; incidence rate, 2.39 vs 1.67; HR, 1.50; 95% CI, 1.35-1.67). HIV/HBV was also associated with higher material vulnerability and healthcare access and engagement composites in both comparisons, including housing instability, food insecurity, financial insecurity, insurance instability, and care disengagement/nonadherence (HR range, 1.22-3.33 vs HIV; 1.31-1.94 vs HBV). In the HBV comparison, HIV/HBV was additionally associated with interpersonal adversity, primary support stressors, and violence or victimization (HR range, 1.36-2.16). Findings were robust across sensitivity analyses. HIV/HBV was associated with more newly documented SDoH than monoinfection, supporting dynamic SDoH assessment.

Over the course of a lifetime, somatic mutations accrue in normal human cells, causing variation in cell phenotype and engendering somatic evolution with outcomes ranging from the adaptive immune system to cancer. To inform understanding of somatic evolution in the human body we report the mutation rates and mutational signatures of 53 normal cell types. Most show evidence of linear mutation accumulation over time with single base substitution mutation rates ranging from ~3.5/year/diploid genome in spermatogonia and sperm, to ~20/year in postmitotic neurons, ~50/year in mitotically active colorectal epithelial cells, ~60/year in kidney proximal tubule cells and hepatocytes, 100s/year in sun-exposed skin epidermal cells and 10-50/year in the remainder. Certain cell types, including skin epidermis, cardiac myocytes, bladder urothelium, kidney proximal tubule cells, and hepatocytes, show substantial variability in mutation burdens around the linear age trend, indicating the influence of additional factors which differ between individuals and modulate mutation accumulation, including exogenous mutagen exposures. At least 18 single-base substitution and nine small insertion and deletion mutational signatures are present, some in all cell types, some in a subset and others in a single cell type. Known exogenous mutagen exposures and endogenous mutational processes account for some mutational signatures, but the origins and mechanisms underlying many are uncertain. This comprehensive survey of mutagenesis provides a foundation for understanding somatic evolution of human cell populations in health and disease.

Background In adults, cold-attributable mortality exceeds heat-attributable mortality roughly 17-fold. Child-specific evidence has begun to emerge only recently - a nationwide Brazilian case-crossover study located the minimum mortality temperature (MMT) for under-five deaths, and a 56-country survey-based analysis linked monthly temperature anomalies to under-five mortality - but no multi-country, climate-zone-resolved estimate of the childhood respiratory-infection MMT exists, and whether temperature variability is independently associated with childhood respiratory mortality at the global scale is unknown. We quantified both. Methods We combined Global Burden of Disease 2023 mortality estimates, lower respiratory infection (LRI) deaths at ages 0-19 years and asthma deaths at ages 0-24 years, 171 countries, 1990-2023 - with 0.5 deg monthly land temperature and diurnal temperature range (DTR) fields from C-LSAT/C-LDTR (1901-2023). Four exposure dimensions (annual mean, DTR, seasonal amplitude, interannual variability) entered two-way fixed-effects models with Driscoll-Kraay standard errors. A quadratic term in mean temperature located the MMT, with percentile confidence intervals from a 300-replication country-cluster bootstrap. Future-exposure leads, country-level detrending, and permutation tests assessed contemporaneous causality, applied to both the linear coefficients and the quadratic term generating the MMT; national pneumococcal conjugate vaccine (PCV3) coverage and ambient PM2.5 exposure series were added as time-varying mechanistic covariates. Results The childhood LRI MMT was 17.1 C (95% CI 14.7-19.8), the 36th percentile of the annual-temperature distribution; zone estimates were 24.7 C in tropical and 15.8 C in subtropical countries, with weak temperate and no subarctic identification. The quadratic term underpinning the MMT, however, failed both falsification checks - future temperatures reproduced the U-shape and country-level detrending erased it - so these MMT values describe a trend-level geographic pattern of the annual construct rather than a contemporaneous dose-response. Interannual temperature variability was positively associated with LRI (+0.278, 95% CI 0.102-0.454; p = 0.002) and asthma mortality (+0.836, 95% CI 0.447-1.226; p = 2.6 x 10^-5) per 1 C, but future-exposure models returned nearly identical significant coefficients and detrending erased significance, supporting only a trend-level association; adjustment for national PCV3 coverage and PM2.5 exposure left these estimates essentially unchanged. Annual mean temperature was likewise inversely associated with both outcomes at the trend level; DTR and seasonal amplitude showed no independent within-country effects. Conclusions This study provides the first multi-country, climate-zone-resolved geography of the optimal temperature for childhood respiratory survival, spanning 171 countries; because the underlying quadratic association is trend-level, the estimates are directional. The observed variability-mortality associations are trend-level signals rather than contemporaneous causal evidence; daily-scale, child-specific designs are required to determine whether short-term thermal variability affects paediatric respiratory mortality.

Purpose: The primary objective of the Stanford Knee Osteoarthritis PET/MRI Evaluation (SKOPE) study is to develop and evaluate a multimodal, dynamic [18F]NaF PET-MRI framework for characterizing whole-joint physiology and its relationship to osteoarthritis (OA) risk, pain, and disease progression. Specifically, we aim to integrate dynamic PET with quantitative and anatomical MRI, to characterize structural, compositional, and metabolic features across the knee and surrounding musculoskeletal system, evaluate acute tissue responses to exercise, and identify imaging biomarkers associated with OA risk, pain, and disease progression. Methods: The SKOPE study includes multimodal PET-MRI of the knee and surrounding musculoskeletal tissues, with imaging of the knee, tibia, ankle, thigh, hip, pelvis, and lumbosacral spine. Dynamic [18F]NaF PET is combined with conventional anatomical MRI and quantitative MRI techniques, including quantitative double-echo steady-state (qDESS) T2 mapping of cartilage, Dixon fat-fraction imaging, ultrashort echo time (UTE) T2* mapping of short-T2 tissues, UTE imaging of tibial bone, and zero echo time (ZTE) imaging for bone morphology and pseudo-CT generation. Additional MRI sequences characterize muscle composition, bone and joint anatomy, intervertebral discs, and regional vascular anatomy. Selected scans are acquired before and after a standardized exercise protocol to assess the acute physiological response of the joint. Automated segmentation is used to generate subject-specific masks of muscles, bones, vertebrae, and intervertebral discs. A subset of the MRI protocol is repeated at 1- and 2-year follow-up to assess longitudinal changes. Expected Impact: By combining dynamic bone metabolic imaging with quantitative measures of cartilage, menisci, muscle, bone, fat, vascular structures, and the spine and hip, the SKOPE protocol provides a whole-joint and multijoint framework for studying the structural, metabolic, and physiological processes associated with OA and pain. Exercise and longitudinal imaging further enable assessment of acute tissue responses and changes over time, supporting the development of quantitative imaging biomarkers for OA risk, pain, and disease progression.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of cardioembolic stroke. Although polygenic risk scores (PRS) are well characterized to quantify inherited susceptibility for AF, they provide limited insight into the pathways and tissues underlying genetic risk, which are critical to uncover for individual risk prediction. In this study, we develop a pathway-level multi-omics representation learning framework that converts individual genetic profiles into interpretable biological features by integrating GWAS-derived pathway burden scores with tissue-specific transcriptomic pathway signals. We constructed machine learning models to assess population-level AF risk prediction performance across genomic and transcriptomic tissue contexts; the pathway-based global attention models substantially improved risk prediction performance over PRS and other baselines (AUROC improved from 0.601 to 0.738). Transformer and graph neural network frameworks then assessed individual-level pathway interpretability, revealing heterogeneous contributions from electrical signaling, cardiac development, and DNA repair pathways to AF risk. This added interpretability highlights the potential of this pathway approach to enable more mechanistically informed risk stratification than static PRS by capturing underlying heterogeneity. To independently assess whether prioritized pathways reflected cardiac regulatory biology, we compared pathway rankings with transcriptional effects predicted by the AlphaGenome foundation model. Variants in highly ranked pathways showed significantly greater predicted effects on expression in atrial and ventricular tissues (FDR = 0.032) relative to controls, providing orthogonal evidence that the model identifies biologically relevant mechanisms. Overall, this work reframes polygenic risk from a single measure of susceptibility to tissue-informed pathway mechanisms, providing a framework for interpretable genomic stratification in complex diseases.

Background: Inequalities exist for many health outcomes, but there is limited evidence regarding menstrual symptoms despite their importance for health and wellbeing. We aimed to investigate inequalities in menstrual symptoms according to socioeconomic position and childhood adversity. Methods: In two generations (G0 mothers and G1 offspring) from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective cohort study, we examined associations of multiple indicators of socioeconomic position (SEP) and adverse childhood experiences (ACEs) with menstrual symptoms (pain, abnormal uterine bleeding, and premenstrual syndrome (PMS) measured 3-8-years post-birth in G0 and 17-21-years-old in G1), using multivariable logistic regression. Samples ranged from 4,828 to 9,335 G0 participants and 1,288 to 2,757 G1 participants depending on the exposure-outcome association. Missing data were addressed using multiple imputation and inverse probability weighting. Results: Financial difficulties were associated with greater odds of menstrual pain (G1 OR 1.41; 95% CI 1.07, 1.86: G0 OR 1.55; 95% CI 1.36, 1.76) and irregular cycles (G1 OR 1.60; 95% CI 1.12, 2.29: G0 OR 1.48; 95% CI 1.27, 1.72) in both generations, as well as with short/long cycle lengths in G0 only. Lower education and manual social class were also associated with these three menstrual symptoms in at least one generation. Conversely, higher SEP was associated with PMS in both generations. Higher cumulative ACEs were consistently associated with menstrual pain (4+ compared to none: G1 OR 2.15; 95% CI 1.48, 3.11: G0 OR 1.52; 95% CI 1.29, 1.80) and irregular cycles (G1 OR 1.92; 95% CI 1.20, 3.09: G0 OR 1.54; 95% CI 1.26, 1.87) but not cycle length. Lower parental education, financial difficulties, and cumulative ACEs were associated with heavy bleeding in G1 offspring only, whereas financial difficulties, own manual social class, and cumulative ACEs were associated with prolonged bleeding in G0 mothers only. Higher cumulative ACEs were also associated with PMS in G1 offspring only. Conclusions: We found evidence of inequalities according to socioeconomic disadvantage and childhood adversity for multiple menstrual symptoms, although some associations were only observed in one generation. Findings suggest that menstrual symptoms are disproportionately experienced by socially and socioeconomically disadvantaged women.

Wildfire smoke is an escalating global public health threat exposing millions of people, including children, to hazardous air pollution each year. Although wildfire smoke toxicants have been linked to a range of adverse health outcomes, including immune dysregulation, the long-term consequences of real-world pediatric wildfire smoke exposure on health and development remain largely unknown. To investigate the persistent effects of early-life exposure on immune health, here we leveraged a cohort of rhesus macaques that experienced nine consecutive days of hazardous wildfire smoke exposure in infancy during the 2020 Oregon Labor Day wildfires. By integrating ex vivo immune stimulations, multiplex cytokine profiling, single-cell transcriptomics, and genome-wide DNA methylation profiling, we identified persistent immunological consequences across molecular and functional levels. We found that a single severe postnatal exposure, in the first three months of life, was associated with persistent change in the innate immune response, including reduced pro-inflammatory cytokine response to a bacterial endotoxin, with subtle but consistent transcriptional changes in myeloid cells, particularly among males. Wildfire smoke exposure was also associated with changes in proportion of B and T/NK cells, and within the T/NK cell compartment, exposed animals exhibited an expansion of cytotoxic cells. Consistent with this, CD8+ T cells displayed extensive transcriptional remodeling and shifted toward more differentiated effector states, with the greatest differentiation observed in animals exposed at the youngest ages. Genome-wide DNA methylation profiling identified smoke-associated methylation changes consistent with acceleration of epigenetic aging, as well as persistent epigenetic alterations impacting genes involved in oxidative stress responses, innate immunity, T cell differentiation, and hematopoiesis. These findings demonstrate that a single severe wildfire smoke exposure during a critical developmental window is associated with extensive immune and epigenetic remodeling that persist years after exposure, providing new insight into the long-term biological consequences of early-life wildfire smoke exposure.

Importance: Chronic stress may contribute to adverse health outcomes through cumulative physiologic dysregulation. Allostatic load (AL), a composite measure of multisystem physiologic burden, may capture biologic effects of structural, social, and psychosocial stress not reflected by self-reported measures. Objective: To evaluate racial and ethnic differences in AL among women with familial cancer risk and examine how socioeconomic status, psychosocial factors, clinical characteristics, and health behaviors contribute to variations in AL. Design: Cross-sectional study of underrepresented minority participants enrolled in the HERSTORY cohort from October 2023 through September 2025, with comparison participants from the UCLA ATLAS biobank. Setting: UCLA academic health system. Participants: The study included 303 racially and ethnically diverse female HERSTORY participants aged [≥]35 years with a family history of cancer and matched non-Hispanic White female ATLAS participants (n=709). Exposures: Race and ethnicity, age, neighborhood deprivation, cancer history and stage, depression, perceived stress, cancer worry, and physical activity. Main Outcomes and Measures: The primary outcome was AL, calculated from cardiometabolic and organ-function measures. A secondary index incorporated race- and ethnicity-specific neutrophil-to-lymphocyte ratio (NLR) derived from 326,826 women in the UCLA Health population. Multivariable regression models evaluated factors associated with elevated AL. Results: Compared with matched non-Hispanic White participants, Black and Asian/Pacific Islander HERSTORY participants had significantly higher AL after adjustment. Hispanic/Latina participants did not have significantly elevated AL. Older age, greater area-level socioeconomic deprivation, and depression were independently associated with higher AL. Prior cancer diagnosis, cancer worry and perceived stress were not significantly associated with AL, whereas regular physical activity was associated with lower AL. Among cancer patients, advanced stage was associated with greater AL. Conclusions and Relevance: This study demonstrates elevated AL among understudied racial/ethnic minority groups with familial cancer risk and identifies associations with neighborhood deprivation, depression, and physical activity. The association between cancer stage and AL suggests that physiologic stress may reflect variation in cancer burden. The lack of association with perceived stress and cancer worry further indicates that physiologic and self-reported psychosocial measures capture distinct dimensions of stress. The development of race/ethnicity-specific NLR thresholds derived from large population samples provide a benchmark for future studies.

Trisomy 21 or Down syndrome (DS) affects multi-organ systems across the lifespan. The presence of an extra chromosome, along with genome dosage imbalance due to triplicated genes, contributes to the DS phenotypes. Of the DS mouse models, few are aneuploid with a freely segregating extra chromosome. We previously showed that the aneuploid Ts65Dn mice exhibit metabolic deficits consistent with the metabolic profile of DS. However, the genotype-phenotype relationships in Ts65Dn mice are complicated by the presence of triplicated genes unrelated to human chromosome 21 (Hsa21). To address this issue, we leveraged a refined model, Ts66Yah, where the extra triplicated genes in Ts65Dn have been removed. Deep phenotyping and multi-omics analyses showed that Ts66Yah mice develop pronounced and widespread metabolic disturbances. Despite sexual dimorphism in weight gain, body temperature, lipid and lipoprotein profiles, hepatic injury and adipose fibrosis, both male and female Ts66Yah mice share a common phenotype of pronounced glucose intolerance and insulin resistance, reduced mitochondrial respiratory capacity in visceral fat, altered serum inflammatory cytokine profile, and dysregulated serum and liver metabolomes. Pan-tissue transcriptomes also reveal signatures of immune activation, disrupted metabolic processes and cellular respiration, altered cytokine signaling, enhanced oxidative stress, and extracellular matrix remodeling. These combined changes across tissues disrupt metabolic homeostasis more severely in Ts66Yah than in Ts65Dn mice. Several phenotypes, including glucose intolerance, insulin resistance, tissue fibrosis, and oxidative stress were further exacerbated by an obesogenic diet. This foundational data establishes Ts66Yah as a valuable reference model for the mechanistic and comparative study of metabolic dysfunction in DS.

Background Global labor migration from LMIC to higher-income destinations has expanded rapidly, placing increasing pressure on destination-country health. Existing research on cross-border migrant workers has focused largely on occupational health, general healthcare utilization, and disease-specific risks, while there is considerably less evidence on their sexual and reproductive health. This study contributes to this understudied field by examining the policy and health-system factors that shape the sexual and reproductive health services for migrant workers in Taiwan. Methods A qualitative study was conducted in Taiwan between November 2025 and August 2026. 22 stakeholders were purposively recruited from academia, healthcare, nongovernmental organizations, government, labor brokerage, and employers. Data were collected through semi-structured interviews and small focus groups. Interviews were conducted in Mandarin Chinese, transcribed verbatim, and translated into English. Data were analyzed using framework analysis combining deductive coding based on the AAAQ framework with inductive coding of implementation and contextual themes. Results Gaps were identified across all four AAAQ dimensions. Participants described limited migrant-responsive SRH programming; physical, financial, administrative, social, and information barriers; shortcomings in linguistic and cultural responsiveness; and weaknesses in interpretation, coordination, and continuity of care, despite generally favorable views of Taiwan's clinical quality. Conclusions Our findings show that broad insurance coverage and strong clinical capacity do not by themselves ensure the realization of migrant workers' SRHR. In Taiwan, rights were mediated through labor brokerage, gendered live-in work arrangements, and fragmented governance across health, labor, immigration, and social-welfare systems. Improving migrant SRHR therefore requires stronger implementation of existing protections, reduced dependence on informal intermediaries, and more integrated institutional responsibility for cross-sector migrant health needs.

The increasing incidence of H5N1 influenza virus transmission from animal species to humans has heightened concerns about an imminent H5N1 pandemic. Prior studies using recombinant hemagglutinin and neuraminidase proteins have reported age-dependent cross-reactivity to H5N1, attributed to immune imprinting from an individual's first influenza virus exposure. However, whether this pattern holds when using whole inactivated virus (WIV), capturing antibodies against diverse viral proteins, and is stable over time remains unknown. We therefore aimed to determine whether H5N1 cross-reactivity of pre-existing antibodies to whole virus follows an age-dependent or imprinting-specific pattern, and whether this pattern is stable over a five-year period. To this end, we measured serum antibody levels in adolescents, adults and seniors by ELISA using whole inactivated H5N1 virus as antigen rather than purified proteins. Detectable, albeit generally low, levels of H5N1-reactive antibodies were present in most individuals, irrespective of age. Comparison of antibody levels against H5N1 with those to five historical influenza virus strains revealed a consistent positive correlation between H5N1-reactive antibodies and responses to the H1N1pdm09 strain A/California/7/2009 (CA), across all age groups. Using unbiased clustering of antibody titers against H5N1, CA, and the H3N2 strain A/Perth/16/2009 (PE), we identified seven distinct age-transcending antibody profiles. These profiles covered individuals with varying titers to all three included viruses but also identified individuals with high anti-CA levels, yet low anti-H5N1 levels and vice versa. Moreover, despite stable antibody levels over a five-year interval in the study population, individual antibody levels and profiles fluctuated considerably over this period. Taken together, our results confirm the presence of H5N1-reactive antibodies in human sera and their association with previously circulating strains. However, they also caution against inferring antibody levels against a new strain based solely on responses to antigenically related strains and highlight the limitations of extrapolating immune status from single timepoint measurements.

Human deep-space missions face bone-kidney risks that cannot be extrapolated from six-month ISS data. We built a 12-state Ca-bone-urine-stone mechanistic ODE model and jointly calibrated its 11 physiological parameters on eight ISS targets by Bayesian identification (M0 base = 19-D; M1 extension adds a GCR-bone coupling term for parsimony testing only), then propagated the M0 posterior to four environments (ISS, Lunar subsurface, Lunar surface, Mars). Lumbar-lower BMD loss increases with mission duration and partial-gravity unloading (ISS 180 d -4.83% -> Mars 730 d -12.15%; 2^3 factorial: duration 82.9%, gravity 12.5%, GCR main effect ~ 0), whereas stone rate follows the opposite gradient (ISS 16.1 vs Mars 13.1 per 1000 person-years), reflecting weakened partial-gravity bone resorption alongside residual urinary chemistry changes. The dominant pathway thus shifts from bone-centric on the ISS to kidney-centric on Mars, where residual urinary-chemistry changes-not bone resorption-drive stone risk. The direct GCR-bone coupling term is unidentifiable at current ISS doses (DeltaWAIC = +0.0076 +/- 0.126 SE), so M0 is retained as the main inference model. Bisphosphonates provide >=84% BMD protection but leave a urinary-chemistry residual, so bisphosphonate monotherapy would underestimate Mars stone risk; potassium-magnesium-citrate combinations (RRR_RSS 51%) should therefore be added to deep-space countermeasures. A Lunar-surface 365-day mission is the earliest environment on the NASA roadmap to cross a composite RED threshold. That profile differs from the regolith-shielded 180-day case in both cumulative GCR (~69x) and duration (2x), so a shielding-specific effect cannot be isolated here; forcing the GCR coupling terms to zero leaves all four composite tiers unchanged (0/4, Supp S24), and the shielded 180-day profile is YELLOW rather than GREEN. Independent hold-out validation (Culliton 2025 60-day HDT-bedrest RCT, n=8 control arm of n=24 total) supports the M0 posterior predictive distribution on the lumbar-BMD sub-scope.

Reflectin proteins drive dynamic structural coloration in cephalopods by organizing into dense intracellular lamellar structures that dictate local refractive index. While reconstituted reflectins readily undergo liquid-liquid phase separation in vitro, these assemblies frequently undergo dynamic arrest, vitrifying into non-dynamic condensates. Here, we investigate the primary sequence features, post-translational modifications, and heterotypic interactions that regulate the material properties of reflectin condensates within the crowded cellular environment of mammalian HeLa cells. Using confocal microscopy and fluorescence recovery after photobleaching (FRAP), we demonstrate that canonical block copolymeric A-type reflectins readily form dynamically arrested condensates, with the linker blocks primarily responsible for the observed arrest. In contrast, non-canonical B/C reflectin variants exhibit significantly greater fluidity and rapid recovery kinetics. We show that phosphomimetic substitutions progressively fluidize some reflectin condensates. Lastly, we find that heterotypic condensates composed of canonical and non-canonical reflectins in combinations associated with reversible iridescence in squid substantially enhance canonical mobility. Our findings establish a biophysical framework in which phosphorylation and heterotypic mixing cooperatively suppress dynamic arrest, enabling the reversible material transitions required for active cephalopod camouflage and communication.

Background. Cardiovascular-kidney-metabolic (CKM) syndrome affects nearly 90% of US adults, yet most individuals at early, modifiable stages remain unidentified outside clinical care. Blood donation centers offer a scalable, non-clinical venue for CKM screening, but the potential benefit of screening in this context remains unclear. We projected the population-level impact of effective digital return of results (ROR) to inform the design of a pragmatic trial. Methods. We developed a Monte Carlo simulation (100,000 iterations) of the incident major adverse cardiovascular events (MACE), end-stage renal disease (ESRD), and type 2 diabetes (T2DM) preventable by ROR-prompted, guideline-concordant follow-up among donors in CKM Stages 1-2. The estimand counts only events averted by donors who act because of ROR; the intervention effect was modeled directly on strictly positive support, and action was translated into prevented events through a hazard-based cumulative-incidence difference that counts each donor at most once. We evaluated 18 design cells (donor volumes 300,000, 1 million, and 8 million/year; 5- and 10-year horizons; action-rate gains of +10, +20, and +30 percentage points [pp]) and, in a complementary two-arm simulation, the assurance (expected power) of detecting the effect in a single deployment. Results. Under the primary +20 pp scenario, ROR at a single large blood center (300,000 donors/year) is projected to prevent a median of 2,201 events (95% uncertainty interval [UI], 1,099-4,364) over 10 years, scaling to 58,526 (29,154-116,769) at the national donor pool. All 18 design cells had strictly positive 95% lower bounds. The number needed to screen was 136 and the screening cost $2,045 per event prevented (at $15/donor), both invariant to donor volume. Impact scaled linearly with volume and effect size but sub-linearly with the horizon. Detection of the effect was effectively certain at gains of +20 pp or larger (assurance [≥]99.6% in every cell and >99.9% in all but the smallest 5-year cell). Conclusions. Even under the conservative scenario, digital CKM ROR at blood donation centers is projected to prevent hundreds to tens of thousands of incident cardiometabolic events at a screening cost per event well within accepted prevention benchmarks, providing prospective, quantitative justification for a pragmatic, randomized evaluation of digital ROR in non-clinical screening settings.

Background: Population-based biomonitoring of contemporary-use pesticides remains limited in the United States, particularly in rural agricultural regions, and few studies have repeated measurements within the same individuals over time. Methods: We analyzed 28 urinary pesticide-related biomarkers among 600 adults from the population-based Survey of the Health of Wisconsin with archived urine collected during 2008-2016; 296 participants provided repeat urine and updated exposure information in 2025. Detection frequencies, co-detection, and within-person detection patterns were characterized. Generalized estimating equations were used for stacked, repeated-measures analyses of factors associated with detection of aminomethylphosphonic acid (AMPA), glyphosate, 2,4-dichlorophenoxyacetic acid (2,4-D), and any of these three. Prospective-only analyses evaluated more detailed agricultural and recent exposure measures. Results: Glyphosate, AMPA, and 2,4-D were detected in 7.7%, 6.2%, and 4.3% of retrospective specimens and 5.4%, 3.1%, and 4.1% of prospective specimens, respectively. Co-detection and persistent detection across the 9 to 17-year interval was rare. In repeated-measures models, greater fruit and vegetable intake, older age, and male sex were associated with higher 2,4-D detection. Lower household income was associated with lower AMPA detection, while afternoon/evening collection was associated with higher AMPA detection. In prospective analyses, working on field-crop agricultural land showed the strongest agricultural associations, particularly for 2,4-D and detection of any of the three pesticides. Associations were not seen with self-reported conventional versus organic produce consumption. Conclusions: Urinary pesticide detections were generally infrequent in this Wisconsin population. Diet and direct agricultural activities may be more informative exposure pathways than residing near cropland or private well drinking-water characteristics.