Epidemiology

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Hearing Loss and Auditory-Visual Episodic Memory among Urban-Dwelling American Indian and Alaska Native Elders in the URBANE Study
(2026-04-20) Bryne, Charlotte; Fretts, Mandy
Hearing loss is an increasingly recognized risk factor for cognitive decline and Alzheimer’s Disease and Related Dementias (ADRD), yet cognitive assessments rarely account for hearing status despite relying heavily on auditory stimuli. Consequently, it remains unclear whether poorer episodic memory performance reflects cognitive decline or suboptimal sensory conditions. Using data from the URBAn Native Elders (URBANE) study (2021-2024), we examined the association between hearing handicap and auditory versus visually presented episodic memory among urban-dwelling American Indian and Alaska Native (AI/AN) Elders. Participants (n = 901) self-identified as AI/AN, were aged 55 years and older, and lived in or commuted to urban areas defined by Rural-Urban Commuting Area codes. Participants completed neurocognitive assessments and structured medical interviews. Self-perceived hearing loss was measured using the Hearing Handicap Inventory for the Elderly-Screening version (HHIE-S). Episodic memory was assessed using the NIH Toolbox Picture Sequence Memory Test (visual episodic memory) and the National Alzheimer’s Coordinating Center (NACC) Craft Story immediate recall tests (auditory episodic memory). Multivariable linear regression models estimated associations between hearing handicap severity and episodic memory performance while adjusting for demographic and cognitive covariates. Higher hearing handicap severity was associated with slightly lower performance across episodic memory measures, though estimates were small and not statistically significant (all p-values > 0.05). Although we did not observe associations of self-perceived hearing loss with markers of auditory and visual episodic memory tasks, our findings highlight the potential burden of hearing loss in this population of AI/AN Elders, and support continued research on hearing health and cognitive function among AI/AN Elders.
Rare genetic variant contributions to multiple cancers
(2026-04-20) Hammermeister Suger, Austin Robert; Lindström, Sara
Clinical and family-based studies have long identified strong associations between rare genetic variants, typically defined as genetic variants with minor allele frequencies < 1% in a population, with pathogenic effects on specific genes and hereditary cancer predisposition syndromes. For example, the lifetime risk of diagnosis across a variety of cancers, including breast and ovarian, among carriers of rare pathogenic BRCA1 or BRCA2 variants estimated to be many times higher than average population risk for those cancers. However, known rare pathogenic variants in established cancer predisposition genes still only account for a small proportion of the total cancer heritability estimated by twin studies. Some of these contributions can be attributed to common genetic variants, typically defined as genetic variants with minor allele frequencies ≥ 1% in a population. Cancer genome wide-association studies (GWAS) have identified many hundreds of genomic loci associated with multiple cancer types including a subset of at least 130 where common variants are associated with multiple cancer types. While these common variants do explain a large proportion of cancer heritability cancer, there are still substantial gaps. Genetic previously unknown rare variants in known cancer predisposition genes or other genes are a potential source of genetic contributions to risk in the population. However, the relationships between these rare variants, and cancer risk at the population level is currently not well understood due to a historical lack of the large sequencing datasets needed to conduct population-based analyses of rare variants. Only a handful of previous studies have been conducted in this area, and most have either 1) focused on a small number of cancers or 2) focused on a limited number of cancer predisposition genes. With the generation of these datasets in studies with linked cancer diagnosis data, more comprehensive examinations of the contributions of rare genetic variants to risk across multiple cancer types is becoming feasible. In this dissertation, we attempted to extend our knowledge of rare variant contributions to cancer risk across multiple cancers and how we may leverage these variants to improve risk prediction models. We conducted exome-wide gene-based mixed-model rare coding variant analyses in two large cohorts to identify genes where rare variants have pleiotropic associations with over 70 cancer types, including cancers that are both common and rare in the population (Chapter 1). We then further characterized the magnitudes and directions of associations between the pleiotropic genes we identified and 27 individual cancer types. We also estimated the contributions of rare variants to breast, colorectal, and prostate cancer heritability (Chapter 2) and their utility in genetic risk prediction models for those cancers (Chapter 3). In summary, this work can expand our understanding of shared rare variant genetic architecture across multiple cancers and how this knowledge might be used to improve risk stratification for some of the most common cancer types. The results of this dissertation suggest that rare coding variation in specific genes may be related to risk across a wide range of cancers and that rare coding variants in a small number of genes play small but important roles in population-level breast, colorectal, and prostate cancer risk.
Mixed Neuropathology and Associations with Cognitive Impairment in Autopsied Older Adults
(2026-04-13) Culhane, Jessica; Phipps, Amanda
Background: Dementia represents a heterogeneous group of clinical syndromes most often driven by multiple coexisting neuropathologic processes. Although Alzheimer’s disease neuropathologic change (ADNC) remains the most recognized contributor, other neurodegenerative and vascular pathologies, including limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), Lewy body disease (LBD), hippocampal sclerosis, and cerebrovascular lesions, are common and substantially influence cognitive outcomes. Understanding how these mixed pathologies cluster together and contribute to resilience or resistance to cognitive impairment is essential for refining diagnostic frameworks and developing targeted interventions.This dissertation aimed to characterize the heterogeneity of neuropathologic disease and its relationship to clinical outcomes through three complementary aims: (1) to identify biologically coherent clusters of mixed neuropathologic profiles using unsupervised clustering methods; (2) to determine how non-Alzheimer’s pathologies contribute to resistance and resilience to ADNC; and (3) to investigate neuropathologic correlates of resilience to LATE-NC across multiple autopsy cohorts. Methods: Chapter 2 applies unsupervised hierarchical clustering to 2,899 autopsied National Alzheimer’s Coordinating Center (NACC) participants using fourteen neuropathologic features. Chapter 3 examines non-AD pathologies among NACC participants classified as resistant (no/low ADNC, cognitively normal), resilient (intermediate/high ADNC, cognitively normal), or impaired (intermediate/high ADNC, cognitively impaired), using multivariable logistic regression and longitudinal cognitive assessments. Chapter 4 examines factors associated with resilience to advanced LATE-NC (stage 2–3) in both NACC and Adult Changes in Thought (ACT) study participants aged ≥75 years, using regression models stratified by age and longitudinal cognitive analyses in ACT. Results: Across Chapters 2–4, mixed neuropathologic disease strongly influenced cognitive outcomes. In Chapter 2, five distinct clusters of neuropathologic disease were identified, reflecting common combinations of ADNC, LATE-NC, LBD, TDP-43, and vascular pathology. These clusters were biologically interpretable and often aligned with traditional clinical diagnoses. In Chapter 3, both resistance and resilience to ADNC were associated with markedly lower burden of non-AD pathologies, particularly LBD, LATE-NC, hippocampal sclerosis, and arteriosclerosis. In Chapter 4, resilience to LATE-NC was linked to reduced ADNC and absence of hippocampal sclerosis. Across analyses, lower mixed pathologic burden was strongly associated with cognitive resilience. Conclusions: Across studies, cognitive outcomes depended on the cumulative and interactive effects of multiple neuropathologic processes. These findings highlight the limitations of single-pathology diagnostic frameworks and support development of biologically grounded subtyping that accounts for mixed pathology. Such approaches will be critical for improving diagnostic precision, understanding mechanisms of resilience, and guiding biomarker and therapeutic development.
Mixed Neuropathology and Associations with Cognitive Impairment in Autopsied Older Adults
(2026-02-05) Culhane, Jessica; Phipps, Amanda
Background: Dementia represents a heterogeneous group of clinical syndromes most often driven by multiple coexisting neuropathologic processes. Although Alzheimer’s disease neuropathologic change (ADNC) remains the most recognized contributor, other neurodegenerative and vascular pathologies, including limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), Lewy body disease (LBD), hippocampal sclerosis, and cerebrovascular lesions, are common and substantially influence cognitive outcomes. Understanding how these mixed pathologies cluster together and contribute to resilience or resistance to cognitive impairment is essential for refining diagnostic frameworks and developing targeted interventions.This dissertation aimed to characterize the heterogeneity of neuropathologic disease and its relationship to clinical outcomes through three complementary aims: (1) to identify biologically coherent clusters of mixed neuropathologic profiles using unsupervised clustering methods; (2) to determine how non-Alzheimer’s pathologies contribute to resistance and resilience to ADNC; and (3) to investigate neuropathologic correlates of resilience to LATE-NC across multiple autopsy cohorts. Methods: Chapter 2 applies unsupervised hierarchical clustering to 2,899 autopsied National Alzheimer’s Coordinating Center (NACC) participants using fourteen neuropathologic features. Chapter 3 examines non-AD pathologies among NACC participants classified as resistant (no/low ADNC, cognitively normal), resilient (intermediate/high ADNC, cognitively normal), or impaired (intermediate/high ADNC, cognitively impaired), using multivariable logistic regression and longitudinal cognitive assessments. Chapter 4 examines factors associated with resilience to advanced LATE-NC (stage 2–3) in both NACC and Adult Changes in Thought (ACT) study participants aged ≥75 years, using regression models stratified by age and longitudinal cognitive analyses in ACT. Results: Across Chapters 2–4, mixed neuropathologic disease strongly influenced cognitive outcomes. In Chapter 2, five distinct clusters of neuropathologic disease were identified, reflecting common combinations of ADNC, LATE-NC, LBD, TDP-43, and vascular pathology. These clusters were biologically interpretable and often aligned with traditional clinical diagnoses. In Chapter 3, both resistance and resilience to ADNC were associated with markedly lower burden of non-AD pathologies, particularly LBD, LATE-NC, hippocampal sclerosis, and arteriosclerosis. In Chapter 4, resilience to LATE-NC was linked to reduced ADNC and absence of hippocampal sclerosis. Across analyses, lower mixed pathologic burden was strongly associated with cognitive resilience. Conclusions: Across studies, cognitive outcomes depended on the cumulative and interactive effects of multiple neuropathologic processes. These findings highlight the limitations of single-pathology diagnostic frameworks and support development of biologically grounded subtyping that accounts for mixed pathology. Such approaches will be critical for improving diagnostic precision, understanding mechanisms of resilience, and guiding biomarker and therapeutic development.
A NATIONWIDE, POPULATION-BASED COHORT STUDY OF EPILEPSY INCIDENCE IN PATIENTS WITH POST-STROKE APHASIA
(2026-02-05) Lin, Hui-Lin; Weiss, Noel S.
Abstract Introduction: Post-stroke epilepsy (PSE) affects 2–20% of stroke survivors. Post-stroke aphasia is associated with a further increase in this risk. Identifying factors associated with developing PSE potentially could guide targeted interventions in future trials. Methods: We utilized Taiwan’s National Health Insurance claims data to identify individuals aged 18 years or older who were hospitalized for a first stroke between 2003 and 2007, including those diagnosed with aphasia during admission or within 90 days after discharge. Beginning 91 days following hospital discharge, the incidence of epilepsy was compared between stroke patients with and without aphasia until December 31, 2020. Hazard ratios controlling for other risk factors for epilepsy were derived using Cox proportional hazards regression, and we calculated adjusted rate differences to quantify the absolute magnitude of the excess risk. Results: With a median follow-up of 7.56 years for the aphasia group (n = 23,431) and 8.67 years for the non-aphasia group (n = 130,058), the incidence of post-stroke epilepsy was higher among patients with aphasia than in those without aphasia (13.02 vs. 4.56 per 1000 person-years, adjusted rate difference [aRD] 2.96, 95% CI 2.60–3.37 per 1,000 person-years). Excess risk was similar (aRD 2.38 and 3.11 per 1,000 person-years) in female and male participants, respectively, and somewhat higher in younger than in older adults (aRD 3.52, 2.42, and 2.88 per 1,000 person-years in the <45, 45–64, and ≥65 age groups, respectively). The excess rate of epilepsy associated with the development of aphasia was 3.52 and 2.64 per 1,000 person-years among those with hemorrhagic and ischemic stroke, respectively. The association was strongest in the first year of follow-up after stroke and declined thereafter. Conclusion: Patients with post-stroke aphasia are at increased risk of epilepsy irrespective of age, sex, and stroke type.
Polycystic ovary syndrome in Mexico: from adolescence to adulthood
(2026-02-05) Lozano Esparza, Susana; Phipps, Amanda
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among individuals of reproductive age with ovaries, yet in Mexico there is no epidemiologic information or explicit public health policies addressing the condition. Given its high prevalence and burdensome metabolic, reproductive, and psychosocial symptoms, there is a clear need to generate evidence that implementation and guideline frameworks identify as necessary to close evidence–practice gaps: quantifying disease burden and current care gaps, identifying modifiable determinants that can be targeted early, and understanding how people experience the condition and encounter barriers within families, workplaces, and health systems. This dissertation addresses each of these elements using the Mexican Teachers’ Cohort. First, a nested validation study developed and evaluated a Spanish-language, symptom-based questionnaire against clinical assessments, showing that a model using menstrual and diagnostic items can classify PCOS with high discrimination, providing a feasible tool to estimate PCOS burden in large epidemiologic studies and inform primary care guidelines. Second, applying this tool to the full cohort, life-course analyses showed that persistently higher and increasing body size from childhood through late adolescence was associated with higher odds of PCOS, whereas adolescent diet showed weaker and less consistent associations, highlighting adolescent adiposity as a key modifiable target for prevention. Third, in-depth interviews with women living with PCOS illuminated how symptoms, weight, fertility concerns, and medical dismissal are negotiated within specific social and institutional contexts, as well as strategies of coping, resistance, and narrative reframing that shape care-seeking. Together, these studies align with core principles for designing effective public health responses by integrating evidence on measurement, modifiable risk, and lived experience, and they provide a foundation for future guideline implementation and policy development for PCOS in Mexico.
Advancing PrEP Use among Pregnant Women in sub-Saharan Africa
(2026-02-05) Wu, Linxuan; Mugwanya, Kenneth KKM
In sub-Saharan Africa (SSA), cisgender women are disproportionately affected by HIV, accounting for approximately 63% of all new infections in this region. Pregnancy, a period experienced by many young women in SSA, is associated with an elevated risk of HIV acquisition due to the combined effects of behavioral, immunological, and hormonal changes. Daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis (PrEP) is highly effective in decreasing HIV acquisition risk when taken as prescribed and is recommended by the World Health Organization (WHO) as one of the prevention options for individuals at substantial HIV risk, including cisgender women. However, additional questions on intracellular exposure in HIV target cells during pregnancy and the long-term growth and bone health outcomes for infants with utero TDF/FTC PrEP, remain unanswered.The adherence–concentration–efficacy relationship for TDF/FTC PrEP has been well established among gay, bisexual, and other men who have sex with men (MSM), indicating that taking four doses/week can reduce HIV acquisition risk by approximately 96%. However, this relationship has been less studied in cisgender women, leading to uncertainty about optimal dosing strategies in this population. Based on pharmacologic evidence showing lower drug penetration in female genital track compared to rectal tissue, cisgender women have been advised to take one pill daily to achieve levels of protection similar to those observed in MSM taking four doses/week. This messaging may pose substantial barriers to PrEP initiation and continuation in cisgender women. Additionally, pregnancy is associated with profound physiological changes that may lead to suboptimal drug exposure, reduced efficacy, and uncertainty regarding optimal PrEP dosing strategies for HIV prevention in this critical period. Several studies have reported decreased concentrations of tenofovir diphosphate (TFV-DP), the active metabolite of TDF, in red blood cells measured using dried blood spots (DBS) during pregnancy; however, changes in drug concentrations at clinically relevant sites for HIV prevention remain less understood. Furthermore, while TDF is generally considered safe, its use has been associated with renal and bone toxicity. During pregnancy, tenofovir (TFV), the parent drug of TDF, readily crosses the placenta and may potentially affect fetal bone development. However, few studies have evaluated the impact of maternal TDF exposure on children bone health, and the findings have been mixed. Additional data are needed to determine whether and to what extent in-utero TDF exposure affect bone outcomes in children. The studies presented in this dissertation address these key knowledge gaps to inform the effective and safe use of oral TDF/FTC PrEP among pregnant women in SSA and has the potential to guide clinical guidelines and policy decisions to optimize PrEP delivery in this population. In Chapter 2, we conducted a systematic review to summarize current evidence and identify knowledge gaps related to protective adherence levels of TDF-based oral PrEP in cisgender women, including during pregnancy. We found that women-specific intracellular TFV-DP adherence benchmarks in DBS and peripheral blood mononuclear cells (PBMC) fall within the range of historical U.S.-based thresholds derived from healthy men and women. Emerging evidence suggests that imperfect but adequate adherence to oral FTC/TDF PrEP with at least four doses/week provides sufficient HIV protection in cisgender women; however more data are still needed to refine the intrinsic achievable efficacy estimates for cisgender women. In Chapter 3, we leveraged a directly observed dosing study in Kenya, in which 18 pregnant and 18 non-pregnant women received daily dosing of TDF/FTC for 8 weeks. Blood for DBS and PBMC was collected weekly for non-pregnant and bi-weekly for pregnant women. We characterized paired TFV-DP concentrations in DBS and PBMCs and quantified matrix-specific pharmacokinetic differences by pregnancy status. We found that steady-state TFV-DP concentrations from daily dosing of TDF/FTC were approximately two-fifths lower in DBS during pregnancy, whereas TFV-DP and emtricitabine triphosphate (FTC-TP) concentrations in PBMCs were not meaningfully different between pregnant and non-pregnant women. We also compared growth outcomes of infants exposed to daily dosing of TDF/FTC in pregnancy to historical TDF/FTC-unexposed infants from the placebo arm of the Partners PrEP Efficacy Study. We found Z-scores for infant weight, length, and head circumference were comparable at 6, and 12 months of age. In Chapter 4, by leveraging a prospective cohort that evaluated the oral TDF/FTC PrEP safety in pregnant and postpartum women in Western Kenya, we conducted a matched cohort study to assess the association between in-utero PrEP exposure and bone mineral content (BMC) for whole body less head and lumbar spine at 36 and 52 months of age. We found that mean BMC for whole body less head and lumbar spine were not lower among children with in-utero PrEP exposure. While the overall prevalence of low BMC in our study population was high (20%-30%), in-utero PrEP exposure was not associated with higher prevalence of low BMC. Our findings are reassuring and support the continued use of oral TDF/FTC PrEP during pregnancy.
Associations between influenza vaccination during pregnancy and outcomes related to maternal influenza disease, infant anthropometry/nutritional status, and cost-effectiveness in Nepal
(2026-02-05) Frivold, Collrane; Chu, Helen Y
Globally, influenza causes 3-5 million severe illnesses and 290,000-650,000 deaths each year. Pregnant individuals and infants are at increased risk of influenza-associated morbidity and mortality, making maternal vaccination a high priority to protect pregnant/postpartum individuals and their infants via maternal antibodies. Although influenza mortality rates are estimated to be higher in low- and middle-income countries (LMICs), empiric data on the influenza disease burden are limited. In addition, the impact of maternal influenza vaccination on infant anthropometry and nutritional status has not been evaluated while accounting for bias related to missing anthropometric measurements due to fetal or infant death. Best practices for implementing maternal immunization programs have also not been established including the potential cost-effectiveness of a maternal influenza vaccine policy by administration trimester. To date, four randomized-controlled trials in LMICs have reported on influenza vaccine efficacy among mother-infant dyads, but data on the influenza disease burden and potential benefits of vaccination beyond prevention of infection are limited in LMICs compared to high-income country (HIC) contexts. In the following dissertation aims, we address these gaps by leveraging data collected between 2011-2014 as part of a maternal influenza vaccine randomized-controlled trial in Sarlahi District, Nepal (NCT01034254) among pregnant participants (15-40 years) and their infants who were followed through 6 months postpartum. Among pregnant/postpartum participants, we assessed the impact of maternal influenza vaccination on maternal influenza disease severity (Chapter 2). Among singleton pregnancies, we characterized the effect of maternal influenza vaccination on infant anthropometry and nutritional status measured at birth while accounting for outcomes truncated by death (Chapter 3). In Chapter 4, we used a decision tree to project costs and health outcomes and to estimate the cost-utility of national maternal influenza vaccine policies in Nepal recommending vaccination in the second or third trimester compared to maintaining the standard of care of no vaccine policy. Overall, our results highlight that maternal influenza vaccination may reduce the risk of moderate influenza illness among pregnant/postpartum individuals as well as moderate-to-severe undernutrition among infants, especially when vaccine and circulating strains are well-matched. However, additional studies are needed to confirm these protective effects. Additionally, the cost-effectiveness analysis illustrated that while third trimester vaccination in Nepal was the most cost-effective intervention, both second and third trimester vaccination were cost-effective under the willingness-to-pay threshold. This dissertation provides important contributions to the evidence base that could inform vaccine policy decision-making and facilitate increased access to maternal influenza vaccines in LMICs.
Interplay of Demographic Factors, Behavioral Factors, and Chronic Disease Status with Diabetes and Tooth Loss
(2026-02-05) ZIA, HAFSA; Fretts, Amanda
Tooth loss is associated with type 2 diabetes, but the extent to which demographic, behavioral, and health factors influence this association remains unclear. To evaluate this association, the 2022 Behavioral Risk Factor Surveillance System (BRFSS) data for 26,152 Washington State adults who provided information on variables of interest was analyzed. Participant characteristics were summarized by frequencies and percentages overall and stratified by tooth loss and diabetes status. Two models were fit to assess the association between self-reported diabetes (yes/no) and tooth loss (none, 1–5 teeth lost, ≥6 teeth lost); a crude model and a fully adjusted multinomial logistic regression model to assess the association controlling for age, sex, race/ethnicity, education, income, insurance status, marital status, county, smoking status, obesity, and cardiovascular disease. An exploratory analysis restricted to adults aged ≥45 years used the same modeling approach. All analyses were conducted in R. Among participants, 11.6% reported diabetes; 28.3% lost 1–5 teeth, 12.5% lost ≥ 6 teeth, and 59.2% reported no tooth loss. In adjusted multinomial model of 17, 373 adults, diabetes was an independent predictor of losing ≥6 teeth (adjusted OR = 1.79; 95 % CI, 1.35–2.37; p < 0.001). Older age, lower household income, lack of private health insurance, unemployment, current or former smoking, and cardiovascular disease were also significantly associated with severe tooth loss. Conclusion: Greater tooth loss was significantly associated with diabetes. This association was impacted by age, income, employment, smoking, and cardiovascular disease status.
Short-Term Cardiac Rhythm and Conduction Abnormalities Among Children Following Atrial Septal Defect Closure
(2026-02-05) Soriano, Brian D; Weiss, Noel S
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Correlates and Metabolic Health Outcomes of Adolescent Loneliness
(2026-02-05) Freije, Sophia L; Enquobahrie, Daniel A
Background: Loneliness among adolescents has drawn public health concern due to its rising rates and established implications for mental and physical health. Global estimates indicate that the percentage of adolescents who reported feeling lonely “often” or “always” nearly doubled from 2012 (12%) to 2018 (23%). These widespread shifts may reflect societal influences and increased time spent online, warranting comprehensive investigation into contextual factors and digital technology interactions that may lead to loneliness. When persistent, the psychological and physiological strains of loneliness can lead to adverse health outcomes such as metabolic syndrome (MetS)—a cluster of factors that raise the risk of cardiometabolic diseases. However, reports on adolescent loneliness and MetS associations were inconsistent. This dissertation examined recent trends, correlates, and longitudinal metabolic risks of adolescent loneliness.Objectives: We aimed to: 1) characterize temporal trends in adolescent loneliness from 2000 to 2022 and associations with country-level factors (COVID-19 mortality, public health distancing laws, unemployment, income inequality, peacefulness, and internet use); 2) investigate associations of digital technology interactions with loneliness overall and among groups defined by risk for problematic internet use, gender identity, and race and ethnicity; and 3) investigate associations of adolescent persistent loneliness with MetS at ages 24-32 and 33-43, and examine if associations are mediated by depressive symptoms or moderated by sex and race/ethnicity. Methods: Aim 1 was addressed using data from the Programme for International Student Assessment (PISA), a school-based survey administered to 1,267,476 adolescents aged 15-16 across 38 Organization for Economic Cooperation and Development-member countries in 2000, 2003, 2012, 2015, 2018, and 2022. Aim 2 was addressed using data from the Youth Health and Social Media (YHSM) survey, a cross-sectional online survey administered to 12–17-year-old U.S. residents in 2019 (N=4,541). Aim 3 was addressed using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a prospective cohort that followed participants from ages 11-21 in 1994 to ages 24-32 (n=10,069) and ages 33-43 (n=4,061). Loneliness was measured using a 6-item school loneliness questionnaire (PISA), the 3-item Comprehensive Inventory of Thriving Loneliness subscale (YHSM), and a single-item direct frequency measure (Add Health). To address Aim 1, multilevel piecewise regression was used to estimate trends in mean loneliness scores during three periods: 2000-2012, 2012-2015, and 2015-2022. Multilevel linear regression was used to estimate associations between country-level factors (COVID-19 mortality, public health distancing measures, internet use, unemployment rate, income inequality, and peacefulness) and loneliness scores. To address Aim 2, multivariable linear regression with robust standard errors was used to estimate the mean change in loneliness scores associated with quartiles of scores on the Adolescents’ Digital Technology Interactions and Importance (ADTI) scale and its three factors (Factor 1, bridging online and offline preferences; Factor 2, escaping offline environments; Factor 3, using technology for social connection). To address Aim 3, we used Poisson regression with robust standard errors to estimate associations between persistent loneliness in adolescence—defined as loneliness reported in two waves, one year apart—and MetS at Wave IV (ages 24-32) and Wave V (ages 33-43). We tested for mediation of the associations by depressive symptoms measured in Wave III (ages 18-26) using counterfactual approaches. Differences in associations according to risk for PIU (Aim 2), gender (Aim 2), sex (Aim 3), and race/ethnicity (Aim 2, 3) were evaluated using stratified analyses and models with interaction terms. Results. In analyses of PISA data, we observed no significant change in mean loneliness scores from 2000 to 2012 (95%CI: -0.022, 0.008), followed by yearly increases of 0.045 points from 2012-2015 (95%CI: 0.035, 0.054), and 0.017 points from 2015-2022 (95%CI: 0.008, 0.025). Within countries, a one-hour higher country-level weekly internet use and one percentage-point higher unemployment rate were associated with 0.012-point (95%CI: -0.021, -0.003) and 0.006-point (95%CI: -0.011, -0.001) lower loneliness scores per year, respectively. Other contextual measures were not associated with loneliness. In analyses of the YHSM survey, participants had mean ADTI and loneliness scores of 48.8 (SD 17.9) and 3.6 (SD 3.6), respectively. We observed a U-shaped relationship between quartiles of ADTI scores and loneliness scores, with participants with moderate scores (Q2, Q3) having similar or lower loneliness scores and participants with high scores (Q4) having similar or higher loneliness scores, compared to respective Q1 categories. For the total ADTI, participants in Q2 or Q3 had 0.24-point (95%CI:-0.45,-0.02) and 0.38-point (95%CI:-0.61,-0.15) lower loneliness scores, respectively, compared with Q1 participants. Participants in Q3 for Factor 1 (bridging online and offline preferences) had 0.31-point (95%CI:-0.52,-0.10) lower loneliness scores, while participants in Q4 for Factor 2 (escaping offline environments) had 0.30-point (95%CI:0.01, 0.59) higher mean loneliness scores, compared with participants in Q1. We observed significant multiplicative interactions between ADTI measures and PIU and gender identity (P-values <0.05) but not race and ethnicity. Among high-risk PIU participants and cisgender males, compared with their counterparts in Q1, moderate total ADTI and Factor 1 scores were associated with lower loneliness, whereas high total ADTI (males only), Factor 1 (males only), or Factor 3 scores were associated with higher loneliness (P-values<0.05). In the Add Health study, the prevalence of persistent loneliness at baseline was 19% across participants eligible for Wave IV or Wave V analyses. The prevalence of MetS was 20% in Wave IV and 27% in Wave V. Persistent loneliness was not associated with Wave IV MetS (aRR: 1.03, 95%CI: 0.89, 1.18) while it was associated with a 21% lower likelihood of Wave V MetS (95%CI: 0.64, 0.99). Loneliness-MetS associations were not modified by sex or race/ethnicity or mediated by depressive symptoms. Conclusions: Loneliness increased from 2012-2015 across 38 countries, followed by smaller annual increases until 2022. Greater increases in country-level unemployment rates and internet use over time were associated with lower loneliness. We also observed a U-shaped relationship between digital technology interactions and loneliness—a pattern observed and stronger among high PIU participants and cisgender men compared with low PIU participants, cisgender women, and TNG youth. Persistent loneliness during adolescence was associated with a lower risk of MetS at ages 33-43 but not at 24-32. Findings of loneliness trends underscore the urgency of promoting social connection through targeted public health strategies. Ongoing examinations of the trends and societal correlates of loneliness are warranted as updated data become available. Longitudinal studies are needed to clarify the temporality of digital technology interactions and loneliness, as well as comprehensive understanding of loneliness and MetS associations.
Integrative Genomic and Proteomic Approaches to Thrombotic Events: Identifying Shared and Distinct Mechanisms and Enhancing Risk Assessment
(2026-02-05) Li, Xumin; Smith, Nicholas
Leveraging data from 37,564 UK Biobank Pharma Proteomics Project participants, we investigated mechanisms and developed risk prediction models for thrombotic events, including ischemic stroke (IS), myocardial infarction (MI), and venous thromboembolism (VTE), within a unified multi-phenotype framework. We conducted proteome-wide association studies for each thrombotic event and a composite endpoint (first occurrence of IS, MI, or VTE), identifying 788 proteins associated with the composite and 325, 419, and 303 proteins associated with IS, MI, and VTE, respectively (FDR-adjusted P < 0.05). Mendelian randomization analyses supported putative causal relationships for 22 proteins, of which 12 were further corroborated by colocalization. Analysis of protein-protein interactions among thrombotic event-associated proteins highlighted core mediators, including inflammatory and leukocyte-trafficking factors (e.g., IL6, TNF, CXCL10, ICAM1, ITGAM) and vascular remodeling or angiogenic factors (e.g., VEGFA). Protein co-expression networks constructed from 2,919 proteins revealed 6 modules significantly associated with thrombotic events, and pathway enrichment analyses indicated both shared and phenotype-specific biology. For prediction, we integrated proteomic and conventional predictors in survival models, using LASSO for embedded selection of proteins. Across outcomes, combined (conventional + proteomics) models outperformed conventional predictors models (C-index improvement ΔC = 0.022 for IS, 0.020 for MI, 0.014 for VTE, and 0.027 for the composite; all P < 0.01). These findings advance mechanistic understanding, nominate druggable targets, and demonstrate improved risk prediction for thrombotic events.
Black Youth Suicidality Through The Lens Of Intersectionality & Policy
(2026-02-05) Buchanan, Zeruiah V; Sharif, Mienah Z
The rate of suicidality (i.e., suicide ideation, nonfatal suicide, and death by suicide) is increasing among Black youth at an alarming rate compared to their non-Black counterparts, pointing to the pivotal demand to investigate the risk and protective factors associated with suicidality in this community. However, there is a notable gap in scholarship examining Black youth suicidality with thoughtful consideration of intersectionality (i.e., interlocking systems of oppression such as racism and ableism) and legal epidemiology (i.e., the examination of law and policy as a factor in the etiology of disease and injury). This dissertation examined Black youth suicidality through the lens of intersectionality and legal epidemiology to inform future policies and practices that are more attentive to the priorities and needs of Black youth and can thereby reverse the trends in the elevated risk of suicidality in these communities. Specifically, this dissertation: 1) collaborated with Black experts to identify the most influential policies in the context of Black youth suicidality, 2) documented the extent to which suicidality and social identities are captured in high school youth surveys across 50 states, and 3) characterized suicidality among multiply marginalized Black youth attending 8th through 12th grade in Washington.
Motivations of pregnant women initiating HIV PrEP within antenatal care enrolled in a randomized trial to improve adherence in Western Kenya
(2026-02-05) Watoyi, Salphine Atieno; John-Stewart, Grace GJs
AbstractVertical HIV transmission remains a significant public health challenge in high-burden settings, where maternal HIV infection during pregnancy and breastfeeding account for nearly one-third of new paediatric infections. HIV incidence doubles during the perinatal period due to biological vulnerability and ongoing behavioral risks, including partners of unknown or positive HIV status. The World Health Organization recommends HIV PrEP for pregnant and postpartum women at substantial HIV risk. HIV PrEP delivery is increasingly integrated into routine maternal and child health (MCH) services, however real-world factors influencing pregnant women's decisions to initiate PrEP remain poorly understood. We conducted a cross-sectional secondary analysis of baseline data from the mWACh-PrEP study, a randomized trial among HIV-negative, PrEP-naïve pregnant women between 24-32 weeks gestation at five public MCH clinics in western Kenya who elected to initiate PrEP. Data on demographics, pregnancy history, HIV risk perception, partner characteristics, psychosocial factors, and PrEP attitudes were collected via structured electronic questionnaires. Poisson regression was used to examine associations between participant characteristics and high self-perceived HIV risk and PrEP initiation motivations. Among 600 women enrolled, 36.3% reported high HIV risk perception at PrEP initiation. High self-perceived risk was associated with having more than three lifetime sexual partners (aRR 1.43), high empiric HIV risk scores (aRR 1.70), experience of intimate partner violence (IPV) (aRR 1.92), and anxiety symptoms (aRR 2.23). Conversely, participants with high self-efficacy for daily pill-taking were less likely to have high risk perception (aRR 0.63). Women with unplanned pregnancies were more likely than those with planned pregnancies to report initiating PrEP due to concerns that their partner had multiple sexual partners (44.4% vs. 32.4%; aPR 0.80; 95% CI: 0.72–0.89) and feeling at risk for HIV (44.7% vs. 32.6%; aPR 0.86; 95% CI: 0.78–0.95) Women who experienced intimate partner violence (IPV) were more likely than those without IPV histories to report initiating PrEP due to concerns that their partner had other sexual partners (66.6% vs. 38.3%; aPR 1.27; 95% CI: 1.05–1.54) and to protect their infants from HIV (77.8% vs. 49.8%; aPR 1.32; 95% CI: 1.16–1.49). Pregnant women's decision to initiate HIV PrEP is influenced by a combination of behavioral risk factors (e.g., multiple lifetime sexual partners, condomless sex), psychosocial stressors (including IPV and anxiety), and pregnancy-specific contexts (notably unplanned pregnancies). Tailored HIV risk counseling that addresses discordance between objective risk and subjective perception, routine IPV screening, and integrated supportive services within MCH settings are critical to improving PrEP uptake and adherence and ultimately reducing maternal HIV acquisition and vertical transmission in high-risk settings
Improving Detection of Tuberculosis Disease Among Children
(2026-02-05) Fajans, Mark Asmoeni; Drain, Paul K
Tuberculosis (TB) remains a major public health concern globally and is a leading infectious cause of morbidity and mortality in both adults and children. Approximately 1.3 million children and young adolescents who developed TB disease in 2023, and among those 191,000 died from TB. The risk of TB infection progressing to disease, and from disease to death, is especially high in young children. Diagnosing TB in children is difficult, with an estimated 51% children globally with TB disease not diagnosed due to the lack of a quality specimen for testing, difficulties with specimen collection and the lack of highly sensitive tests for use in children. As a result, the majority of children with TB are empirically initiated on treatment based on their symptoms alone. This dissertation aims to address specific knowledge gaps and potential areas in the patient care cascade where gaps may occur to improve detection of TB in children. In my first aim, our objective was to evaluate the clinical diagnostic accuracy of lipoarabinomannan (LAM) in urine and whole blood samples in children with clinical TB symptoms using highly sensitive electrochemiluminescent immunoassays and the most accurate known LAM antibodies (FIND28:A194-01 & S4-20:A194-01). We used data from a prospective longitudinal cohort study of predominantly HIV-negative children with clinical TB symptoms recruited from inpatient and outpatient wards at Harry Gwala Regional Hospital in KwaZulu-Natal, South Africa. Using a composite reference standard for pediatric clinical TB diagnosis, we found that neither of the two current anti-LAM antibodies did not meet the WHO target product profile criteria for a non-sputum POC test (65% sensitivity, 98% specificity) in clinically diagnosed children. More sensitive and improved LAM detection antibodies are needed if LAM is to be a viable biomarker for diagnosing TB in children without advanced HIV disease. In my second aim, we applied machine learning methods to identify clinical, biomarker and rapid diagnostic features predictive of unconfirmed TB in children in KwaZulu-Natal, South Africa. Using data from the previous study, we trained random forest models using kNN imputation and minority class oversampling strategies to predict TB status from a range of available features. Using mean decrease in accuracy and SHAP values to highlight model variable importance, we found that respiratory rate, serum C-reactive protein levels, asthmatic episodes, LAM positivity, admission for a lower respiratory tract infection and having a sick household member were offered predictive value in differentiating between unconfirmed and unlikely TB. Models incorporating inverse probability weighting to account for class imbalance prioritized medical history and exposure related predictors, while models using synthetic oversampling prioritized clinical and laboratory testing results for prediction. Including these accessible, non-sputum-based measures in pediatric TB treatment decision algorithms may improve diagnostic accuracy. In my final aim, we used an agent-based model (TBSim) to estimate the effect of introducing novel diagnostics for both adults and children on pediatric TB outcomes in uMgungundlovu district, KwaZulu-Natal, South Africa. We evaluated four separate diagnostic strategies: (1) Xpert MTB/RIF Ultra alone; (2) Xpert plus oral swabs; (3) Xpert plus FujiLAM; and (4) Xpert plus a computer assisted detection for chest X-ray(CAD-CXR) for children. We found that when used as an add-on test to Xpert Ultra, oral swabs had the greatest impact on reducing pediatric TB incidence over the simulation period, especially in children 0-4 years of age. Surprisingly, none of the interventions substantially reduced overall TB mortality compared to Xpert Ultra alone. The inclusion of TPT prevention and social household contact network in future simulations are needed to verify findings. Our findings illustrate that there are several opportunities to expand upon existing work in order to improve detection of TB disease in children. Improving detection, diagnosis and reporting of pediatric TB remains a complex challenge to address globally. Our findings highlight the need for child-centered approaches to developing novel TB diagnostics.
The Urban Environment and Active Living: The Case of Bogotá, Colombia
(2025-10-02) Zewdie, Hiwot; Mooney, Stephen J
The built environment fundamentally shapes health opportunities, including those for active living. While research from the Global North has identified the types of built environments that support choice-based physical activity, less is known about their distribution and active-living promoting potential in Global South cities, where activity is often necessity-driven and socioeconomic inequalities and segregation are pronounced. This dissertation addressed this gap by using a neighborhood typology approach to examine how socioeconomic residential segregation and neighborhood built environments relate to shape active living patterns in Bogotá, Colombia. Findings showed that more segregated neighborhoods were less likely to be characterized as active living-supporting built environments, but were not directly associated with physical activity levels, likely due to misalignment between researcher-defined and perceived access to neighborhood characteristics. Despite limitations, including cross-sectional data, temporal mismatches, and reliance on proximity-based measures, this work highlights important areas for future place-based epidemiologic research in Global South cities. When leveraged intentionally, the built environment has the potential to foster cities that are fundamentally just, promoting equitable opportunities, mobility, and health for all residents.
Assessing the Concordance Between AI and Oncologist Treatment Recommendations in Breast Cancer Care: A Blinded Validation Study at Kenyatta National Hospital
(2025-10-02) Quig, Anya; Hawes, Stephen
Artificial intelligence (AI) has emerged as a promising tool in oncology, with the potential to support clinical decision-making and expand access to evidence-based care. This study examines the clinical validity of Gukiza, a proprietary AI platform developed by Hurone AI for cancer management. For this study, a total of 21 de-identified breast cancer patients from Kenyatta National Hosptial were assessed. Treatment plans were created by Gukiza and a team of oncologists, and evaluated by an expert panel, as well as against National Comprehensive Cancer Network (NCCN) Clinical Guidelines. Results showed that AI-generated treatment plans were not significantly correlated with oncologist-generated plans, potentially reflecting limitations in the scoring framework, restricted variability in responses, or underlying differences in clinical reasoning. Although clinician-generated plans received a higher proportion of "Acceptable" and "Exceptional" ratings, this difference was not statistically significant. In contrast, an AI-assisted analysis of AI-generated plans demonstrated strong concordance with NCCN guidelines, highlighting their potential alignment with evidence-based standards despite limited agreement with clinician ratings. Subgroup analyses indicated that postmenopausal status was associated with lower odds of treatment plan unacceptability, while the presence of comorbidities was associated with higher odds, although neither association reached statistical significance. These findings suggest that AI-generated treatment recommendations are largely NCCN guideline-adherent, and while the data from the blinded concordance assessment did not show significant correlation, the analysis highlights some of inherent challenges in comparing AI tools with clinical standards of care. Further validation in larger, more diverse patient populations is needed.
Streptococcus pneumoniae carriage and antimicrobial resistance among Kenyan children discharged from hospital
(2025-10-02) Libby, Tanya; Pavlinac, Patricia B
Streptococcus pneumoniae is a leading cause of morbidity and mortality among children under five in sub-Saharan Africa, particularly in the vulnerable period following hospital discharge. This dissertation investigates the dynamics of pneumococcal carriage and antimicrobial resistance (AMR) in this high-risk population through a series of analyses nested within the Toto Bora trial, a randomized, placebo-controlled study of azithromycin in 1,398 Kenyan children discharged from hospital and followed for six months. This collection of nested studies aims to inform strategies for preventing AMR and improving child health by evaluating the impact of azithromycin treatment, identifying risk factors for carriage and resistance, and assessing the clinical consequences of pneumococcal carriage.The first study evaluates the effect of a 5-day course of azithromycin versus placebo administered at hospital discharge on S. pneumoniae carriage and AMR. No significant differences were observed in carriage prevalence or azithromycin resistance at 3- or 6-months post-discharge between treatment arms. This may be due in part to high inpatient antibiotic use in this population, reducing any further impact of azithromycin. Notably, resistance to multiple antimicrobial classes was already prevalent at discharge, with nearly 35% of isolates classified as multidrug-resistant. This study underscores the importance of considering inpatient antibiotic use when evaluating the downstream effects of post-discharge antimicrobial interventions. The second study explores clinical and environmental risk factors for pneumococcal carriage and AMR using longitudinal data from nasopharyngeal swabs collected at discharge and follow-up. Pneumococcal carriage at hospital discharge was inversely associated with inpatient antibiotic use and longer hospital stays whereas carriage at 3 and 6 months was linked to household-level exposures such as unimproved water sources, untreated drinking water, and shared sanitation facilities. Resistance to doxycycline was more common among children with multiple young siblings, while receipt of the recommended doses of pneumococcal conjugate vaccine (PCV) was associated with reduced resistance to doxycycline and clindamycin. These findings highlight the role of water, sanitation, and hygiene (WASH) interventions in shaping post-discharge colonization and support the role of PCVs in AMR mitigation strategies. The third study investigates whether S. pneumoniae carriage at discharge is associated with increased risk of rehospitalization or death. Notably, carriage was not linked to adverse outcomes and was associated with a significantly lower risk of all-cause mortality, even after adjusting for key confounders. This inverse association may reflect protective mucosal immunity conferred by colonization with less virulent strains. Given the persistently high post-discharge mortality observed among children without S. pneumoniae carriage, this group may warrant particular attention in future interventions targeting vulnerable populations. Azithromycin-resistant pneumococcal carriage was associated with poorer clinical outcomes among children treated with azithromycin, underscoring the importance of appropriate antimicrobial therapy. Together, this dissertation provides a comprehensive view of pneumococcal dynamics in the period following discharge from hospital. The findings suggest that short-course azithromycin does not meaningfully alter carriage or antimicrobial resistance patterns in settings with high inpatient antibiotic use, and that household environmental conditions play a critical role in shaping post-discharge colonization. Importantly, pneumococcal carriage at discharge was not associated with increased morbidity or mortality. These insights have implications for antimicrobial policy, vaccine strategy, and post-discharge care in low-resource settings, emphasizing the need for integrated approaches that address both clinical and environmental drivers of AMR and child health.
The Impact of Introducing Mycoplasma genitalium (MG) Testing for Acute Non-Gonococcal Urethritis (NGU) and MG-Specific Treatment on Persistent NGU Cases
(2025-10-02) Parker, Anika; Manhart, Lisa E
Mycoplasma genitalium (MG) is a common cause of non-gonococcal urethritis (NGU), particularly in persistent cases that often result from undetected and not optimally treated infections. In response to rising local prevalence of macrolide resistance, the Public Health-Seattle & King County (PHSKC) Sexual Health Clinic (SHC) began MG testing at first NGU presentation in 2018 and treating MG infections with doxycycline followed by moxifloxacin, a non-macrolide antibiotic. We conducted a pre-post analysis using data from patients assigned male sex at birth who were diagnosed with NGU at the PHSKC SHC between October 1, 2013 and December 31, 2023 to evaluate the impact of introducing MG testing and targeted treatment on persistent NGU cases. Data were collected from electronic health records. Statistical significance of differences in characteristics between Period 1 (prior to the introduction of MG testing for acute NGU cases and MG-specific therapy) and Period 2 (after the introduction of MG testing for acute NGU cases and MG-specific therapy) and visits with acute NGU and persistent NGU were assessed using Pearson's chi-square or Fisher's exact tests and Wilcoxon rank sum tests. Multivariable Poisson regression with generalized estimating equations and robust standard errors was used to estimate the prevalence ratio (PR) of visits for persistent NGU in Period 2 relative to Period 1. Among 5,060 NGU visits over both periods of time, 205 (4.1%) were classified as persistent NGU. Adjusting for race/ethnicity, Chlamydia trachomatis nucleic acid amplification test results at acute NGU visits, and human immunodeficiency virus status, the introduction of MG testing plus MG-specific therapy (Period 2) was associated with a non-significant 12% reduction in the prevalence of persistent NGU relative to the time period prior to this introduction (Period 1; adjusted PR: 0.88, 95% confidence interval: 0.67-1.16, p=0.353). Introducing MG testing and sequential doxycycline and moxifloxacin treatment for MG infections was associated with a modest, non-significant reduction in persistent NGU. These findings suggest that recommending MG testing at first presentation of NGU and providing targeted treatment for MG infections may not result in fewer persistent NGU cases.
Saying "Yes" to PrEP: Examining PrEP acceptance among urban men who have sex with men (MSM) at a Seattle public sexual health clinic.
(2025-10-02) Pfau, Brian; Kerani, Roxanne
Pre-exposure prophylaxis (PrEP) is extremely effective at preventing HIV, but uptake has been below targets. PrEP acceptance and uptake are commonly examined through hypothetical acceptability and active use, but the act of accepting a PrEP recommendation from a clinical provider is under-studied. This cross-sectional study used patient survey data and health records from the Public Health—Seattle & King County Sexual Health Clinic in Seattle, WA to examine how PrEP acceptance differed by key covariates among men who have sex with men (MSM). Among 1721 patient visits where a provider recommended PrEP to an MSM, PrEP was accepted at 1168 (68%) visits. Prevalence of PrEP acceptance was lower among patients aged 25 years or older compared to patients under age 25 (PR = 0.92, 95% CI = 0.85, 0.99) and higher among patients who reported greater numbers of recent sexual partners compared to those reporting one or fewer (PR = 1.38 95% CI = 1.13-1.68), but was lower among Black patients compared to White patients (61%, PR = 0.85, 95% CI = 0.76-0.96) and patients identifying as bisexual compared to those identifying as gay (PR = 0.84, 95% CI = 0.75-0.93). According to visit notes recorded by providers, patients who declined commonly believed their risk of HIV exposure was too low to warrant daily PrEP, were concerned about side effects, or preferred to discuss with their primary care provider, while some preferred to abstain from sex altogether following the HIV/STI exposure which brought them to the clinic. To increase PrEP uptake, future work should identify and test strategies to maximally support some MSM who have an indication for but less often accept PrEP.

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