BACKGROUND:We aimed to examine how coronary artery calcium (CAC) and its progression relate to cognitive function in midlife, an important time for cognitive aging. METHODS:We studied participants enrolled in the prospective CARDIA (Coronary Artery Risk Development in Young Adults) study, a longitudinal cohort of Black and White adults aged 18 to 30 years at baseline, who completed CAC measurements using computed tomography at year 15 (2000-2001; our baseline), had at least 1 follow-up CAC measurement at years 20 (2005-2006) or 25 (2010-2011), and completed cognitive assessments with a battery of 5 tests at years 30 (2015-2016) or 35 (2020-2022). CAC progression was defined as: (1) CAC >0 at follow-up among participants with baseline CAC=0; (2) an annualized change of ≥10 units at follow-up among those with 00) and CAC progression. RESULTS:Among the 2341 participants (mean baseline age 40.3±3.6 years; 56% female), baseline CAC >0 (9%) was associated with lower processing speed, verbal memory, and global cognition, whereas CAC progression (26%) was associated with lower processing speed and global cognition after adjusting for demographics, education, physical activity, depressive symptoms, APOE ε4 allele, and baseline CAC score. The standardized cognitive differences (95% CI) for CAC progression versus no progression were -0.14 (95% CI, -0.23 to -0.06) for the Digit Symbol Substitution Test and -0.09 (95% CI, -0.17 to -0.01) for the Montreal Cognitive Assessment. CONCLUSIONS:CAC progression was associated with worse midlife processing speed and global cognition, independent of baseline CAC score and established risk factors. Repeated CAC assessments may offer clinical value for identifying individuals at increased risk for midlife cognitive decline.

Background: Little is known about how nursing programs teach sexual and reproductive health (SRH), particularly abortion and contraception.Purpose: To assess SRH content in California nursing programs and examine faculty views on training quality.Method: Participants in this cross-sectional survey were eligible if they held a current California nursing license and were involved in curriculum development in a California-accredited nursing program.Findings: Faculty from 32 nursing programs across California completed surveys. SRH content differed by program type: online/hybrid programs were more likely to include basic SRH, abortion, and contraception, whereas advanced practice nursing programs provided more prenatal care. Discussion: SRH content is inconsistently taught to nurses across California. There is a need for comprehensive SRH core competencies to guide nursing SRH curricula.

Polygenic risk scores (PRS) summarize genetic variants associated with cardiovascular disease (CVD) risk. Socioeconomic status (SES) impacts CVD risk, but whether SES modifies genetic risk remains unclear. We investigated total and direct effects of the PRS for CVD on CVD events while accounting for SES and traditional risk factors. We followed UK Biobank participants recruited from 2006 to 2010 through 2022 with available PRS for CVD, SES (deprivation index, income, education), and cardiovascular risk factor data (diet, physical activity, smoking, sleep, body mass index, cholesterol, hbA1c, blood pressure). The primary outcome was first incident CVD event (myocardial infarction, heart failure, stroke, or CVD death). Competing-risk models were used to estimate total and direct effects of the PRS on CVD events after adjustment for age, sex, SES, and CVD risk factors. We additionally tested for interactions. Among 36,244 participants (mean age 55.3 ± 8.2 years; 53.6% female) with complete data, 1,900 (5.2%) experienced a CVD event. Each standard deviation increase in the PRS was associated with a higher risk of CVD events (HR 1.26, 95% CI 1.21 to 1.33), remaining significant after full adjustment (HR 1.23, 95% CI 1.18 to 1.29). Compared with the lowest-income group, participants with the highest income had 0.54 times the risk of a CVD event (HR 0.54, 95% CI 0.51 to 0.81). No significant interactions were observed. SES is independently associated with CVD events but does not modify genetic risk. CVD PRS remains directly associated with CVD after accounting for SES and traditional risk factors.

The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer's disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer's disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer's Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer's disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)-an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer's disease. Subtype 2/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer's disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.

INTRODUCTION:The Apolipoprotein E ε4 allele (APOE-ε4) is a well-established dementia risk factor among non-Latino White individuals but remains understudied among Asian Americans. We estimated its association with dementia risk among Chinese, Japanese, Filipino, and non-Latino White older adults in California. METHODS:This longitudinal study included 1078 Chinese, 843 Japanese, 583 Filipino, and 43,821 non-Latino White participants from the Genetic Epidemiology Research in Adult Health and Aging cohort (mean baseline age = 70 years). Dementia was identified using electronic health records. We estimated effects of APOE-ε4 carriership on dementia risk using pooled logistic regression. RESULTS:APOE-ε4 carriership prevalence ranged from 14% among Filipino to 25% among non-Latino White participants. APOE-ε4 carriership was associated with higher dementia risk across groups; 10-year risk ratios (95% confidence interval [CI]) ranged from 1.59 (0.66-3.10) among Filipino to 1.96 (1.36-2.78) among Japanese participants. DISCUSSION:Despite differences in prevalence of APOE-ε4, its association with dementia risk was similar across Chinese, Japanese, Filipino, and non-Latino White participants.

How to integrate genetic ancestry into clinical care remains unsettled. We assessed (i) agreement between two commercial ancestry providers, (ii) concordance between multiple ancestry algorithms and self‑identified race/ethnicity (SIRE) recorded in the electronic health record (EHR), and (iii) participant perspectives on accuracy, clinical utility, discrimination risk, and EHR integration. Using data from 451 adults in the UCSF 3D Health Study, we harmonized ancestry outputs to five continental categories and quantified cross‑provider agreement and ancestry–SIRE concordance at ≥ 50

Background: Depression, a known comorbidity in coronary heart disease (CHD), is associated with adverse cardiac events, mortality, symptom burden, physical limitation, and poor quality of life (QOL). Evidence has shown that depression impedes self-care behaviors including, physical activity. Similarly, regular physical activity has been shown to lessen depressive symptoms and improve cardiovascular health. However, there is limited research to determine whether depressive symptoms mediate or moderate the association between physical activity and overall QOL in the older adult population living with chronic CHD. Hypothesis: Depression mediates the positive association between physical activity and QOL. Depression is a moderator of physical activity and QOL. Objectives: 1) To determine the direct effect of depressive symptoms on physical activity and QOL; 2) to investigate the mediating effect of physical activity and depressive symptoms on QOL; and 3) to test the moderating effect of depressive symptoms on physical activity and QOL. Methods: This cross-sectional study collected 20-year follow-up survey data from 126 survivors from the Heart and Soul prospective cohort study of people living with CHD. Mediation testing was conducted using the steps described by Baron and Kenny. Results: Physical activity significantly predicted QOL ( β =.133, p =.02) and significantly predicted depressive symptoms ( β =-.1918, p =.0002); depressive symptoms significantly predicted QOL( β =-0.762, p <.0001). After depression was added to the model, the relationship between physical activity and QOL was no longer significant, indicating a mediating effect. The average causal mediation effect was statistically significant (.1463, p =.0002). Depression was not a moderator of physical activity and QOL (p>.05). Conclusions: This study demonstrated that depression mediated the effect of physical activity on QOL. The findings underscore the importance of addressing physical activity and depressive symptoms in interventions to improve the overall well-being and quality of life of individuals living with chronic CHD.

INTRODUCTION:Decreases in body mass index (BMI) may be early consequences of Alzheimer's disease (AD) pathophysiological changes. Previous research in the UK Biobank estimated that AD-related genes began affecting BMI around age 47. We assessed whether this result could be replicated using longitudinal data in an independent cohort. METHODS:Using All of Us (AOU) (N = 197,619, aged 30+) data, we estimated linear mixed models for associations of Z-scored AD-Genetic Risk Score (AD-GRS) with BMI, stratified by decade of age. We calculated the earliest age at which AD-GRS was associated with differences in BMI using cross-validated models adjusted for demographics. RESULTS:Higher AD-GRS was statistically associated with lower BMI in participants aged 60-70 (b = -0.060 [-0.113, -0.007]). Best fitting models suggested the inverse association of AD-GRS and BMI emerged beginning at ages 47-54. DISCUSSION:AD genes accelerate age-related weight loss starting in middle age. HIGHLIGHTS:Understanding when physiological changes from amyloid pathology begin is key for AD prevention. Our findings indicate that AD-associated genes accelerate midlife weight loss, starting between 47 and 54 years. AD prevention research should consider that disease pathology likely begins by middle age.

BACKGROUND:Family-centered care (FCC) contributes to improved health care delivery and outcomes in pediatrics. OBJECTIVE:To conduct a global survey of hospital leaders' views on FCC culture, policies, and practices in health care organizations serving children, including in the post-COVID-19 pandemic era. RESEARCH DESIGN:A cross-sectional electronic survey. RESULTS:Surveys were received from 256 leaders from 215 hospitals in 38 countries. Preliminary psychometric analysis yielded a 44-item instrument wherein a higher total score indicated leaders had more positive views of their hospital's FCC. A majority reported high levels of FCC culture at bedside and supportive policies for family presence and participation. Fewer leaders reported family partnership at the organizational level, health professional education on FCC, or organizational accountability for FCC. In multivariable analyses, having an active patient and family advisory council (PFAC) was associated with higher FCC scores. Free-text comments reflected respondents' commitment to family presence and participation in care and decision-making, factors that facilitated or impeded active PFACs, variability in FCC practices, and the COVID-19 pandemic's impact on FCC. CONCLUSIONS:These findings suggest a commitment to FCC by leaders in hospitals providing pediatric care globally, and that an active PFAC is associated with higher ratings of hospital FCC culture, policies, and practices. Expanded adoption of PFACs, along with standardized measurement and quality improvement monitoring, may improve the family-centeredness of pediatric health care, and thereby contribute to quality and safety. Barriers such as a lack of organizational accountability for FCC must be addressed so that FCC can function optimally in pediatric settings.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Some evidence suggests the effect of APOE genotype on dementia risk may vary by race/ethnicity and genetic ancestral background. We evaluated APOE genotype and associated dementia risk by genetic ancestry, with a focus on expanding research among participants with non-European ancestry. The Kaiser Permanente Research Bank (KPRB), one of the largest biobanks in the US, enrolled members of an integrated health system, collected genotyping and health surveys and link to electronic health records (EHR). Genetic ancestry proportions (range 0-1) were estimated using the program ADMIXTURE. First diagnosis of all-cause dementia was collected from EHR over a mean follow-up time of 14.6 years. Logistic regressions evaluated associations of APOE e4 and e2 allele status with dementia adjusted for sex and age. We tested interactions between APOE and race/ethnicity (from self-report and/or EHR) and separately APOE and genetic ancestry. Preliminary analyses included 180,345 participants (mean age at consent 56.17 years), including 17,356 Asian, 11,595 Black, 926 Hawaiian/Pacific Islander, 22,663 Hispanic, 3,714 multiracial, and 498 Native American/Alaska Native participants. APOE e4 allele prevalence was highest among Black participants (34%) and lowest among Asian participants (17%). APOE e2 allele prevalence was highest among Black participants (17%) and lowest among Hispanic (8%) and Native American/Alaskan Native (9%) participants. APOE e4 allele (but not APOE e2) significantly interacted with both race/ethnicity and genetic ancestry, although associations were elevated among all groups. The association of APOE e4 with dementia diagnosis (n = 8,288) was strongest among White participants (OR: 1.67; 95%CI:1.59,1.75) and was significantly lower among Black (OR interaction: 0.83; 95%CI:0.69,0.99) and Hispanic participants (OR interaction:0.79; 95%CI:0.65,0.95). Similarly, the association of APOE e4 with dementia increased with higher proportion of European ancestry (OR interaction:1.30, 95%CI:1.13,1.49). The association of APOE e4 allele with dementia was reduced with higher proportion African ancestry (OR interaction:0.71, 95%CI: 0.57,0.90), and Native American ancestry (OR interaction: 0.52, 95%CI: 0.30,0.91). In preliminary analyses, we found APOE e4 allele association with dementia differed by European, African, and American genetic ancestries, which correlated with differences by race/ethnicity. Our findings suggest genetic ancestral background is important when utilizing APOE genotype in determining risk for dementia.

Coronary heart disease (CHD) is a significant public health problem among older adults that is associated with reduced physical activity (PA) and impaired functional capacity, commonly measured by activities of daily living (ADL) and instrumental activities of daily living (iADL). Maintaining independence in ADLs is critical for older adults' quality of life and healthcare outcomes. While social support is known to improve health outcomes, its long-term impact on PA and functional status in CHD patients has not been fully explored. This study aimed to investigate the association between social support and functional outcomes, including PA, in a cohort of long-term survivors with established CHD. This study leverages 2 decades of the Heart and Soul Study, a multicenter investigation into mental health factors and clinical outcomes in individuals with CHD. We report a longitudinal analysis of baseline (2000–2002) and 20-year follow-up data (2022) to detect differences in social support and its association with functional status and PA over 20 years of surviving participants. Social support was measured using the 12-item Interpersonal Support Evaluation List (ISEL) subscales. Functional status was assessed using a combination of Katz and Lawton ADL scales, and PA was measured with self-reported data. Logistic regression models assessed associations between social support, ADL, and PA, accounting for change over time (baseline and 20 years), adjusting for sociodemographic factors and depressive symptoms. The sample included 129 participants (mean age 80.9 years, SD ± 9.1), 72.9

BACKGROUND:In hospitalized patients, QT/QTc (heart rate corrected) prolongation on the electrocardiogram (ECG) increases the risk of torsade de pointes. Manual measurements are time-consuming and often inaccurate. Some bedside monitors automatically and continuously measure QT/QTc; however, the agreement between computerized versus nurse-measured values has not been evaluated. OBJECTIVE:The aim of this study was to examine the agreement between computerized QT/QTc and bedside and expert nurses who used electronic calipers. METHODS:This was a prospective observational study in 3 intensive care units. Up to 2 QT/QTc measurements (milliseconds) per patient were collected. Bland-Altman test was used to analyze measurement agreement. RESULTS:A total of 54 QT/QTc measurements from 34 patients admitted to the ICU were included. The mean difference (bias) for QT comparisons was as follows: computerized versus expert nurses, -11.04 ± 4.45 milliseconds (95% confidence interval [CI], -2.3 to -19.8; P = .016), and computerized versus bedside nurses, -13.72 ± 6.70 (95% CI, -0.70 to -26.8; P = .044). The mean bias for QTc comparisons was as follows: computerized versus expert nurses, -12.46 ± 5.80 (95% CI, -1.1 to -23.8; P = .035), and computerized versus bedside nurses, -18.49 ± 7.90 (95% CI, -3.0 to -33.9; P = .022). CONCLUSION:Computerized QT/QTc measurements calculated by bedside monitor software and measurements performed by nurses were in close agreement; statistically significant differences were found, but differences were less than 20 milliseconds (on-half of a small box), indicating no clinical significance. Computerized measurements may be a suitable alternative to nurse-measured QT/QTc. This could reduce inaccuracies and nurse burden while increasing adherence to practice recommendations. Further research comparing computerized QT/QTc from bedside monitoring to standard 12-lead electrocardiogram in a larger sample, including non-ICU patients, is needed.

BACKGROUND AND OBJECTIVES:Previous research of associations between statins and Alzheimer disease and Alzheimer disease-related dementias (AD/ADRDs) has been limited by short follow-up, small samples, and confounding. We aimed to estimate the association between the 1st statin prescription and incident AD/ADRD among members of a large population-based cohort of older adults. METHODS:We used a cohort study design emulating a target trial using data from Kaiser Permanente Northern California (KPNC), an integrated health care delivery system. Participants were born before 1951 and KPNC members for 4+ years during 1997-2010. Embedded subsamples included sociodemographic and genetic data. Statin initiators were matched at first prescription ("baseline") with up to 5 "noninitiators" based on age and low-density lipoprotein cholesterol (LDL-C). Participants with extreme propensity scores were excluded. The outcome was time to incident AD/ADRD diagnosis, censoring, or the administrative end of study (December 31, 2020). Cox proportional hazard models were used to estimate hazard ratios for statin initiation on AD/ADRD incidence. Follow-up time was divided at the first year of follow-up to account for increased AD/ADRD detection in the first year due to increased interaction with the health care system after a statin prescription. RESULTS:Among eligible participants (n = 705,061), 264,294 individuals (37.5% of eligible participants) initiated any statin during 2001-2010 ("initiators"), of whom 249,613 (94.4%) were matched with 255,937 unique noninitiators to create the analytic sample (322,358 unique participants; mean age at baseline = 67.4 years; 55.1% female). The average follow-up was 11.8 years. In the first year after initiating statins, AD/ADRD diagnoses were elevated by 46% (hazard ratio [HR] = 1.46, 95% CI 1.42-1.53) compared with noninitiators. After 1 year, statin initiators experienced no difference in AD/ADRD incidence (full sample: HR = 1.00, 95% CI 0.99-1.01; subsample with survey covariates: HR = 1.01, 95% CI 0.98-1.06; subsample with survey and genetic covariates: HR = 0.97, 95% CI 0.91-1.07). Adjustment for sociodemographic covariates and apolipoprotein E e4 allele count did not materially change the findings. DISCUSSION:In this large emulated target trial, statin initiation was inconsistent with more than a 3% increase or decrease in the hazard of AD/ADRD after the first year of follow-up. This intent-to-treat analysis does not directly quantify effects of long-term exposure to statins. Associations in the first year likely reflect increased medical observation immediately after statin initiation. CLASSIFICATION OF EVIDENCE:This emulated trial provides Class II evidence that statin initiation is not associated with AD/ADRD or AD incidence after the first year of follow-up.

Background/Objectives: Despite the importance of parent mental health for child health, there are no global prevalence data on parental mental health symptoms when children are hospitalized. We aimed to describe depression and anxiety symptom prevalence and associated factors among parents of hospitalized children. Methods: We conducted this 14-country prospective cohort survey with parents/primary caregivers staying at a nearby Ronald McDonald House® during their child’s hospital treatment. We used the Hospital Anxiety and Depression Scale to measure depression and anxiety symptoms and validated scales and theory-based questions to measure parent, family, and child covariates. We calculated the prevalence of clinically significant or concerning symptoms of depression and anxiety, and used multivariable regression analyses to examine associations between covariates and outcomes. Results: Among 3350 participants, 1789 (49.7%) reported depression symptoms and 2286 (69.0%) reported anxiety symptoms. Worry about housing and poorer ratings of their child’s health were associated with increased risk of depression symptoms. Poorer rating of the child’s health, living with a partner, and discrimination in daily life were associated with increased risk of anxiety symptoms. Higher levels of self-care, hospital family-centered care, and social support were associated with reduced risk of depression symptoms. Higher levels of self-care and social support were associated with reduced risk of anxiety symptoms. Conclusions: Clinically significant or concerning depression and anxiety symptoms are common among parents of hospitalized children globally. Hospitals should consider offering routine mental health symptom screening and preventative mental health and support services to all parents.

Abdominal hernias are caused by the protrusion of an organ or tissue through a weakened abdominal wall. Genome-wide association studies (GWASs) have identified 81 genetic susceptibility loci for different hernia subtypes, with 26 loci associated with more than one hernia type; however, additional work is needed to prioritize causal genes at known GWAS loci, identify novel ones, and characterize shared genetic effects across hernia subtypes. We conduct transcriptome-wide association study (TWAS) analyses of four hernia subtypes (i.e., inguinal, umbilical, ventral, femoral) using GWAS summary statistics from up to 57,291 hernia cases and 436,717 controls of European ancestry. Our TWAS, which leveraged imputed gene expression from 54 tissues, identifies 211 unique genes, of which 85 did not overlap with known hernia-associated loci. We also investigate patterns of pleiotropy and identify four genes (LYPLAL1-AS1, RIMKLBP2, AL513283.1, and EFEMP1) associated with all four hernia subtypes. Our findings enhance understanding of transcriptomic mechanisms through which hernias develop.

Purpose:To identify novel candidates for cataract and evaluate the contribution of protein-coding variants to cataract susceptibility. Methods:We first leveraged a publicly-available browser, Genebass, to extract significant gene-based and single-variant association results for cataract in UK Biobank exomes (30,550 cataract cases and 364,291 controls). We then validated findings using genome-wide association study (GWAS) summary statistics from the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (28,092 cataract cases and 50,487 controls). Finally, we examined the expression of the prioritized genes in lens tissue using the iSyTE database. Results:Gene-based association testing identified four genes (KDM5B, COL2A1, MIP and CRYBB2) that were associated with cataract (P < 2.50 × 10-6), of which one (KDM5B) was neither previously reported to be associated with congenital cataract nor reported in GWAS. Single-variant association testing identified seven variants within six genes (BFSP2, ZNF800, MIP, HERC2, TSPAN10 and CPAMD8) that were associated with cataract (P < 1.00 × 10-8). Among the identified cataract variants, we found four missense, one synonymous, one frameshift, and one stop-gained variant. Associations at COL2A1, HERC2, and ZNF800 were validated in GERA. Importantly, majority of prioritized cataract genes were robustly expressed in iSyTE lens data and were enriched in structural constituent of eye lens, lens development in camera-type eye, visual perception, and collagen type II trimer pathways. Conclusions:Our results demonstrate the value of gene-based and single-variant association testing for understanding cataract etiology and uncovering novel genetic risk factors. Our findings also show that cataract-associated genes are significantly expressed in lens tissues and lens-related biological pathways.

With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies. Our GWAS identified six lead variants across five genomic regions that were significantly associated (P<5×10-8) with the risk of developing multiple primary tumors (overall and invasive) relative to cancer-free controls (at 3q26, 8q24, 10q24, 11q13.3, and 17p13). We also found one variant significantly associated with multiple cancers when comparing to single cancer cases (at 22q13.1). Multi-tissue TWAS detected associations with genes involved in telomere maintenance in two of these regions (ACTRT3in 3q26 andSLKandSTN1in 10q24) and the development of multiple cancers. Additionally, the TWAS also identified several novel genes associated with multiple cancers, including two immune-related genes,IRF4andTNFRSF6B. Telomere maintenance and immune dysregulation emerge as central, common pathways influencing susceptibility to multiple cancers. These findings underscore the importance of exploring shared mechanisms in carcinogenesis, offering insights for targeted prevention and intervention strategies.

INTRODUCTION:We evaluated the independent associations between high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels with Alzheimer's disease and related dementias (ADRD). METHODS:Among 177,680 members of Kaiser Permanente Northern California who completed a survey on health risks, we residualized TGs and HDL-C conditional on age, sex, and body mass index. We included these residuals individually and concurrently in Cox models predicting ADRD incidence. RESULTS:Low (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02-1.10) and high quintiles (HR 1.07, 95% CI 1.03-1.12) of HDL-C residuals were associated with an increased risk of ADRD compared to the middle quintile. Additional adjustment for TGs attenuated the association with high HDL-C (HR 1.03, 95% CI 0.99-1.08). Low TG residuals were associated with an increased ADRD risk (HR 1.10, 95% CI 1.06-1.15); high TG residuals were protective (HR 0.92, 95% CI 0.88-0.96). These estimates were unaffected by HDL-C adjustment. DISCUSSION:Low HDL-C and TG levels are independently associated with increased ADRD risk. The correlation with low TG level explains the association of high HDL-C with ADRD. HIGHLIGHTS:Strong correlations between lipid levels are important considerations when investigating lipids as late-life risk factors for Alzheimer's disease and related dementias (ADRD). Low levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) were independently associated with an increased risk of ADRD. We found no evidence for an association between high HDL-C and increased ADRD risk after adjustment for TGs. High levels of TGs were consistently associated with a decreased risk of ADRD. There may be interaction between TG and HDL-C levels, where both low HDL-C and TG levels increase the risk of ADRD compared to average levels of both.