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Alzheimer's disease (AD) is the 3rd leading cause of global deaths. COPD and AD have a bi-directional positive relationship, increasing the interrelated mortality. To analyze the mortality trends associated with COPD in Alzheimer's disease among older adults (>55 years of age) in the United States, using CDC WONDER data from 1999 to 2020. A retrospective analysis using the CDC WONDER database was conducted to analyse the mortality trends due to COPD in Alzheimer's disease patients, stratified by sex, race/ethnicity, census region, states and urbanization status. A total of 58,495 deaths due to COPD-associated Alzheimer's disease occurred among older adults (aged >55 years). Overall mortality increased from an AAMR of 2.04 per 100,000 in 1999 to 5.19 per 100,000 in 2020 (AAPC=4.31%, p&#x202f;<&#x202f;0.05). Men exhibited higher mortality than women (AAMR 4.00&#x202f;vs. 3.58 per 100,000). Non-Hispanic Whites had the highest mortality (AAMR 4.04), followed by Hispanics (AAMR; 2.58) and Non-Hispanic Blacks (AAMR; 2.39). The mortality was highest in the Western region (AAMR; 4.3), followed by Southern region (AAMR; 4.14), Midwestern region (AAMR; 3.94) and least in Northeastern region (AAMR; 2.26). Non-Metropolitan areas exhibit higher AAMR (4.62) than Metropolitan areas (AAMR; 3.52). Tennessee, Kentucky, and Washington were the top 3 states with the highest mortality. Significant increases in mortality were observed across most demographic groups (p&#x202f;<&#x202f;0.05). These findings highlight the increasing COPD-related mortality among Alzheimer's patients and reveal significant disparities by sex, race, and urbanization status. Systemic inflammation, oxidative stress, and COPD-induced hypoxia may contribute to cognitive impairment and dementia. These results underscore the urgent need for targeted healthcare strategies and further research to address these disparities.

Inflammatory diseases of the nervous system, though uncommon, cause substantial mortality; yet their long-term trends in the U.S. remain underexplored. This study aims to evaluate mortality trends and patterns of inflammatory diseases of the nervous system in the US from 1999 to 2023, comparing patterns before and after 2018. We used the CDC WONDER database to extract age-adjusted mortality rates (AAMRs) per 100,000 adults for inflammatory diseases of nervous system (G00-G09) mortality in the US adults (>25 years) from 1999 to 2023, with the study period divided into two eras (ie, pre- and post-2018). Joinpoint regression was used to evaluate average annual percent change (AAPCs) and their confidence intervals (CIs). From 1999 to 2023, inflammatory diseases of the nervous system caused 71,894 deaths with a decreasing trend [AAPC: -0.31; p-value <0.001]. The AAMR was higher in the post-2017 era (1.36) than in the pre-2017 era (1.29). Overall, the trend declined in pre-2017 era [AAPC: -1.68; p-value <0.001] than in post-2017 era [AAPC: 4.19; p-value= 0.002]. In both eras, males (1.56&#x202f;vs 1.67) demonstrated higher AAMRs than females (1.09&#x202f;vs 1.11). The incline in mortality was significantly greater in females (AAPC: -1.96%; p-value <0.001&#x202f;vs 5.01%, p-value <0.001) than in males (AAPC: -1.65%; p-value <0.001&#x202f;vs 4.14%; p-value&#x202f;=&#x202f;0.05) in both the eras. A similar trend was observed across racial/ethnic groups, except for NH Blacks (AAMRs: 2.0&#x202f;vs 1.78) and NH Asians (AAMRs: 0.84&#x202f;vs 0.81) who showed greater mortality rates in the pre-2017 era. NH American Indians (AIs) showed the highest incline in mortality burden between pre-2018 and post-2018 (AAPC: 1.01%; p-value&#x202f;=&#x202f;0.18&#x202f;vs 8.46%; p-value&#x202f;=&#x202f;0.002). Overall inflammatory diseases of the nervous system in US adults declined from 1999 to 2023 but increased markedly after 2017. Males showed consistently higher mortality than females. Except for NH AI patients, other racial/ethnic groups show smaller inclined in mortality post-2018.

Emerging adulthood (ages 18-25) involves significant changes, made more challenging for those with inflammatory bowel disease (IBD), especially when transitioning from pediatric to adult care. Research has focused on transition readiness, with less attention to patient-prioritized outcomes after transfer. Less is also known about those diagnosed during emerging adulthood, who must navigate a new diagnosis and disease management. This study estimated the prevalence of behaviors reflecting health care autonomy among emerging adults with IBD, comparing pediatric- and adult-diagnosed cases. In this cross-sectional study, emerging adults with IBD in Alberta, Canada completed a questionnaire assessing IBD knowledge, self-management, relationship with their IBD care team, and disease management. Participants were grouped as pediatric-diagnosed (<18 years) or adult-diagnosed (18-25 years). Descriptive and comparative analyses were conducted. Among 178 participants (122 pediatric-diagnosed; 56 adult-diagnosed), pediatric-diagnosed cases were younger on average than adult-diagnosed cases (21.0 vs. 22.2 years), with similar distributions of gender, ethnicity and disease type. IBD knowledge scores, relationship ratings, and medication adherence scores were similar between groups. Pediatric-diagnosed cases were less independent than adult-diagnosed cases in some self-management tasks, including scheduling visits (72.6% vs. 92.9%), contacting their care team (76.0% vs. 94.6%), calling in medication refills (75.5% vs. 90.7%), and preparing questions for providers (63.3% vs. 79.3%). Pediatric-diagnosed cases demonstrated similar IBD knowledge, medication adherence, and satisfaction with their care team, but were less independent in some self-management tasks compared to adult-diagnosed cases. These findings highlight the need for targeted education and support for emerging adults with IBD.

Physical inactivity is a critical global public health concern. While guidelines often focus on moderate-to-vigorous physical activity, step-based targets are more feasible for contemporary lifestyles and provide a practical tool for clinicians and nurses to support patient education, lifestyle counseling, and long-term health management. However, evidence linking wearable device-measured daily steps to a broad spectrum of specific incident disease phenotypes remains limited. To systematically examine the associations between accelerometer-derived daily step counts and the risk of more than 400 incident diseases. A prospective, population-based cohort study using a Phenome-Wide Association Study approach. The UK Biobank, a large-scale resource with participants from England, Wales, and Scotland. We included 61,047 to 69,853 UK Biobank participants providing a full week of acceleration data between 2013 and 2015. Daily steps were calculated using the validated Verisense algorithm from seven-day accelerometer data. Disease phenotypes were derived from electronic health records and categorized via Phecode Map v1.2 based on standard International Classification of Disease, 10th revision codes. Cox proportional hazards models were used to analyze 435 disease phenotypes (grouped by Phecodes) with &#x2265;120 events. Models were adjusted for age, sex, ethnicity, education, smoking, alcohol, body mass index, deprivation, and self-reported health. Dose-response relationships were explored using restricted cubic splines. During a median follow-up of 7.9&#xa0;years, an increase of 5000 steps/day was associated with a lower risk of 64 incident diseases (HR range: 0.57 to 0.95). The strongest inverse associations were observed for type 2 diabetes (HR 0.80, 95% CI 0.76-0.84), acute renal failure (HR 0.82, 95% CI 0.78-0.86), Parkinson's disease (HR 0.57, 95% CI 0.49-0.67), essential hypertension (HR 0.93, 95% CI 0.91-0.95), and cholelithiasis (HR 0.77, 95% CI 0.71-0.83). For these conditions, the minimum dose for substantial benefit ranged from 8697 to 13,240 steps/day. Conversely, five conditions showed higher risk with increased steps, primarily musculoskeletal issues like internal derangement of the knee (HR 1.15, 95% CI 1.07-1.23) and osteoarthrosis (HR 1.15, 95% CI 1.06-1.24). The remaining 366 disease phenotypes showed no significant associations. Higher daily step counts are associated with a 5% to 43% lower risk for a wide array of diseases across the human phenome. These findings support the use of step-based metrics as a simple, effective tool for clinical monitoring and health promotion, providing accessible alternatives to traditional intensity-based physical activity guidelines and offering potential applications for healthcare professionals in patient counseling and lifestyle management.

Early-onset gastric cancer (EOGC), defined as diagnosis before age 45, represents a distinct and increasingly recognized subset of gastric cancer. Emerging evidence suggests that clinical behavior, treatment patterns, and outcomes differ from average-onset disease, yet these differences remain incompletely characterized. We evaluated demographic, geographic, pathologic, treatment, and survival patterns in patients with EOGC. This retrospective cohort study included patients with stage II-III gastric cancer diagnosed between 2006 and 2022 who underwent curative-intent gastrectomy in the National Cancer Database (NCDB). EOGC was defined as age&#x2009;&#x2264;&#x2009;45&#x2009;years at diagnosis. Demographic, pathologic, and treatment variables were analyzed. Overall survival (OS) was estimated using Kaplan-Meier methods and Cox proportional hazards models. A landmark analysis excluding patients with <&#x2009;6&#x2009;months of follow-up addressed survivorship bias. Across nearly two decades, EOGC accounted for 7.3% of the cohort and demonstrated demographic and geographic concentration, particularly among Hispanic, Black, and Asian patients. EOGC was associated with aggressive clinicopathologic features, including diffuse or signet-ring histology, poor differentiation, and advanced nodal disease. Although patients with EOGC more frequently received perioperative or neoadjuvant chemotherapy compared with older cohorts, pathologic complete response rates remained low, underscoring limited benefit from treatment intensification alone. Despite receipt of more intensive multimodality therapy, EOGC did not demonstrate superior survival outcomes. These findings highlight EOGC as a clinically distinct, high-risk disease subtype and support the need for biomarker-driven therapeutic strategies and earlier detection efforts in high-risk populations.

ASCVD and stroke remain leading causes of death in the United States, sharing overlapping risk factors and clinical consequences. Long-term declines in vascular mortality have slowed while disparities persist. We evaluated national trends and disparities in mortality involving coexisting ASCVD- and stroke-related conditions among U.S. adults from 1999 to 2025. We performed a retrospective population-based study using the CDC WONDER Multiple Cause of Death database. Adults aged &#x2265;25 years were included. Deaths were identified when prespecified ASCVD-related and stroke-related ICD-10 codes were both documented on the same death certificate, whether as underlying or contributing causes. The outcome represents a death-certificate-defined mortality phenotype rather than clinically adjudicated concurrent disease. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated using the 2000 U.S. standard population. Trends were assessed overall and by sex, age group, race/ethnicity, census region, urbanization, and state. Urbanization analyses were restricted to 1999-2020. Sensitivity analyses included restriction to atherosclerotic-specific codes (I25.x) and exclusion of provisional 2025 data. A total of 876,383 deaths were identified. Overall average AAMR was 15.01 per 100,000. Mortality declined from 26.82 in 1999 to 10.91 per 100,000 in 2025, with an AAPC of -3.53% (95% CI, -4.27 to -2.78; p&#x2009;<&#x2009;0.001). After sustained declines through 2018, AAMR showed a borderline significant increase during 2018-2021 (APC: 6.06%; 95% CI, 0.01-12.48; p&#x2009;=&#x2009;0.050), not replicated under stricter cause-of-death definitions, followed by renewed decline from 2021 to 2025 (APC: -2.85%; 95% CI, -4.58 to -1.09; p&#x2009;=&#x2009;0.004). Mortality burden remained higher among men, older adults, Black individuals, residents of the South, and non-metropolitan populations. Adults aged 25-44 years showed a significant increase after 2015, though absolute rates remain low and this finding warrants cautious interpretation. Although mortality involving coexisting ASCVD- and stroke-related conditions declined substantially from 1999 to 2025, this progress was interrupted by a borderline reversal in the pandemic period and remained marked by persistent disparities. These findings support the need for stronger and more equitable prevention strategies, particularly for younger adults and high-burden populations and regions.

Medication non-adherence among chronic disease patients remains a major contributor to poor health outcomes and medication wastage, particularly in multi-ethnic populations such as Malaysia where cultural and religious beliefs strongly influence health behaviours. This study aimed to develop and evaluate machine learning models that integrate demographic, clinical, and complementary and alternative medicine (CAM) belief factors to predict medication non-adherence among patients with type 2 diabetes mellitus, hypertension, and dyslipidaemia. A cross-sectional survey was conducted using a structured questionnaire comprising demographic and clinical data, history of CAM use, the 17-item Complementary and Alternative Medicine Beliefs Inventory (CAMBI), and the Malaysian Medication Adherence Scale (MALMAS). Twelve conventional machine learning algorithms and three stacked ensemble models were utilised using both balanced and unbalanced datasets with all variables as well as feature-selected variables. The best-performing model was a stacked ensemble using logistic regression-selected variables with the unbalanced dataset, achieving the highest AUC of 0.816. Feature selection identified significant variables including CAM beliefs (natural and holistic), race, number of daily doses, number of medications prescribed, religion, educational level, treatment duration, and hypertension status which were later interpreted using SHapley Additive exPlanations (SHAP) analysis. Model performance was further evaluated using the Youden Index and Decision Curve Analysis (DCA) to stratify patients into lower- and higher-risk groups, with a suitable cutoff identified at 0.4. These findings show that incorporating cultural and belief-related factors into machine learning models provides a novel, population-specific approach to predict better non-adherence and guide targeted interventions to reduce medication wastage in chronic disease management.

Ten-year atherosclerotic cardiovascular disease (ASCVD) risk prediction models include the pooled cohort equations (PCE) and the Predicting Risk of Cardiovascular Disease Events (PREVENT) models. We evaluated the relative contributions of predictors in these models, along with social determinants and emerging biomarkers. We pooled data from 13&#x2009;108 participants (58.4% female, 22.6% Black participants, median age 61&#x2009;years) across 3 prospective cohorts: ARIC (Atherosclerosis Risk in Communities), FOS (Framingham Offspring Study), and MESA (Multi-Ethnic Study of Atherosclerosis). Of these participants, 873 (6.7%) developed ASCVD within 10&#x2009;years. Candidate predictors included variables from PCE and PREVENT-ASCVD, alongside small dense low-density lipoprotein cholesterol, hs-CRP (high-sensitivity C-reactive protein), lipoprotein(a), and education level. We fit Cox proportional hazards models and applied stepwise selection, elastic net, and random forest for variable selection. Selected predictors were integrated into an exploratory model, Expanded ASCVD Non-traditional Determinants (EXPAND), which was compared with PCE and PREVENT-ASCVD both as originally published and after refitting in our sample. Most predictors shared by PCE and PREVENT-ASCVD were selected across methods; small dense low-density lipoprotein cholesterol, hs-CRP, and education were also selected, whereas self-reported race was not. Using published coefficients, PCE overestimated 10-year ASCVD risk, whereas PREVENT-ASCVD underestimated risk. Compared with PCE and PREVENT-ASCVD models refitted in our sample, EXPAND showed modest calibration advantages, particularly among Black men, and consistently achieved higher C-statistics. In our sample, self-reported race did not improve ASCVD risk prediction, whereas small dense low-density lipoprotein cholesterol, hs-CRP, and education level added predictive value, suggesting potential utility in including additional biomarkers and social factors.

With the acceleration of global population aging, the pathological accumulation of senescent cells (SnCs) has been confirmed as the core biological mechanism driving multiple aging-related diseases. This article aims to systematically review the formation mechanism of SnCs and their pathological roles in various tissue lesions, and to specifically evaluate the progress of three cutting-edge intervention strategies (Senolytics, Immuno-senolytics and Senomorphics). Senolytics selectively induces programmed apoptosis in SnCs by antagonizing senescent cell anti-apoptotic pathways. Immuno-senolytics include vaccines, engineered cell therapy and specific antibodies, which utilize the immune surveillance mechanism to achieve efficient elimination of SnCs. Senomorphics precisely reshape the SASP profile by targeting signaling axis or interfering with epigenetic modifications. Although the strategies have demonstrated remarkable potential for reversing pathology, their clinical translation still faces challenges such as the heterogeneity of SnCs, the lack of specific markers, and potential off-target toxicity. Future research should focus on multidisciplinary collaboration, aiming to optimize spatiotemporal targeted delivery systems and combination drug regimens to build a safer and more precise anti-senescence treatment system.

Adverse social determinants of health (SDOH) are associated with higher risk of acute kidney injury (AKI). This study evaluated the association of individual- and neighborhood-level SDOH with incident ESKD among intensive care unit (ICU) survivors of AKI. 30,498 adult ICU survivors of AKI at a major academic medical center between January 1, 2012, and December 31, 2022, were included. Individual-level SDOH (race, ethnicity, and insurance status) were obtained from the hospital electronic health record, whereas neighborhood-level SDOH (Area Deprivation Index (ADI), among others) were derived from census-based indices. ESKD was defined by kidney failure with an estimated glomerular filtration rate <15 mL/min/1.73 m2 or the initiation of kidney replacement therapy, including maintenance dialysis or kidney transplantation. Association of individual- and neighborhood-level SDOH with incident ESKD were evaluated using multivariable cause-specific Cox proportional hazards models adjusting for clinical factors. The median age was 58 years, 40% were women, 31% were Black, and 12% were uninsured. The median follow-up time was 730 days, during which 326 (1%) patients developed ESKD and 2,723 (9%) died. In adjusted models, Black race was associated with a higher hazard of ESKD compared with White race (adjusted hazard ratio [aHR] 1.43, 95% CI 1.05-1.94), whereas having health insurance was associated with a lower hazard of ESKD (aHR 0.60, 95% CI 0.39-0.92). Higher neighborhood-level socioeconomic disadvantage was also independently associated with higher risk of ESKD (ADI tertile 2: aHR 1.42, 95% CI 1.01-2.00; tertile 3: aHR 1.58, 95% CI 1.08-2.33). Black race, lack of health insurance, and residence in socioeconomically deprived neighborhoods were independently associated with a higher hazard of incident ESKD among ICU survivors of AKI. Standardized SDOH assessment in clinical practice may improve risk stratification of ESKD and identify AKI survivors most likely to benefit from post-discharge interventions.

Black individuals have a lower incidence of atrial fibrillation (AF) than White individuals, despite a higher burden of traditional risk factors. Prior studies have suggested that European genetic ancestry may contribute to this paradox, but findings have been inconsistent. We examined the association between European genetic ancestry and incident AF among 6920 UK Biobank (UKB) participants who self-identified as Black and were free of AF at baseline. European ancestry proportions were estimated by comparing participants to HapMap populations and were analysed both continuously and categorically using Cox proportional hazards models. Non-linear associations were evaluated using flexible spline curves. We then conducted a meta-analysis combining these results with those from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study and the Women's Health Initiative. During a median follow-up of 13.7 years, 205 (3%) participants developed incident AF. Each 10% increase in European ancestry was non-significantly associated with increased AF risk (HR 1.07 (95% CI 0.95 to 1.20)), and individuals in the highest European ancestry category had a higher AF incidence rate compared with all other categories. Random-effects meta-analysis of all four cohorts yielded a pooled relative risk (RR) of 1.09 (95% CI 0.99 to 1.21), with substantial heterogeneity largely driven by the Women's Health Initiative (WHI) study. Excluding WHI resulted in a pooled estimate (RR 1.14 (95% CI 1.05 to 1.23)) without heterogeneity. In UKB, European ancestry proportion was not significantly linked to incident AF, and pooled cross-cohort results were heterogeneous. Excluding WHI in sensitivity analyses produced a modest positive pooled association with no heterogeneity.

To evaluate the effectiveness and safety of ocrelizumab in self-identified black and Hispanic people with relapsing multiple sclerosis. The Characterization of Ocrelizumab in Minorities with Multiple Sclerosis (CHIMES) trial, a prospective, open-label, single-arm, phase 4 study, intentionally recruited underrepresented populations in the US, Puerto Rico, and Kenya. Black and Hispanic people with relapsing multiple sclerosis aged 18-65&#x2009;years with Expanded Disability Status Scale score 0-5.5 received ocrelizumab for 2&#x2009;years. The primary endpoint was the proportion of participants with no evidence of disease activity in 3 components at week 48: protocol-defined relapse, 24-week confirmed disability progression, and disease activity on magnetic resonance imaging. Of 113 black and 69 Hispanic people with relapsing multiple sclerosis, most were women (72%), with a mean age of 35.5 (SD 10.5) years, body mass index of 31.0 (SD 7.4) kg/m2, and Expanded Disability Status Scale score of 2.4 (SD 1.4). Genetic ancestry aligned with self-identified race or ethnicity. At week 48, 50.5% of CHIMES participants had no evidence of disease activity, including 94.5% free from 24-week confirmed disability progression, 95.1% free from relapse, 95.6% free from T1-contrast-enhancing lesions, and 52.7% free from new/enlarging T2 lesions. Serious adverse events were experienced by 8.2%, and 2.2% discontinued treatment. Infusion-related reactions were more frequent in Hispanic versus black participants (42.0% vs 29.2%), whereas gastrointestinal adverse events were more frequent in black versus Hispanic participants (23.0% vs 1.4%). Ocrelizumab treatment controlled disease activity in black and Hispanic people with relapsing multiple sclerosis. Results were consistent with pivotal ocrelizumab trials, supporting ocrelizumab's effectiveness and tolerability in these populations. ANN NEUROL 2026.

BMI is widely used to define obesity but does not capture adiposity distribution and related functional impairment. This study assessed obesity prevalence, disease burden, and incident cardiometabolic risk using the new criteria proposed by The Lancet Commission and compared disease burden across BMI-based and functional classifications. A population-based cohort study included 436,751 UK Biobank participants cross-classified according to ethnicity-specific BMI thresholds and the new criteria for preclinical and clinical obesity. Obesity was defined using integrated anthropometric and body-composition measures, while clinical obesity was further characterized by obesity-related organ dysfunction. Prevalence, disease burden, incident outcomes, and predictive performance were assessed across obesity categories. Data collected during 2006-2010 and were analyzed in 2026. BMI-defined obesity prevalence was 23.92%, whereas obesity prevalence increased to 67.58% under the new criteria, with clinical obesity accounting for 62.70% of the total population. Among individuals with non-obese BMI, 173,698 met criteria for clinical obesity and exhibited higher cardiometabolic burden. Compared with individuals classified as non-obese according to both BMI and the new criteria, participants with non-obese BMI but clinical obesity had increased risks of incident T2D (HR 3.18, 95% CI 3.04 to 3.33), NAFLD (2.01, 1.91 to 2.13), CKF (1.52, 1.46 to 1.59), HF (1.37, 1.31 to 1.44), and thrombosis (1.36, 1.28 to 1.45). Disease burden and multimorbidity were higher among individuals with clinical obesity, particularly among those with non-obese BMI. Although alternative obesity frameworks modestly improved discrimination for selected outcomes, predictive performance remained broadly comparable with BMI-based classification. Defining obesity based on abnormal adiposity and obesity-related organ dysfunction may increase the estimated population burden of obesity compared with BMI alone. Individuals with non-obese BMI but clinical obesity represent a clinically meaningful high-risk subgroup with markedly elevated cardiometabolic risk. These findings support the clinical utility of multidimensional obesity definitions beyond BMI-based classification.

Racial and ethnic differences in diabetic cardiomyopathy (DbCM) exist, with black and Hispanic participants showing poorer health status. It remains unclear whether these differences affect the natural progression of the disease. We aimed to evaluate disease progression in individuals with DbCM, as well as racial differences in the response to AT-001. A total of 625 participants with DbCM were randomised to either placebo or AT-001 and followed for 15 months. The primary outcome was change in peak oxygen uptake (peak VO2) and secondary outcomes included Kansas City Cardiomyopathy Questionnaire (KCCQ) and Physical Activity Scale for the Elderly scores. Analyses were stratified by race and ethnicity (black, Hispanic, white). Black and Hispanic participants who received placebo experienced greater declines in peak VO2 (-0.74 and -1.67&#x2009;mL/kg/min, respectively) compared with white participants (-0.23&#x2009;mL/kg/min, p=0.005). AT-001 demonstrated a non-statistically significant trend towards slower declines in peak VO2 in black and Hispanic participants (-0.31 and -0.62&#x2009;mL/kg/min, p=0.29, respectively). Black participants who received placebo had the largest declines in most KCCQ scores. Black and Hispanic participants with DbCM experienced faster disease progression, with black participants showing the most pronounced functional and quality of life declines. The effect of AT-001 on peak VO2 changes was not statistically significant with similar effects between racial and ethnic groups (NCT04083339). NCT04083339.

CAG repeat expansions in ATXN2 are implicated as risk factors for several neurological diseases, including spinocerebellar ataxia type 2 (SCA2) when >=33 CAG repeats are present, and amyotrophic lateral sclerosis (ALS) when 27-33 CAG repeats are present. However, how haplotypes around the repeats and CAA interruptions within the repeats are associated with disease phenotypes remains poorly understood. Previous studies on haplotypes around ATXN2 were limited to SNPs very close to the repeats (<5kb) or were based on statistical inference only. Here, we used long-read sequencing on the Oxford Nanopore Technologies (ONT) platform to simultaneously infer haplotypes around ATXN2 , the number of CAG repeats, and the number of CAA interruptions, along with NYGC ALS Consortium NGS dataset. We further sequenced 41 individuals (EUR = 39) with neurological diseases with intermediate repeats by ONT. We found that haplotypes around ATXN2 and the number of interruptions show ethnicity-specific and ALS-specific distribution. Three CAA interruptions are present at low prevalence (&#x223c;1%) in control populations in multiple ancestry groups, but high prevalence (&#x223c;55%) in ALS individuals with intermediate repeats. Furthermore, we examined 159 individuals with ALS (&#x223c;90% European ancestry) with intermediate ATXN2 repeats and found a unique haplotype in ALS individuals with three CAA interruptions, which can be tagged by an SNV, rs148019457. We also validated that the rs148019457-G allele is only present in haplotypes with three CAA interruptions. In summary, our study shows that 3 CAA interruptions are rarely seen in healthy controls but are common in those with expanded ATXN2 CAG repeats who have neurological disorders, and that rs148019457 tags a specific haplotype with 3 CAA interruptions within expanded ATXN2 CAG repeats in individuals of European ancestry. These results have implications for the development of precision genomic medicine for neurological disorders, and the tag SNP may help identify those with interruptions from existing population genotyping data.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of cardiovascular events and frequently coexists with other atherosclerosis risk factors, including obesity, metabolic syndrome, sleep apnea, and insulin resistance. Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like particle bound to apolipoprotein(a), that has been studied to have pro-thrombotic and pro-inflammatory properties and is an established independent risk factor for atherosclerotic disease. However, the association between MASLD and Lp(a) and their impact on long-term clinical outcomes have not been evaluated previously. We performed a secondary analysis of the prospectively collected data from the Multi-Ethnic Study of Atherosclerosis (MESA). Baseline MASLD was defined as either a liver-to-spleen (L:S) attenuation ratio less than 1.0 or liver attenuation <40 HU on computed tomography (CT) imaging, excluding individuals with excess alcohol consumption (>15 drinks/week for men and&#x202f;>&#x202f;10 drinks/week for women) and the presence of at least one cardiometabolic risk factor, including elevated BMI or waist circumference, type 2 diabetes mellitus, hypertension, hypertriglyceridemia, or reduced HDLC. Baseline Lp(a) levels were measured using a latex-enhanced turbidimetric immunoassay (Denka Seiken, Tokyo, Japan). Median Lp(a) levels were significantly lower in those with baseline MASLD compared to those without MASLD (11.9 vs 18.1&#x202f;mg/dL, p-value <0.001). Individuals with MASLD and low Lp(a) levels (&#x2264; 50&#x202f;mg/dL) had a significantly higher risk of all-cause mortality compared to those without MASLD and with low Lp(a) (HR 1.28; 95% CI: 1.025-1.56), independent of traditional cardiovascular risk factors. Additionally, individuals with baseline MASLD and elevated Lp(a) were independently associated with an increased risk of hard cardiovascular disease (HR 2.07, 95% CI: 1.39-3.09), compared to individuals without MASLD and with Lp(a)&#x202f;&#x2264;&#x202f;50&#x202f;mg/dL. MASLD is independently associated with lower levels of Lp(a). Patients with baseline MASLD and elevated levels of Lp(a) exhibit nearly twice the risk of cardiovascular diseases as compared to the cohort with no MASLD and lower Lp(a) levels. Importantly, even in the absence of elevated Lp(a), MASLD is associated with increased all-cause mortality. These findings suggest that while Lp(a) is a strong contributor to cardiovascular risk, MASLD itself is an independent determinant of long-term mortality.

The infection theory of dementia states that viral infections and chronic inflammation play a role in its pathogenesis. We aimed to test whether testing positive for inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6) is associated with an increased dementia incidence, inflammation, and other dementia risk factors. We included n&#x2009;=&#x2009;247,731 participants of the UK Biobank in the analysis, of whom n&#x2009;=&#x2009;3388 (1.4%) tested positive for iciHHV-6. Linear and logistic regression models were performed to assess the associations between iciHHV-6 with HHV-6 antigens, blood-based biomarkers of inflammation, and other dementia risk factors. Cox proportional hazards regression models were applied to assess the associations of iciHHV-6 with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD). Subjects with iciHHV-6 exhibited statistically significantly higher antibody responses to the HHV-6 antigens IE1A (p&#x2009;=&#x2009;0.002) and IE1B (p&#x2009;<&#x2009;0.001). IciHHV-6 positivity was significantly more frequent among subjects with European or Chinese ethnicity, with lower education, higher alcohol consumption, current smoking, and longer telomere length. Interestingly, iciHHV-6 positive subjects had lower C-reactive protein (CRP) levels (p&#x2009;=&#x2009;0.029). All other inflammatory biomarkers did not differ according to iciHHV-6 status. Overall, 6615 participants were diagnosed with all-cause dementia during a median of 13.6 years, including 3340 with AD and 1708 with VD. There was no significant association between iciHHV-6 positivity and the risk of any dementia outcome. IciHHV-6 positivity was not a risk factor for dementia outcomes or increased inflammation in this large study, but was associated with higher antibody responses against HHV-6 antigens, ethnicity, telomere length, and lifestyle factors.

People who identify as Black, Indigenous, and People of Color (BIPOC) represent an increasing proportion of patients with cystic fibrosis (CF). Despite the transformative potential of highly effective modulator therapies, BIPOC people with CF (pwCF) experience disproportionately worse outcomes, including lower lung function and increased risk of hospitalization. Social and structural conditions exacerbate these inequities. To better understand these dynamics, this study used photovoice, a community-based participatory research method, to explore how BIPOC pwCF describe the influence of systemic and structural inequities on their health and disease management. Using the photovoice method, participants documented their lived experiences through photography and facilitated group discussion using the See, Happening, Our, Why, Exist, Do, or SHOWED method. Group generated prompts focused on CF-related experiences, barriers, and supports. Transcripts were analyzed using the Sort and Sift, Think and Shift&#xa9; method. Participants described challenges unique to BIPOC pwCF, including delayed diagnosis of CF, limited CF knowledge among nonspecialist providers, and systemic barriers such as geographic isolation, language differences, and ineligibility for modulator therapies. Many described the need to self-advocate, seek alternative resources, or forgo local care in favor of distant CF centers. BIPOC pwCF face systemic barriers across the care continuum that reflect a gap between the promise of modern CF care and equitable access to it. Participants' narratives underscore the enduring consequences of viewing CF as a "White disease" and the urgent need for structural reform to ensure that advances in CF treatment are accessible and effective for all patients, regardless of race or ethnicity. Cystic Fibrosis Foundation.

Postpartum depression affects 1 in 7 women in the U.S. and antidepressant medications during pregnancy are recommended by obstetric and psychiatric professional societies for select patients with a history of depressive disorders. However, prenatal antidepressant medication use remains controversial, and current evidence does not allow conclusions regarding prenatal antidepressant medication effectiveness in preventing postpartum depression. To determine postpartum depression risk in women stopping versus continuing antidepressant medications during pregnancy and examine if risk varies by race, ethnicity, age, and prenatal depressive symptoms. We hypothesized continuing prenatal antidepressant medications would be associated with lower postpartum depression risk. This retrospective cohort study, conducted in a large, diverse, integrated community-based health care system, included patients &#x2265;18 years old with a live birth between 2010-2019 and depression taking antidepressant medication in the year prior to their last menstrual period. Exclusion criteria included bipolar, psychotic, or active substance use disorders. Based on medication fill history, patients were classified as continuing, stopping then restarting, or stopping antidepressant medications during pregnancy. Postpartum depression was defined as an international classification of diseases diagnostic code or a patient health questionnaire (PHQ)-9 score of &#x2265;10 up to a year after delivery. PHQ-9 scores of 0-4 define none-minimal, 5-9 mild, 10-14 moderate, 15-19 moderately-severe, and &#x2265;20 severe symptoms. Of 6,552 patients who continued (n=2,216), stopped then restarted (n=1,258), or stopped (n=3,078) antidepressant medications during pregnancy, 37.7% (n=2,469) developed postpartum depression. Compared to continuing, stopping then restarting or stopping antidepressant medications during pregnancy was associated with a higher risk of postpartum depression (adjusted relative risk (aRR)=1.14, 95%CI:1.05-1.24 and 1.14, 95%CI:1.06-1.22 moderate-severe depression and 1.33, 95%CI:1.09-1.62 severe depression for stopping). Risk was higher for patients with at least mild depressive symptoms at the first pregnancy depression screening (50.8% of patients; aRR=1.55; 95%CI 1.45-1.65), and highest for women with symptoms and stopping their antidepressant during pregnancy (aRR=2.72, 95%CI 1.94-3.82) compared to patients continuing antidepressants with none-minimal depressive symptoms. There were no statistically significant interactions by race, ethnicity, or age. Antidepressant medications during pregnancy may benefit patients with past depressive disorders to prevent postpartum depression. Depressive symptom severity during pregnancy may inform shared treatment decision-making between patients and prescribers.