The Association of Urinary Sodium Excretion with Glaucoma and Related Traits in a Large United Kingdom Population.

OBJECTIVE: Excessive dietary sodium intake has known adverse effects on intravascular fluid volume and systemic blood pressure, which may influence intraocular pressure (IOP) and glaucoma risk. This study aimed to assess the association of urinary sodium excretion, a biomarker of dietary intake, with glaucoma and related traits, and to determine whether this relationship is modified by genetic susceptibility to disease. DESIGN: Cross-sectional observational and gene-environment interaction analyses in the population-based UK Biobank study. PARTICIPANTS: Up to 103 634 individuals (mean age 57 years, 51% women) with complete urinary, ocular, and covariable data. METHODS: Urine sodium:creatinine ratio (UNa:Cr; mmol:mmol) was calculated from a midstream urine sample. Ocular parameters were measured as part of a comprehensive eye examination and glaucoma case ascertainment was through a combination of self-report and linked national hospital records. Genetic susceptibility to glaucoma was calculated based on a glaucoma polygenic risk score (PRS) comprising 2 673 common genetic variants. Multivariable linear and logistic regression, adjusted for key sociodemographic, medical, anthropometric, and lifestyle factors, were used to model associations and gene-environment interactions. MAIN OUTCOME MEASURES: Corneal-compensated IOP, optical coherence tomography derived macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness, and prevalent glaucoma. RESULTS: In maximally adjusted regression models, a one standard deviation increase in UNa:Cr was associated with higher IOP (0.14mmHg; 95% CI, 0.12 to 0.17; P<0.001) and greater prevalence of glaucoma (OR, 1.11; 95% CI, 1.07 to 1.14; P<0.001), but not mRNFL or GCIPL thickness. Compared to those with UNa:Cr in the lowest quintile, those in the highest quintile had significantly higher IOP (0.45mmHg; 95% CI, 0.36 to 0.53, P<0.001) and prevalence of glaucoma (OR, 1.30; 95% CI, 1.17 to 1.45; P<0.001). Stronger associations with glaucoma (P interaction=0.001) were noted in participants with a higher glaucoma PRS. CONCLUSIONS: Urinary sodium excretion, a biomarker of dietary intake, may represent an important modifiable risk factor for glaucoma, especially in individuals at high underlying genetic risk. These findings warrant further investigation as they may have important clinical and public health implications.

Disparities in cancer incidence by sexual orientation.

INTRODUCTION: Cancer risk factors are more common among sexual minority populations (e.g., lesbian, bisexual) than their heterosexual peers, yet little is known about cancer incidence across sexual orientation groups. METHODS: The 1989-2017 data from the Nurses' Health Study II, a longitudinal cohort of female nurses across the United States, were analyzed (N = 101,543). Sexual orientation-related cancer disparities were quantified by comparing any cancer incidence among four sexual minority groups based on self-disclosure-(1) heterosexual with past same-sex attractions/partners/identity; (2) mostly heterosexual; (3) bisexual; and (4) lesbian women-to completely heterosexual women using age-adjusted incidence rate ratios (aIRR) calculated by the Mantel-Haenszel method. Additionally, subanalyses at 21 cancer disease sites (e.g., breast, colon/rectum) were conducted. RESULTS: For all-cancer analyses, there were no statistically significant differences in cancer incidence at the 5% type I error cutoff among sexual minority groups when compared to completely heterosexual women; the aIRR was 1.17 (95% CI,0.99-1.38) among lesbian women and 0.80 (0.58-1.10) among bisexual women. For the site-specific analyses, incidences at multiple sites were significantly higher among lesbian women compared to completely heterosexual women: thyroid cancer (aIRR, 1.87 [1.03-3.41]), basal cell carcinoma (aIRR, 1.85 [1.09-3.14]), and non-Hodgkin lymphoma (aIRR, 2.13 [1.10-4.12]). CONCLUSION: Lesbian women may be disproportionately burdened by cancer relative to their heterosexual peers. Sexual minority populations must be explicitly included in cancer prevention efforts. Comprehensive and standardized sexual orientation data must be systematically collected so nuanced sexual orientation-related cancer disparities can be accurately assessed for both common and rare cancers.

Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Relationship between Oral Health and Glaucoma Traits in the United Kingdom.

PRECIS: In this cross-sectional analysis of UK Biobank participants, we find no adverse association between self-reported oral health conditions and either glaucoma or elevated intraocular pressures. PURPOSE: Poor oral health may cause inflammation that accelerates the progression of neurodegenerative diseases. We investigated the relationship between oral health and glaucoma. PATIENTS: United Kingdom (UK) Biobank participants. METHODS: This is a cross-sectional analysis of participants categorized by self-reported oral health status. Multivariable linear and logistic regression models were employed. Primary analysis examined the association with glaucoma prevalence. Secondary analyses examined associations with IOP, macular retinal nerve fiber layer (mRNFL), and ganglion cell inner plexiform layer (mGCIPL) thicknesses, and interaction terms with multi-trait glaucoma polygenic risk scores (MTAG PRS) or intraocular pressure (IOP) PRS. RESULTS: 170,815 participants (34.3%) reported current oral health problems, including painful or bleeding gums, toothache, loose teeth, and/or denture wear. 33,059, 33,004, 14,652, and 14,613 participants were available for analysis of glaucoma, IOP, mRNFL, and mGCIPL, respectively. No association between oral health and glaucoma was identified (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.95, 1.14). IOPs were slightly lower among those with oral disease (-0.08 mmHg, 95% CI: -0.15, -0.009); specifically, among those with loose teeth (P=0.03) and denture-wearers (P<0.0001). mRNFL measurements were lower among those with oral health conditions (-0.14 microns, 95% CI: -0.27, -0.0009), but mGCIPL measurements (P=0.96) were not significantly different. A PRS for IOP or glaucoma did not modify relations between oral health and IOP nor glaucoma (P-for-interactions0.17). CONCLUSIONS: Self-reported oral health was not associated with elevated IOP nor increased risk of glaucoma. Future studies should confirm the null association between clinically diagnosed oral health conditions and glaucoma.

Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies.

We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.

Apolipoprotein E and Its Association With Cognitive Change and Modification of Treatment Effects of Vitamin D3 and Omega-3s on Cognitive Change: Results From the In-Clinic Subset of a Randomized Clinical Trial.

BACKGROUND: Apolipoprotein E (APOE)-ε4 allele is associated with cognitive decline; however, its potential to modify effects of vitamin D3 and omega-3s supplementation on later-life cognition is unclear. Our objectives were to estimate among the in-clinic subset of a randomized trial: (1) associations between APOE-ε4 and global and domain-specific cognitive change, with exploration of potential sex and race differences; and (2) modification by APOE-ε4 of effects of vitamin D3 and omega-3s supplementation on cognitive change. METHODS: From an ancillary study of depression prevention within a completed 2 × 2 factorial trial testing vitamin D3 (2 000 IU per day), omega-3s (1 g per day), and/or placebos, we included 743 older adults with baseline in-person neuropsychiatric assessments and APOE genotyping data. The primary outcome was change in global cognition (averaging z-scores of 9 tests) over 2 years. Secondarily, episodic memory and executive function/attention z-scores were examined. General linear models of response profiles with multiplicative interaction terms were constructed; stratified results were reported. RESULTS: Mean age (standard deviation) was 67.1 (5.3) years; 50.6% were females; 24.9% were APOE-ε4 carriers. Compared to noncarriers, APOE-ε4 carriers had worse 2-year change in global cognition and episodic memory; differences were more apparent among females than males. There was no variation by race in APOE-ε4 associations with cognition. APOE-ε4 did not significantly modify effects of vitamin D3 or omega-3s, compared to placebo, on change in global cognition, episodic memory, or executive function/attention. CONCLUSIONS: APOE-ε4 was associated with worse cognition but did not modify overall effects of vitamin D3 or omega-3 supplementation on cognition over 2 years.

Post-traumatic stress disorder symptom remission and cognition in a large cohort of civilian women.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit. METHODS: Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively. RESULTS: Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression. CONCLUSION: Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms.

Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease: A Novel Analysis of the VITAL Trial Using Win Ratio and Hierarchical Composite Outcomes.

This study aimed to investigate whether n-3 fatty acid supplementation reduced cardiovascular disease (CVD) events in a novel analysis using hierarchical composite CVD outcomes based on win ratio in the VITamin D and OmegA-3 TriaL (VITAL). This was a secondary analysis of our VITAL randomized trial, which assessed the effects of marine n-3 fatty acids (1 g/day) and vitamin D3 on incident CVD and cancer among healthy older adults (n = 25,871). The primary analysis estimated win ratios of a composite of major CVD outcomes prioritized as fatal coronary heart disease, other fatal CVD including stroke, non-fatal myocardial infarction (MI), and non-fatal stroke, comparing n-3 fatty acids to placebo. The primary result was a nonsignificant benefit of this supplementation for the prioritized primary CVD outcome (reciprocal win ratio [95% confidence interval]: 0.90 [0.78-1.04]), similar to the 0.92 (0.80-1.06) hazard ratio in our original time-to-first event analysis without outcome prioritization. Its benefits came from reducing MI (0.71 [0.57-0.88]) but not stroke (1.01 [0.80 to 1.28]) components. For the primary CVD outcome, participants with low fish consumption at baseline benefited (0.79 [0.65-0.96]) more than those with high consumption (1.05 [0.85-1.30]). These results are consistent with, but slightly stronger than, those without outcome prioritization.

Association Between Bowel Movement Pattern and Cognitive Function: Prospective Cohort Study and a Metagenomic Analysis of the Gut Microbiome.

BACKGROUND AND OBJECTIVES: Little is known regarding the association between intestinal motility patterns and cognitive function in individuals who are baseline cognitively healthy. The gut microbiome may contribute to the association. We examined the association between bowel movement (BM) pattern and cognitive function and explored the role of the gut microbiome in explaining this association. METHODS: In this prospective study, we leveraged 3 cohort studies, Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS). Participants reported BM frequency and subjective cognitive function. In a subset of NHSII participants, we assessed cognitive function using an objective neuropsychological battery. We profiled the gut microbiome in a subset of participants using whole-genome shotgun metagenomics. General linear models, Poisson regression, and logistic regression were used to quantify the association of BM frequency with different cognitive measurements. RESULTS: We followed 112,753 men and women (women: 87.6%) with a mean age of 67.2 years at baseline (NHS: 76 years, NHSII: 59 years, HPFS: 75 years) for a median follow-up of 4 years (NHSII and HPFS: 4 years, NHS: 2 years). Compared with those with BM once daily, participants with BM frequency every 3+ days had significantly worse objective cognitive function, equivalent to 3.0 (95% confidence interval [CI],1.2-4.7) years of chronological cognitive aging. We observed similar J-shape dose-response relationships of BM frequency with the odds of subjective cognitive decline and the likelihood of having more subsequent subjective cognitive complaints (both p nonlinearity < 0.001). BM frequencies of every 3+ days and ≥twice/day, compared with once daily, were associated with the odds ratios of subjective cognitive decline of 1.73 (95% CI 1.60-1.86) and 1.37 (95% CI 1.33-1.44), respectively. BM frequency and subjective cognitive decline were significantly associated with the overall gut microbiome configuration (both p < 0.005) and specific microbial species in the 515 participants with microbiome data. Butyrate-producing microbial species were depleted in those with less frequent BM and worse cognition, whereas a higher abundance of proinflammatory species was associated with BM frequency of ≥twice/day and worse cognition. DISCUSSION: Lower BM frequency was associated with worse cognitive function. The gut microbial dysbiosis may be a mechanistic link underlying the association.

Calcium Channel Blocker Use and Associated Glaucoma and Related Traits Among UK Biobank Participants.

Importance: Calcium channel blocker (CCB) use has been associated with an increased risk of glaucoma in exploratory studies. Objective: To examine the association of systemic CCB use with glaucoma and related traits among UK Biobank participants. Design, Setting, and Participants: This population-based cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis of glaucoma status, intraocular pressure (IOP), and optical coherence tomography (OCT)-derived inner retinal layer thicknesses. Data analysis was conducted in January 2023. Exposure: Calcium channel blocker use was assessed in a baseline touchscreen questionnaire and confirmed during an interview led by a trained nurse. Main Outcomes and Measures: The primary outcome measures included glaucoma status, corneal-compensated IOP, and 2 OCT-derived inner retinal thickness parameters (macular retinal nerve fiber layer [mRNFL] and macular ganglion cell-inner plexiform layer [mGCIPL] thicknesses). We performed logistic regression and linear regression analyses to test for associations with glaucoma status and IOP and OCT-derived inner retinal thickness parameters, respectively. Results: This study included 427 480 adults. Their median age was 58 (IQR, 50-63) years, and more than half (54.1%) were women. There were 33 175 CCB users (7.8%). Participants who had complete data for glaucoma status (n = 427 480), IOP (n = 97 100), and OCT-derived inner retinal layer thicknesses (n = 41 023) were eligible for respective analyses. After adjustment for key sociodemographic, medical, anthropometric, and lifestyle factors, use of CCBs (but not other antihypertensive agents) was associated with greater odds of glaucoma (odds ratio [OR], 1.39 [95% CI, 1.14 to 1.69]; P = .001). Calcium channel blocker use was also associated with thinner mGCIPL (-0.34 µm [95% CI, -0.54 to -0.15 µm]; P = .001) and mRNFL (-0.16 µm [95% CI, -0.30 to -0.02 µm]; P = .03) thicknesses but not IOP (-0.01 mm Hg [95% CI, -0.09 to 0.07 mm Hg]; P = .84). Conclusions and Relevance: In this study, an adverse association between CCB use and glaucoma was observed, with CCB users having, on average, 39% higher odds of glaucoma. Calcium channel blocker use was also associated with thinner mGCIPL and mRNFL thicknesses, providing a structural basis that supports the association with glaucoma. The lack of association of CCB use with IOP suggests that an IOP-independent mechanism of glaucomatous neurodegeneration may be involved. Although a causal relationship has not been established, CCB replacement or withdrawal may be considered should glaucoma progress despite optimal care.

Metabolite and Lipid Biomarkers Associated With Intraocular Pressure and Inner Retinal Morphology: 1H NMR Spectroscopy Results From the UK Biobank.

Purpose: The purpose of this study was to assess metabolites associated with intraocular pressure (IOP) and inner retina structure. Methods: We cross-sectionally assessed 168 non-fasting plasma metabolites measured by nuclear magnetic resonance (NMR) spectroscopy with IOP (n = 28,195), macular retinal nerve fiber layer thickness (mRNFL; n = 10,584), and macular ganglion cell inner plexiform layer thickness (mGCIPL; n = 10,554) in the UK Biobank. We used multiple linear regression models adjusting for various covariates with probit-transformed metabolite levels as predictors for each outcome. Each estimate represents the difference in outcome variable per standard deviation increase in the probit-transformed metabolite values. We used the number of effective (NEF) tests and false discovery rate (FDR) to adjust for multiple comparisons for metabolites and metabolite classes, respectively. Results: In individual metabolite analysis, multiple amino acids, especially branched-chain amino acids, were associated with lower IOP (-0.12 mm Hg; 95% confidence interval = -0.16 to -0.07; NEF = 2.7E-05). Albumin, 3 hydroxybutyrate, lactate, and several lipids were associated with higher IOP (range = 0.07 to 0.18 mm Hg, NEF = ≤ 0.039). In IOP-adjusted analyses, five HDL-related metabolites were associated with thinner mRNFL (-0.15 microns for all metabolites, NEF = ≤ 0.027), whereas five LDL-related metabolites were associated with thicker mGCIPL (range = 0.17 to 0.20 microns; NEF = ≤ 0.044). In metabolite class analysis, the lipid components of lipoproteins (cholesterol, triglycerides, etc.) were not associated with our outcomes (FDR > 0.2 for all); yet multiple lipoproteins were significantly (FDR < 0.05) associated with all outcomes. Conclusions: Branched-chain amino acids were associated with lower IOP, HDL metabolites were associated with thinner mRNFL, and LDL metabolites were associated with thicker mGCIPL.

Towards modifying the genetic predisposition for glaucoma: An overview of the contribution and interaction of genetic and environmental factors.

Glaucoma, the leading cause of irreversible blindness worldwide, is a complex human disease, with both genetic and environmental determinants. The availability of large-scale, population-based cohorts and biobanks, combining genotyping and detailed phenotyping, has greatly accelerated research into the aetiology of glaucoma in recent years. Hypothesis-free genome-wide association studies have furthered our understanding of the complex genetic architecture underpinning the disease, while epidemiological studies have provided advances in the identification and characterisation of environmental risk factors. It is increasingly recognised that the combined effects of genetic and environmental factors may confer a disease risk that reflects a departure from the simple additive effect of the two. These gene-environment interactions have been implicated in a host of complex human diseases, including glaucoma, and have several important diagnostic and therapeutic implications for future clinical practice. Importantly, the ability to modify the risk associated with a particular genetic makeup promises to lead to personalised recommendations for glaucoma prevention, as well as novel treatment approaches in years to come. Here we provide an overview of genetic and environmental risk factors for glaucoma, as well as reviewing the evidence and discussing the implications of gene-environment interactions for the disease.

Bereavement, Memorial Attendance, and Mental Health During the COVID-19 Pandemic: Longitudinal Results from the Nurses' Health Study.

BACKGROUND: Mortality increased during the COVID-19 pandemic. Many bereaved individuals were not able to gather to memorialize their loved ones, yet it is unknown if this contributed to worsening mental health. OBJECTIVE: Examine the association of bereavement in the early part of the COVID-19 pandemic with subsequent psychological distress and the role of memorial attendance in reducing psychological distress among the bereaved. DESIGN, SETTINGS, SUBJECTS: In May 2020, 39,564 older females from the Nurses' Health Study II enrolled in a longitudinal COVID-19 substudy (meanage = 65.2 years, SD = 4.5). METHODS: Linear regression analyses estimated associations of bereavement reported between March and October, 2020 with subsequent psychological distress between January and October 2021, adjusting for sociodemographic and prepandemic depression symptoms. Secondary models examined associations between memorial attendance and psychological distress. RESULTS: Bereavement during the early part of the COVID-19 pandemic was associated with higher psychological distress (adjusted ß = 0.21, 95% CI: 0.15, 0.26) assessed over the next year. Among the bereaved, memorial attendance was associated with lower psychological distress (in-person: adjusted ß = -0.41, 95% CI: -0.53, -0.29; online: adjusted ß = -0.24, 95% CI: -0.46, --0.02). CONCLUSION: Attending memorials was associated with lower subsequent psychological distress among bereaved older females.

The Association of Physical Activity with Glaucoma and Related Traits in the UK Biobank.

PURPOSE: To examine the association of physical activity (PA) with glaucoma and related traits, to assess whether genetic predisposition to glaucoma modified these associations, and to probe causal relationships using Mendelian randomization (MR). DESIGN: Cross-sectional observational and gene-environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia. PARTICIPANTS: UK Biobank participants with data on self-reported or accelerometer-derived PA and intraocular pressure (IOP; n = 94 206 and n = 27 777, respectively), macular inner retinal OCT measurements (n = 36 274 and n = 9991, respectively), and glaucoma status (n = 86 803 and n = 23 556, respectively). METHODS: We evaluated multivariable-adjusted associations of self-reported (International Physical Activity Questionnaire) and accelerometer-derived PA with IOP and macular inner retinal OCT parameters using linear regression and with glaucoma status using logistic regression. For all outcomes, we examined gene-PA interactions using a polygenic risk score (PRS) that combined the effects of 2673 genetic variants associated with glaucoma. MAIN OUTCOME MEASURES: Intraocular pressure, macular retinal nerve fiber layer (mRNFL) thickness, macular ganglion cell-inner plexiform layer (mGCIPL) thickness, and glaucoma status. RESULTS: In multivariable-adjusted regression models, we found no association of PA level or time spent in PA with glaucoma status. Higher overall levels and greater time spent in higher levels of both self-reported and accelerometer-derived PA were associated positively with thicker mGCIPL (P < 0.001 for trend for each). Compared with the lowest quartile of PA, participants in the highest quartiles of accelerometer-derived moderate- and vigorous-intensity PA showed a thicker mGCIPL by +0.57 µm (P < 0.001) and +0.42 µm (P = 0.005). No association was found with mRNFL thickness. High overall level of self-reported PA was associated with a modestly higher IOP of +0.08 mmHg (P = 0.01), but this was not replicated in the accelerometry data. No associations were modified by a glaucoma PRS, and MR analyses did not support a causal relationship between PA and any glaucoma-related outcome. CONCLUSIONS: Higher overall PA level and greater time spent in moderate and vigorous PA were not associated with glaucoma status but were associated with thicker mGCIPL. Associations with IOP were modest and inconsistent. Despite the well-documented acute reduction in IOP after PA, we found no evidence that high levels of habitual PA are associated with glaucoma status or IOP in the general population. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Indicated and Selective Prevention of Depression in Older Adults: Results From the Clinical Center Sub-Cohort of the VITamin D and OmegA-3 TriaL (VITAL).

Objective: To test vitamin D3 and omega-3 fatty acids (omega-3s) for late-life depression prevention under the National Academy of Medicine framework for indicated (targeting subthreshold depression) and selective (targeting presence of high-risk factors) prevention.Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a 2 × 2 factorial trial of vitamin D3 (2,000 IU/d) and/or omega-3s (1 g/d) for cardiovascular and cancer prevention (enrollment: November 2011-March 2014; end date: December 31, 2017). In this targeted prevention study, we included 720 VITAL clinical sub-cohort participants who completed neurobehavioral assessments at baseline and 2 years (91.9% retention). High-risk factors were subthreshold or clinical anxiety, impaired activities of daily living, physical/functional limitation, medical comorbidity, cognitive impairment, caregiving burden, problem drinking, and low psychosocial support. Coprimary outcomes were incident major depressive disorder (MDD), adjudicated using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), and change in mood (Patient Health Questionnaire-9 [PHQ-9]). We used exact tests to determine treatment effects on MDD incidence and repeated-measures models to determine treatment effects on PHQ-9.Results: A total of 11.1% had subthreshold depression, 60.8% had ≥ 1 high-risk factor, MDD incidence was 4.7% (5.1% among completers), and mean PHQ-9 score change was 0.02 points. Among those with subthreshold depression, the MDD risk ratio (95% confidence interval) was 0.36 (0.06 to 1.28) for vitamin D3 and 0.85 (0.25 to 2.92) for omega-3s, compared to placebo; results were also null among those with ≥ 1 high-risk factor (vitamin D3 vs placebo: 0.63 [0.25 to 1.53]; omega-3s vs placebo: 1.08 [0.46 to 2.71]). There were no significant differences in PHQ-9 score change comparing either supplement with placebo.Conclusions: Neither vitamin D3 nor omega-3s showed benefits for indicated and selective prevention of late-life depression; statistical power was limited.Trial Registration: ClinicalTrials.gov identifier: NCT01696435.

Multidimensional Sleep Health Prior to SARS-CoV-2 Infection and Risk of Post-COVID-19 Condition.

Importance: The association of multiple healthy sleep dimensions with post-COVID-19 condition (PCC), also known as long COVID, has not been investigated. Objective: To examine whether multidimensional sleep health before and during the COVID-19 pandemic, prior to SARS-CoV-2 infection, was associated with the risk of PCC. Design, Setting, and Participants: This prospective cohort study (2015-2021) included Nurses' Health Study II participants who reported testing positive (n = 2303) for SARS-CoV-2 infection in a substudy series of COVID-19-related surveys (n = 32 249) between April 2020 and November 2021. After exclusion for incomplete information about sleep health and nonresponse to a question about PCC, 1979 women were included in the analysis. Exposures: Sleep health was measured both before (June 1, 2015, to May 31, 2017) and early (April 1 to August 31, 2020) in the COVID-19 pandemic. Prepandemic sleep score was defined according to 5 dimensions: morning chronotype (assessed in 2015), 7 to 8 hours of sleep per day, low insomnia symptoms, no snoring, and no frequent daytime dysfunction (all assessed in 2017). On the first COVID-19 substudy survey (returned between April and August 2020), average daily sleep duration and sleep quality for the past 7 days were queried. Main Outcomes and Measures: SARS-CoV-2 infection and PCC (≥4 weeks of symptoms) were self-reported during 1 year of follow-up. Comparisons were examined between June 8, 2022, and January 9, 2023, using Poisson regression models. Results: Of the 1979 participants reporting SARS-CoV-2 infection (mean [SD] age, 64.7 [4.6] years; 1979 [100%] female; and 1924 [97.2%] White vs 55 [2.8%] other races and ethnicities), 845 (42.7%) were frontline health care workers, and 870 (44.0%) developed PCC. Compared with women who had a prepandemic sleep score of 0 or 1 (least healthy), those who scored 5 (most healthy) had a 30% lower risk of developing PCC (multivariable-adjusted relative risk, 0.70; 95% CI, 0.52-0.94; P for trend <.001). Associations did not differ by health care worker status. No or little daytime dysfunction prepandemic and good sleep quality during the pandemic were independently associated with a lower risk of PCC (relative risk, 0.83 [95% CI, 0.71-0.98] and 0.82 [95% CI, 0.69-0.99], respectively). Results were similar when PCC was defined as having 8 or more weeks of symptoms or as having ongoing symptoms at the time of PCC assessment. Conclusions and Relevance: The findings indicate that healthy sleep measured prior to SARS-CoV-2 infection, both before and during the COVID-19 pandemic, may be protective against PCC. Future research should investigate whether interventions on sleep health may prevent PCC or improve PCC symptoms.

Pilot Study of Second-Generation DNA Methylation Epigenetic Markers in Relation to Cognitive and Neuropsychiatric Symptoms in Older Adults.

BACKGROUND: Associations between epigenetic aging with cognitive aging and neuropsychiatric measures are not well-understood. OBJECTIVE: 1) To assess cross-sectional correlations between second-generation DNA methylation (DNAm)-based clocks of healthspan and lifespan (i.e., GrimAge, PhenoAge, and DNAm-based estimator of telomere length [DNAmTL]) and cognitive and neuropsychiatric measures; 2) To examine longitudinal associations between change in DNAm markers and change in cognition over 2 years. METHODS: Participants were members of VITAL-DEP (VITamin D and OmegA-3 TriaL- Depression Endpoint Prevention) study. From previously ascertained cognitive groups (i.e., cognitively normal and mild cognitive impairment), we randomly selected 45 participants, aged≥60 years, who completed in-person neuropsychiatric assessments at baseline and 2 years. The primary outcome was global cognitive score (averaging z-scores of 9 tests). Neuropsychiatric Inventory severity scores were mapped from neuropsychiatric symptoms (NPS) from psychological scales and structured diagnostic interviews. DNAm was assayed using Illumina MethylationEPIC 850K BeadChip at baseline and 2 years. We calculated baseline partial Spearman correlations between DNAm markers and cognitive and NPS measures. We constructed multivariable linear regression models to examine longitudinal relations between DNAm markers and cognition. RESULTS: At baseline, we observed a suggestive negative correlation between GrimAge clock markers and global cognition but no signal between DNAm markers and NPS measures. Over 2 years: each 1-year increase in DNAmGrimAge was significantly associated with faster declines in global cognition; each 100-base pair increase in DNAmTL was significantly associated with better global cognition. CONCLUSION: We found preliminary evidence of cross-sectional and longitudinal associations between DNAm markers and global cognition.

Plasma metabolite profile for primary open-angle glaucoma in three US cohorts and the UK Biobank.

Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma is the most common form, and yet the etiology of this multifactorial disease is poorly understood. We aimed to identify plasma metabolites associated with the risk of developing POAG in a case-control study (599 cases and 599 matched controls) nested within the Nurses' Health Studies, and Health Professionals' Follow-Up Study. Plasma metabolites were measured with LC-MS/MS at the Broad Institute (Cambridge, MA, USA); 369 metabolites from 18 metabolite classes passed quality control analyses. For comparison, in a cross-sectional study in the UK Biobank, 168 metabolites were measured in plasma samples from 2,238 prevalent glaucoma cases and 44,723 controls using NMR spectroscopy (Nightingale, Finland; version 2020). Here we show higher levels of diglycerides and triglycerides are adversely associated with glaucoma in all four cohorts, suggesting that they play an important role in glaucoma pathogenesis.

Intimate Partner Violence, Mental Health Symptoms, and Modifiable Health Factors in Women During the COVID-19 Pandemic in the US.

Importance: During the COVID-19 pandemic, the prevalence and severity of intimate partner violence (IPV) increased. Associations between IPV and mental health symptoms and modifiable health factors early in the pandemic have yet to be explored. Objective: To prospectively investigate the association of IPV with greater risk of mental health symptoms and adverse health factors during the COVID-19 pandemic in 3 cohorts of female participants. Design, Setting, and Participants: This cohort study used observational data from 3 prospective, population-based, longitudinal cohorts in the US: the Nurses' Health Study II, Growing Up Today Study, and Nurses' Health Study 3. Data analyzed included baseline and follow-up survey responses about IPV experiences early in the pandemic (March-September 2020); mental health domains of depression, anxiety, and posttraumatic stress symptoms (PTSS); and modifiable health factors (May 2020-October 2021). Female participants (both health care professionals and non-health care workers) aged 21 to 60 years from the 3 cohorts were included in the full analytic sample. Exposures: Experience of IPV measured by the Relationship Assessment Tool and fear of partner. Main Outcomes and Measures: Mental health symptoms, including depression, anxiety, and PTSS, and modifiable health factors, including sleep duration, sleep quality, physical activity, alcohol use, and use of alcohol or other substances to cope with stress. Results: The full analytic sample included 13 597 female participants with a mean (SD) age of 44 (10.6) years. Accounting for sociodemographic factors and prepandemic mental health symptoms and correcting for multiple testing, experiencing IPV was associated with higher endorsement of depression (odds ratio [OR], 1.44; 95% CI, 1.38-1.50), anxiety (OR, 1.31; 95% CI, 1.26-1.36), and PTSS (OR, 1.22; 95% CI, 1.15-1.29) in random-effects meta-analyses across the 3 cohorts. The IPV experience was also associated with poorer sleep quality (OR, 1.21; 95% CI, 1.16-1.26), shorter sleep duration (OR, 1.13; 95% CI, 1.08-1.19), increased use of alcohol (OR, 1.10; 95% CI, 1.06-1.14), and use of alcohol or other substances to cope with stress (OR, 1.13; 95% CI, 1.08-1.18) across all cohorts as well as decreased physical activity (OR, 1.17; 95% CI, 1.09-1.26) in the Nurses' Health Study II only. Conclusions and Relevance: Results of the study showed that IPV experiences at the start of the pandemic were associated with worse mental health symptoms and modifiable health factors for female participants younger than 60 years. Screening and interventions for IPV and related health factors are needed to prevent severe, long-term health consequences.