JoAnn E. Manson

Association of Clonal Hematopoiesis With Total and Cause-Specific Mortality Among Older Women

Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women’s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] ≥ 2%) and large CHIP (VAF ≥ 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non- DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non- DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

Joint BMI-waist circumference categories linked to ~40% higher incident diabetes risk, with modest discrimination.

Body Roundness Index and Cancer Risk in Postmenopausal Women: Findings from the Women’s Health Initiative

Background Body Roundness Index (BRI) is an anthropometric measure that combines waist circumference and height. It reflects central adiposity more accurately than body mass index (BMI). Evidence linking BRI to long-term cancer risk, particularly in postmenopausal women, remains limited. Methods We examined associations between BRI and incident site-specific cancers (n=33,892) in 144,865 postmenopausal women aged 50-79 years at enrollment into the Women's Health Initiative and followed for a median of 17.9 years. BRI was assessed at baseline in all participants and at year 3 in 60% of participants. Cox proportional hazards models estimated associations between BRI and cancer incidence, adjusting for sociodemographic, reproductive, and lifestyle factors. Results Higher BRI levels were associated with increased risks of kidney, endometrial, liver, esophageal, thyroid, colorectal, stomach, pancreas, bladder, breast, and lung cancers, and with non-Hodgkin's lymphoma, particularly diffuse large B-cell lymphoma. Adjustment for BMI attenuated associations for endometrial, breast, and kidney cancers but strengthened those for liver, lung, and esophageal cancers. Results were consistent across sensitivity analyses and models incorporating repeated BRI measurements. Age-stratified (< /≥ 63 years) models indicated stronger associations for kidney cancer among younger women and a significant positive association for melanoma among older women. Conclusions Among postmenopausal women, higher BRI was associated with increased risk of cancer at multiple sites independently of BMI. These findings support an important role for central adiposity in cancer risk beyond overall body size. Impact In postmenopausal women, BRI may improve estimation of site-specific cancer risk beyond BMI by capturing central adiposity.

High ambient temperature variability is linked to ~60% lower risk of incident hypertension.

Hypertensive disorders of pregnancy linked to ~3.4-fold higher odds of advanced CKM syndrome stage.

Multi-ethnic metabolite distress score links to ~45% higher depression odds per SD in Black adults.

Replacing ultra-processed foods with minimally processed alternatives is linked to lower cardiovascular disease risk.

Functional Hypothalamic Amenorrhea Phenotype and Cardiovascular Disease Risk.

Associations of psychosocial supports and stressors with cognition in midlife women

OBJECTIVES: Psychosocial supports and stressors can influence neurocognitive function, but associations are understudied among women in midlife. METHODS: Among 492 parous women in the longitudinal Project Viva cohort, we surveyed several psychosocial supports and stressors in 2019-2022. At subsequent in-person visits (2022-2024) we performed the Montreal Cognitive Assessment (MoCA), which assesses global cognition, and four scales of the Cambridge Neuropsychological Test Automated Battery (CANTAB) that assess episodic memory, working memory, executive functioning, and attention. We examined associations using multivariable linear regression adjusted for age, education, spoken English, race, and ethnicity. RESULTS: Mean (SD) age was 55.5 (4.9) years, 71% were postmenopausal, and 20% scored below 26 on the MoCA, a threshold for cognitive impairment. In age-adjusted analyses, associations with both MoCA and total CANTAB were in the hypothesized directions (higher scores with supports, lower scores with stressors). For MoCA, adjustment for demographics resulted in attenuation of all associations to null. However, financial and food insecurity measures remained associated with several CANTAB scales in adjusted models, for example, having difficulty paying bills was associated with lower executive functioning (-0.37; 95% CI: -0.69 to -0.06), attention (-0.42; 95% CI: -0.66 to -0.18), and total CANTAB (-0.19; 95% CI: -0.35 to -0.03) internal z-scores. Measures of social support, perceived stress, and everyday discrimination were not associated with total CANTAB or its subscores. Adjustment for menopause status had negligible effect. CONCLUSIONS: Financial and food insecurity, but not social support, perceived stress, or discrimination, were associated with poorer memory, executive function, and attention in midlife women.

KimJournal of the American College of Cardiology

Adding a 5-biomarker panel to traditional factors improves 5-year CHD risk prediction, yielding ~6% reclassification.

Circulating oxLDL measured with antibody 4E6 was not an independent predictor of coronary heart disease after adjustment for lipid markers, and was less predictive than apoB and TC/HDL-C ratio.

The effect of vitamin D3 supplementation on fracture incidence in an aging population — The Finnish vitamin D trial

BACKGROUND: The effectiveness of vitamin D supplementation for fracture prevention at the population level remains a matter of debate. In this study, we evaluated the impact of vitamin D₃ supplementation on fracture risk among an aging population in Finland. METHODS: The study included 2495 participants, men ≥60 years and women ≥65 years, who were randomized for 5 years into three groups: 1600 IU/day or 3200 IU/day of vitamin D₃, or placebo. Fracture diagnoses were retrieved from two national care notification registers. RESULTS: During the mean 4.1-year supplementation period, there were 49, 73 and 52 fractures in the placebo, 1600 IU/day (compared to placebo: HR = 1.52, 95% CI = 1.06-2.18) and 3200 IU/day (HR = 1.07, 95% CI = 0.72-1.58) arms, respectively. During the extended 7.3-year follow-up, 104, 139 and 111 fractures occurred in the placebo, 1600 IU/day (HR = 1.40, 95% CI = 1.08-1.80) and 3200 IU/day (HR = 1.08, 95% CI = 0.83-1.41) arms, respectively. No statistically significant differences were observed in fracture subtypes. Age, sex, BMI, history of fracture or fall, osteoporosis diagnosis, or calcium supplement use did not modify the effects. In the sub-cohort of 550 participants, the mean ± SD baseline serum 25-hydroxyvitamin D concentration was 74.8 ± 18.2 nmol/L. After 12 months, the concentrations were 73.0 ± 17.8, 99.7 ± 21.1 and 120.4 ± 21.8 nmol/L in the placebo, 1600 IU/day and 3200 IU/day arms, respectively (P < 0.001). CONCLUSIONS: supplementation of 1600 IU/day or 3200 IU/day did not reduce the risk of fractures among a largely vitamin D-sufficient aging population. The findings do not support use of high vitamin D doses for fracture prevention in such populations. CLINICAL TRIAL REGISTRY NUMBER: ClinicalTrials.gov: NCT01463813, https://clinicaltrials.gov/ct2/show/NCT01463813.

High 1-hour glucose metabolomic score linked to ~48% higher CHD risk in women.

Higher dietary lignan intake linked to ~15% lower CHD risk.

Stress-related DNA methylation risk scores are linked to ~35% higher incident CHD risk.

Relationship Between Urinary tract Stones and Incident Hypertension Among Postmenopausal Women: Results from The Women's Health Initiative

Purpose To evaluate: whether self-reported urinary tract stones (UTS) are associated with incident hypertension in postmenopausal women in the Women’s Health Initiative; potential effect modification by diet-related inflammation and lifestyle factors; whether recurrent UTS further increased risk. Methods We conducted a prospective cohort study of 100,562 postmenopausal women aged 50–79 years without baseline hypertension. UTS were self-reported and modeled as a time-varying exposure. Effect modification by the dietary inflammatory index (DII®) and energy-adjusted DII (E- DII TM) , physical activity, alcohol consumption, and neighborhood socioeconomic status were evaluated. Incident hypertension was assessed using Cox hazards models adjusted for age and metabolic, lifestyle, socioeconomic, and dietary factors. Results In unadjusted models, UTS were associated with higher incident hypertension risk (HR = 1.29; 95% CI: 1.11-1.45, p = 0.001) and after full adjustment(HR = 1.16; 95% CI: 1.02–1.35; p =0.05). DII/E-DII did not significantly modify the association (interaction p> 0.20), while physical activity did (interaction p=0.03). Recurrent UTS increased hypertension risk versus no stone history (HR = 1.14; 95% CI: 1.02–1.28; p = 0.03), but not versus a single episode (HR = 1.09; 95% CI: 0.96–1.23; p = 0.18). Conclusion UTS were associated with a modestly increased risk of hypertension in postmenopausal women.

Low-fat dietary pattern and dietary advanced glycation end-products intake: a secondary analysis of the Women’s Health Initiative randomized trial

Higher dietary isoflavone intake is linked to ~13% lower coronary heart disease risk.