Supplemental Figure 1. Study Schematic of Women’s Health Initiative Participant Selection. Flowchart detailing the selection process of study participants, and the final cohort size for the study.

OBJECTIVES:Cognitive impairment is a major public health concern among older adults. This study examined the associations of purpose in life (PIL), personal growth (PG), and life satisfaction (LS) with cognitive impairment risk, as well as potential underlying pathways. METHODS:The study population comprised 1,179 U.S. women (aged 77-93 years) from the Women's Health Initiative Memory Study - Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) cohort who completed psychological well-being assessments in 2012 and were followed until 2021. Cognitive status was evaluated annually using standardized assessments and central adjudication. RESULTS:Over an average of 5.4 years of follow-up, 355 participants were classified with MCI (175) or dementia (180). The association between PIL and cognitive impairment was largely mediated by lower perceived stress and higher physical activity (61%), rendering the direct effect non-significant. Women in the highest PG quartile had a 33% lower risk of impairment (HR = 0.67, 95% CI: 0.46-0.96). Mediation analyses showed both direct and indirect effects of PG. No association was found for LS. CONCLUSIONS:PG and PIL were linked to lower cognitive impairment risk, primarily via stress reduction and physical activity. Targeting these factors may promote cognitive health among aging populations.

INTRODUCTION:Cognitive impairment among older adults is often due to multiple pathologies and heterogenous risk factors. We assessed whether Alzheimer's blood-based biomarkers (BBMs) were associated with incident mild cognitive impairment (MCI)/probable dementia, and whether associations were modified by age, apolipoprotein E (APOE), and hormone therapy (HT). METHODS:Analyses included 2467 Women's Health Initiative Memory Study women (≥65 years of age) randomized between 1995 and 1998 to 3-5-years of HT or placebo. Cox regression (mean 18-year follow-up) assessed associations between the z-scored BBMs and MCI/dementia. RESULTS:Lower baseline amyloid beta (Aβ)42/40 ratio and higher phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were associated with an increased risk of MCI and dementia; GFAP was most strongly associated. The p-tau181 and NfL associations were stronger among APOE ε4 carriers; BBMs varied non-linearly by age. The associations of BBMs with the cognitive outcomes also varied inconsistently between HT groups. DISCUSSION:BBMs for AD and related dementias (ADRD) are associated with incident MCI/dementia in older women. Interactions between the BBMs and HT were inconsistent and require further investigation.

Supplemental Figure 5. Hazard ratios and 95% confidence intervals for the association of metabolic phenotype defined by ATP III criteria with obesity-related cancer risk, stratified by cancer type among postmenopausal women in the Women’s Health Initiative. Model adjusted for demographics (age, education, race/ethnicity, marital status), lifestyle (smoking status, physical activity, alcohol use, fruits and vegetable intake, fiber intake, read meat intake), hormonal factors for female cancers (parity, hormone therapy use), family history of ORC and study ID. MUNW=metabolically unhealthy normal weight; MHO=metabolically healthy overweight/obese; MUO= metabolically unhealthy overweight/obese. Metabolically healthy normal weight (MHNW) is the comparison group.

Background The global use of social media and video games has increased rapidly, especially among young people. The current study conducted a national survey with high school students in Saudi Arabia to identify the prevalence of Social Media Disorder (SMD) and Internet Gaming Disorder (IGD) and associations with social and mental wellbeing. Methods Cross-sectional survey data were collected in 28 schools and 7 major regions across Saudi Arabia in 2024. The total sample included 2,990 high school students (M=16.8 years old, 50.3% female). We calculated several prevalence rates for SMD and IGD based on different Likert-scale cutoffs (stringent vs. lenient) and number of criteria endorsed (5 vs. 6). We examined the relation of SMD and IGD with loneliness and mental distress using Chi-squared tests, correlations, and multivariable regressions. Results The different classification approaches resulted in a range of disorder prevalences. For SMD, prevalence ranged from 3.3% (6 criteria stringent) to 20.7% (5 criteria lenient). For IGD, prevalence ranged from 3.4% (6 criteria stringent) to 16.2% (5 criteria lenient). Individuals with SMD and IGD endorsed more loneliness and mental distress compared to those without a disorder. Compared to those with single disorders, those endorsing both SMD and IGD also reported more loneliness and mental distress, although these differences were not always statistically significant. Conclusions A substantial number of high school students in Saudi Arabia report SMD and IGD and these disorders are associated with loneliness and mental distress. Targeted interventions are needed to prevent these disorders and provide effective treatment.

Supplemental Table 7. Association between metabolic phenotypes defined by Wildman criteria with obesity-related cancer (ORC) risk after excluding participants diagnosed with ORC within the first three years of follow-up in the Women’s Health Initiative cohort (N= 20,320).

Supplemental Table 4. Association between metabolic phenotypes defined by high sensitivity C-Reactive Protein (hs-CRP) ≥ 3 mg/L with obesity-related cancer risk in the Women’s Health Initiative cohort (N= 21,245).

Supplemental Table 6. Association between metabolic phenotypes defined by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) with obesity-related cancer risk in the Women’s Health Initiative cohort (N= 23,232).

Supplemental Figure 4. Hazard ratios and 95% confidence intervals for the association of metabolic phenotype defined by the Wildman criteria with obesity-related cancer risk, stratified by cancer type among postmenopausal women in the Women’s Health Initiative. Model adjusted for demographics (age, education, race/ethnicity, marital status), lifestyle (smoking status, physical activity, alcohol use, fruits and vegetable intake, fiber intake, read meat intake), hormonal factors for female cancers (parity, hormone therapy use), family history of ORC and study ID. MUNW=metabolically unhealthy normal weight; MHO=metabolically healthy overweight/obese; MUO= metabolically unhealthy overweight/obese. Metabolically healthy normal weight (MHNW) is the comparison group.

Supplemental Table 2. Association between metabolic phenotypes defined by Wildman criteria with obesity-related cancer risk in the Women’s Health Initiative cohort (N= 20,593).

Postmenopausal women tend to experience significant changes in body composition, particularly abdominal adipose tissue (AAT) deposition patterns, which are hypothesized to be critical factors influencing future chronic disease risk. The level of protein intake to maintain or achieve a more favorable body composition for health in postmenopausal women is a central, largely unanswered question relating to the appropriateness of current dietary guideline recommendations for sufficient protein intake (set at 0.8 g/kg/day). To estimate the hypothetical effect of a range of protein intake levels on 3-year mean changes in body composition measures in postmenopausal women. We analyzed data from 3789 postmenopausal women aged 50–79 enrolled in the Women’s Health Initiative (WHI) to emulate a 3-year target trial of adhering to increasing levels of protein intake: ≥0.8 g/kg/d, ≥1.0 g/kg/d, ≥1.2 g/kg/d, and ≥1.5 g/kg/d. All participants had repeated Dual X-Ray Absorptiometry (DXA) scans with derived abdominal visceral (VAT) and subcutaneous adipose tissue (SAT). The measured differences in average levels of VAT, SAT, and other body composition measures determined at end of follow-up were estimated with the parametric-g formula. Over 3 years, hypothetical interventions of increasing levels of dietary protein intake are estimated to have dose-dependent reductions in abdominal VAT, SAT, and overall body fat, and increases in lean soft tissue, with potential benefits observed at ≥1.2 g/kg/day and the greatest estimated benefit at ≥1.5 g/kg/day of dietary protein. Compared to no intervention, if all participants hypothetically adhered to a total daily protein intake of ≥1.5 g/kg/day over 3 years, they would be estimated to have lower levels of VAT (−13.1 cm2, 95% Confidence Interval [CI] −18.9, −7.3), SAT (−25.3 cm2, 95% CI −39.7, −11.0), total body fat % (−1.0%, 95% CI −1.7, −0.3), body weight (−2.5 kg, 95% CI −3.7, −1.2) and greater lean soft tissue % (0.9%, 95% CI 0.3, 1.6) over 3 years. This hypothetical emulated intervention suggests that postmenopausal women who maintain a hypothetical total protein intake of at least 1.2 g/kg/day could experience beneficial changes in abdominal VAT, SAT, and overall body composition over three years, with even greater estimated benefits observed at an intake of 1.5 g/kg/day. These findings suggest that protein intake higher than guideline recommendations may better support healthier body composition and lower chronic disease risk in postmenopausal women.

Supplemental Table 8. Association between individual metabolic dysfunction components with obesity-related cancer risk in the Women’s Health Initiative cohort (N= 20,593).

Excessive screen time among adolescents is associated with mental distress, poor sleep, physical inactivity, and, in some cases, problematic digital media use, including symptoms of social media disorder and internet gaming disorder. In Saudi Arabia, national survey data indicate high rates of screen time and problematic use among youth, yet no culturally tailored interventions exist. The goal of this paper is to present the design of a cluster-randomized trial to test the efficacy of a school- and family-based digital wellbeing intervention among Saudi high school students. This study aims to evaluate the efficacy of a digital wellbeing intervention (DWI) that integrates the Saudi Ministry of Education Digital Wellbeing Module with structured parental engagement delivered via WhatsApp, compared to the Digital Wellbeing Module alone (DW). We hypothesize that students in the DWI arm will demonstrate significantly greater reductions in weekday leisure screen time compared with those in the DW arm (the primary outcome). This two-arm, parallel-group, cluster-randomized controlled trial will enroll approximately 2500 grade 12 students from 24 public high schools in Riyadh City and the Qassim Region of Saudi Arabia. Schools will be stratified by region and randomized 1:1 to receive either (1) DW alone, delivered as part of the standard Ministry of Education Digital Citizenship Curriculum, or (2) DWI, which includes the Digital Wellbeing module plus a parent WhatsApp engagement program. The parent program delivers daily multimedia content aligned with classroom curriculum, focusing on family communication, goal setting, non-digital activities, and parental role modeling. The primary outcome is weekday leisure screen time assessed via student self-report. Secondary outcomes include reductions in symptoms of social media and internet gaming disorders, as well as improvements in mental health, sleep quality, and physical activity. Data will be collected at three timepoints: baseline (T1), pre-intervention (T2, two months post-baseline), and post-intervention (T3, immediately following the four-week intervention). Linear mixed-effects models will examine intervention effects using an intention-to-treat analysis, accounting for clustering within schools and repeated measures. The intervention was developed through extensive formative work, including stakeholder engagement surveys (N=92) and focus groups/interviews (N=58), as well as Intervention Mapping workshops with Saudi and international experts. Data collection began in January 2026, with results expected by mid-2026. This trial will provide the first rigorous evidence on culturally tailored digital wellbeing interventions that integrate Saudi Arabia's national curriculum with family media education. Findings will inform scalable approaches to promoting balanced digital media use among adolescents in Saudi Arabia and similar cultural contexts, such as neighboring Gulf Countries. ClinicalTrials.gov NCT07344142 (https://clinicaltrials.gov/study/NCT07344142)

STUDY OBJECTIVES:Insomnia is highly prevalent among postmenopausal women and is associated with adverse health outcomes, highlighting the need to identify modifiable determinants of sleep. Diet and sleep are interrelated; however, few studies have evaluated longitudinal associations of complete dietary patterns with incident insomnia in postmenopausal women. This study evaluates prospective associations of established diet quality metrics with insomnia in the Women's Health Initiative Observational Study (WHI-OS). METHODS:The WHI-OS enrolled 93 676 postmenopausal women from across the United States. Alternate Mediterranean (aMed) diet and Dietary Approaches to Stop Hypertension (DASH) diet quality scores were quantified from a Food Frequency Questionnaire at baseline and dichotomized scores using a data-driven approach. Insomnia was assessed at baseline and Year 3 using the WHI Insomnia Rating Scale. Multivariable logistic regression models adjusted for sociodemographic, lifestyle, and health factors evaluated associations of baseline diet quality with incident insomnia and longitudinal insomnia status (stable/new onset insomnia vs. stable absence/remission of insomnia). RESULTS:Among women without insomnia at baseline (n = 50 644), good vs. poor diet quality at baseline was associated with lower risk for incident insomnia at 3-year follow-up (OR [95% CI], aMed: 0.925 [0.879-0.974], p=.003; DASH: 0.937 [0.891-0.985], p=.01]). In longitudinal analyses (n = 74 513), greater baseline adherence to aMed and DASH diets related to 6.3% (0.903-0.971) and 8.5% (0.883-0.948) lower odds, respectively, of having stable or new onset insomnia over 3 years (both p<.005). CONCLUSIONS:Better diet quality predicts lower insomnia risk in postmenopausal women. Clinical trials are needed to determine whether strategies to enhance diet quality improve insomnia symptoms. CLINICAL TRIAL INFORMATION:The Women's Health Initiative Observational Study is registered on Clinicaltrials.gov #NCT00000611: https://clinicaltrials.gov/study/NCT00000611.

BACKGROUND:Accumulating evidence suggests that diet plays an important role in the development of liver disease. Compared with individual nutrients or foods, dietary patterns better represent overall eating behaviors, but their associations with liver cancer and chronic liver disease (CLD) remain poorly understood. OBJECTIVES:We evaluated whether greater adherence to healthy dietary patterns was associated with lower liver cancer risk and CLD mortality. METHODS:We analyzed data from 78,345 postmenopausal women enrolled in the Women's Health Initiative Observational Study. Four dietary patterns [Alternative Healthy Eating Index-2010 (AHEI-2010), Healthy Eating Index-2020 (HEI-2020), alternate Mediterranean Diet (aMED), Dietary Approach to Stop Hypertension (DASH)] were calculated using dietary data collected via a validated food-frequency questionnaire. Liver cancer incidence and CLD death were ascertained by review of medical records or linkage to the National Death Index. Cox proportional hazards regression was performed to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS:During a median follow-up of 22.1 y, 176 liver cancer cases and 128 CLD deaths were documented. For liver cancer, significant inverse associations were observed with HEI-2020 (HR Quartile 4 compared with Quartile 1 = 0.58, 95% CI: 0.37, 0.93, P-trend = 0.02) and DASH (HR Q4 compared with Q1 = 0.58, 95% CI: 0.35, 0.98, P-trend = 0.07). For CLD mortality, significant inverse associations were observed with AHEI-2010 (HR Q4 compared with Q1 = 0.50, 95% CI: 0.27, 0.92, P-trend = 0.02), HEI-2020 (HR Q4 compared with Q1 = 0.59, 95% CI: 0.33, 1.04, P-trend = 0.04), aMED (HR Q4 compared with Q1 = 0.48, 95% CI: 0.25, 0.90, P-trend = 0.02), and DASH (HR Q4 compared with Q1 = 0.49, 95% CI: 0.25, 0.95, P-trend = 0.02). CONCLUSIONS:Maintaining an overall healthy diet may be associated with lower liver cancer risk and CLD mortality among postmenopausal women.

Supplemental Table 3. Association between metabolic phenotypes defined by ATP III criteria with obesity-related cancer risk in the Women’s Health Initiative cohort (N= 23,915).

Supplemental Figure 3. Kaplan–Meier cumulative incidence curves for obesity-related cancer risk among Women’s Health Initiative (WHI) participants according to metabolic phenotype defined by (A) Wildman criteria, (B) ATP III criteria, (C) HOMA-IR, and (D) hs-CRP ≥ 3 mg/L.

BACKGROUND:Plant-based diets have been associated with lower risks of chronic diseases; however, not all plant-based diets confer equal health benefits. Data-driven methods provide an opportunity to empirically identify distinct plant-based dietary subtypes and examine their associations with health outcomes. OBJECTIVE:To categorize subtypes of plant-based dietary patterns using a data-driven approach and evaluate their associations with cardiovascular disease (CVD), type 2 diabetes (T2D), and cancer incidence among postmenopausal women in the Women's Health Initiative (WHI). DESIGN:Prospective cohort study using principal component analysis (PCA) and k-means clustering to empirically derive dietary subtypes. PARTICIPANTS/SETTING:A total of 823 postmenopausal women from the WHI Observational Study who were healthy at baseline and reported low meat or poultry consumption during screening (1993 - 1998) were included and followed prospectively for incident chronic disease outcomes during WHI follow-up and extension periods (2023). A stratified comparison group of 823 higher-meat consumers also drawn from WHI Observational Study, was constructed using stratified random sampling on dietary pattern position, and key demographic variables. MAIN OUTCOME MEASURES:Incident cases of CVD, T2D, and any type of cancer (except nonmelanoma skin cancer), verified through adjudicated clinical outcomes. STATISTICAL ANALYSES PERFORMED:Cox proportional hazards models estimated associations with CVD, T2D, and cancer outcomes, adjusting for sociodemographic, lifestyle, and clinical factors. RESULTS:Three dietary clusters were identified: (1) Lower Meat; Fruit and Vegetable, (2) Lower Meat; Dairy and Solid Fat, (3) Lower Meat; Fish and Meat (classified as lower-meat based on screening but reporting relatively higher fish and moderate meat intake on the FFQ). No statistically significant associations were observed between any lower-meat dietary pattern and overall cancer incidence. Compared to higher-meat consumers, the Fish and Meat cluster was associated with a significant 67% lower risk of T2D (HR = 0.33, 95% CI: 0.14-0.81, p = 0.02). The Dairy and Solid Fat and Fruit and Vegetable clusters did not reach statistical significance for T2D risk (HR = 0.77, 95% CI: 0.34-1.75 and HR = 1.10, 95% CI: 0.46-2.61, respectively). For CVD, the Dairy and Solid Fat cluster was associated with a statistically significant higher risk (HR = 2.63, 95% CI: 1.05-6.56, p = 0.04), while results for the Fruit and Vegetable cluster did not reach statistical significance (HR = 0.47, 95% CI: 0.13-1.73, p = 0.26). CONCLUSION:This combined PCA-clustering approach revealed meaningful heterogeneity within lower-meat dietary patterns, offering a novel framework for characterizing plant-based diets and improving precision in future diet-disease investigations.

IntroductionDigital media use is rising among Saudi youth, raising concerns about mental health and wellbeing.MethodsThis qualitative study aimed to gather perspectives from relevant stakeholders (e.g., teachers, religious leaders, community members, influencers, etc.) to inform the development of a culturally tailored intervention to improve digital wellbeing among adolescents in Saudi Arabia. Using snowball sampling, we recruited 58 stakeholders to complete either semi-structured individual interviews or focus groups in Arabic. Thematic analysis by bilingual coders identified key themes around participants' definitions of digital wellbeing, perceived positive and negative impacts of digital media use, suggested strategies to regulate digital media use, and identified potential intervention pathways to promote digital wellbeing in Saudi society.ResultsStakeholders emphasized a multi-level approach that integrates self-regulation, school- and family-based intervention components, community activities, and general awareness campaigns as essential for addressing problematic digital media use.DiscussionIntervention efforts must resonate culturally and align with the Kingdom's evolving social dynamics, traditional values, and rapid technological advancement.

Supplemental Figure 6. Hazard ratios and 95% confidence intervals for the association of metabolic phenotype defined by C-Reactive Protein (hs-CRP) (A) ≥ 3 mg/L, (B) ≥ 10 mg/L with obesity-related cancer risk, stratified by cancer type among postmenopausal women in the Women’s Health Initiative. Model adjusted for demographics (age, education, race/ethnicity, marital status), lifestyle (smoking status, physical activity, alcohol use, fruits and vegetable intake, fiber intake, read meat intake), hormonal factors for female cancers (parity, hormone therapy use), family history of ORC and study ID. MUNW=metabolically unhealthy normal weight; MHO=metabolically healthy overweight/obese; MUO= metabolically unhealthy overweight/obese. Metabolically healthy normal weight (MHNW) is the comparison group.