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PURPOSE: The purpose of this study was to determine if improvements observed in clinical, behavioral, and psychosocial outcomes measured at 12 months following a multifaceted diabetes care intervention were sustained at 3-year follow-up. METHODS: This study was a multilevel, nonblinded, cluster design, randomized controlled trial that took place in an underserved suburb of Pittsburgh, Pennsylvania, between 1999 and 2005. Eleven primary care practices, and their patients, were randomly assigned to 3 groups: chronic care model (CCM) intervention (n = 30), provider education only (PROV) (n = 38), and usual care (UC) (n = 51). Subjects were followed for 3 years. RESULTS: Improvements observed at 12-month follow-up in glycemic (-0.5%) and blood pressure control (-4.8 mm Hg), and the proportion of participants who self-monitor their blood glucose (86.7%-100%), were sustained at 3-year follow-up in the CCM group. Additional improvements occurred in non-HDLc levels in all study groups and quality of well-being scores in the CCM intervention group. All associations remained after controlling for medication treatment intensification. CONCLUSIONS: We have demonstrated that improvements in outcomes can be sustained over time following a multifaceted diabetes care intervention. Future research in this area is necessary to understand if improvements in outcomes can be sustained following diabetes self-management education (DSME) and what type of patient fares the best from multifaceted diabetes care interventions. [ABSTRACT FROM AUTHOR]

Objective: To determine whether obesity increases platelet reactivity and thrombin activity in patients with type 2 diabetes plus stable coronary artery disease.Research Design and Methods: We assessed platelet reactivity and markers of thrombin generation and activity in 193 patients from nine clinical sites of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D). Blood taken at the time of enrollment was used for assay of the concentration of prothrombin fragment 1.2 (PT1.2, released when prothrombin is activated) and fibrinopeptide A (FPA, released when fibrinogen is cleaved). Platelet activation was identified with the use of flow cytometry in response to 0, 0.2, and 1 micromol/l adenosine diphosphate (ADP).Results: Concentrations of FPA, PT1.2, and platelet activation in the absence of agonist were low. Greater BMI was associated with higher platelet reactivity in response to 1 microm ADP as assessed by surface expression of P-selectin (r = 0.29, P < 0.0001) but not reflected by the binding of fibrinogen to activated glycoprotein IIb-IIIa. BMI was not associated with concentrations of FPA or PT1.2. Platelet reactivity correlated negatively with A1C (P < 0.04), was not related to the concentration of triglycerides in blood, and did not correlate with the concentration of C-reactive peptide. CONCLUSIONS Among patients enrolled in this substudy of BARI 2D, a greater BMI was associated with higher platelet reactivity at the time of enrollment. Our results suggest that obesity and insulin resistance that accompanies obesity may influence platelet reactivity in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To determine whether using the chronic care model (CCM) in an underserved community leads to improved clinical and behavioral outcomes for people with diabetes.Research Design and Methods: This multilevel, cluster-design, randomized controlled trial examined the effectiveness of a CCM-based intervention in an underserved urban community. Eleven primary care practices, along with their patients, were randomized to three groups: CCM intervention (n = 30 patients), provider education only (PROV group) (n = 38), and usual care (UC group) (n = 51).Results: A marked decline in HbA(1c) was observed in the CCM group (-0.6%, P = 0.008) but not in the other groups. The magnitude of the association remained strong after adjustment for clustering (P = 0.01). The same pattern was observed for a decline in non-HDL cholesterol and for the proportion of participants who self-monitor blood glucose in the CCM group (non-HDL cholesterol: -10.4 mg/dl, P = 0.24; self-monitor blood glucose: +22.2%, P < 0.0001), with statistically significant between-group differences in improvement (non-HDL cholesterol: P = 0.05; self-monitor blood glucose: P = 0.03) after adjustment. The CCM group also showed improvement in HDL cholesterol (+5.5 mg/dl, P = 0.0004), diabetes knowledge test scores (+6.7%, P = 0.07), and empowerment scores (+2, P = 0.02).Conclusions: These results suggest that implementing the CCM in the community is effective in improving clinical and behavioral outcomes in patients with diabetes. [ABSTRACT FROM AUTHOR]

Cardiac procedures are performed less frequently in Canada than in the United States (US), yet rates of cardiac death and myocardial infarction are similar. We therefore sought to compare long-term symptoms and quality of life in Canadian and American patients undergoing initial coronary revascularization. The 161 patients enrolled in the Bypass Angioplasty Revascularization Investigation at the Montreal Heart Institute were compared with 934 patients enrolled at 7 US sites. Patients' outcomes were documented for 5 years after random assignment to percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery. Functional status was assessed using the Duke Activity Status Index. Canadian patients were significantly younger and had more angina at study entry. Death and nonfatal myocardial infarction were not significantly different between Canadian and US patients after adjustment for baseline risk. Canadian patients had significantly greater improvements in functional status at 1-year follow-up (Duke Activity Status Index score + 13.5 vs. + 6.0, p = 0.002), but this difference progressively narrowed over 5 years. Angina was equally prevalent in Canadian and US patients at 1 year (16% vs. 19%), but significantly more prevalent in Canadian patients at 5 years (36% vs. 16%, p = 0.001). Repeat revascularization procedures were performed less often over 5 years among Canadian patients (26% vs. 34%, p = 0.08), especially coronary artery bypass graft surgery after initial percutaneous transluminal coronary angioplasty (18% vs. 32%, p = 0.03). These results suggest more anginal symptoms are required in Canada before coronary revascularization, but as a result Canadians receive greater improvements in quality of life after the procedure. [ABSTRACT FROM AUTHOR]

Objectives. We explored whether and how race shapes perceived health status in patients with type 2 diabetes mellitus and coronary artery disease. Methods. We analyzed self-rated health (fair or poor versus good, very good, or excellent) and associated clinical risk factors among 866 white and 333 black participants in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. Results. Michigan Neuropathy Screening Instrument scores, regular exercise, and employment were associated with higher self-rated health (P < .05). Blacks were more likely than were whites to rate their health as fair or poor (adjusted odds ratio [OR] = 1.88; 95% confidence interval [CI] = 1.38, 2.57; P < .001). Among whites but not blacks, a clinical history of myocardial infarction (OR = 1.61; 95% CI = 1.12, 2.31; P < .001) and insulin use (OR = 1.62; 95% CI = 1.10, 2.38; P = .01) was associated with a fair or poor rating. A post-high school education was related to poorer self-rated health among blacks (OR = 1.86; 95% CI = 1.07, 3.24; P < .001). Conclusions. Symptomatic clinical factors played a proportionally larger role in self-assessment of health among whites with diabetes and coronary artery disease than among blacks with the same conditions. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to determine the extent to which effectiveness of cardiac and diabetes treatment strategies varies by patient age.Background: The impact of age on the effectiveness of revascularization and hyperglycemia treatments has not been thoroughly investigated.Methods: In the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial, 2,368 patients with documented stable heart disease and type 2 diabetes were randomized to receive prompt revascularization versus initial medical therapy with deferred revascularization and insulin sensitization versus insulin provision for hyperglycemia treatment. Patients were followed for an average of 5.3 years. Cox regression and mixed models were used to investigate the effect of age and randomized treatment assignment on clinical and health status outcomes.Results: The effect of prompt revascularization versus medical therapy did not differ by age for death (interaction p = 0.99), major cardiovascular events (interaction p = 0.081), angina (interaction p = 0.98), or health status outcomes. After intervention, participants of all ages had significant angina and health status improvement. Younger participants experienced a smaller decline in health status during follow-up than older participants (age by time interaction p < 0.01). The effect of the randomized glycemia treatment on clinical and health status outcomes was similar for patients of different ages.Conclusions: Among patients with stable heart disease and type 2 diabetes, the relative beneficial effects of a strategy of prompt revascularization versus initial medical therapy and insulin-sensitizing versus insulin-providing therapy on clinical endpoints, symptom relief, and perceived health status outcomes do not vary by age. Health status improved significantly after treatment for all ages, and this improvement was sustained longer among younger patients. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305). [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to determine whether women undergoing contemporary percutaneous coronary intervention (PCI) remain at increased risk in comparison with men and whether the outcomes in women have improved.Background: Previous studies have shown that women treated with coronary angioplasty have a higher incidence of procedural morbidity and mortality than men.Methods: Gender differences in wave 1 of the National Heart, Lung and Blood Institute (NHLBI) Dynamic registry were evaluated. Baseline characteristics and outcomes in women in the Dynamic registry were compared with those in women in the 1985-1986 and 1993-1994 NHLBI Percutaneous Transluminal Coronary Angioplasty (PTCA) registries.Results: Women were older with a higher prevalence of diabetes mellitus, hypertension, congestive heart failure, unstable angina and single vessel disease in comparison with men. Although procedural success and in-hospital death (2.2% vs. 1.3%), myocardial infarction (MI) (2.3% vs. 3.0%) and coronary artery bypass graft surgery (CABG) (1.3% vs. 1.4%) were similar in women and men, respectively, one-year mortality (6.5% vs. 4.3%, p = 0.02) and combined end point of death/MI/CABG (18.3% vs. 14.4%, p = 0.03) were higher in women than in men. After controlling for other factors, gender was not a significant predictor of death or death plus MI at one year. Despite a higher risk profile in women in the Dynamic registry in comparison with women in the 1985-1986 NHLBI PTCA registry, in-hospital death/MI/CABG was lower (6.0% vs. 11.6%, p < 0.001).Conclusions: Despite persistent high-risk characteristics in women, gender differences in outcomes in patients undergoing contemporary PCI have decreased, and outcomes in women have improved. [ABSTRACT FROM AUTHOR]

Importance: In patients with acute myocardial infarction (MI), limited physiologic adaptation to acute anemia might lead to greater benefit from a liberal red blood cell (RBC) transfusion strategy. Data on such a possible benefit are lacking., Objectives: To compare acute anemia with chronic anemia and post-MI outcomes and estimate the differential effect of a restrictive RBC transfusion strategy compared with a liberal strategy on post-MI outcomes according to anemia acuity., Design, Setting, and Participants: A prespecified subgroup analysis of the Myocardial Ischemia and Transfusion (MINT) multicenter randomized clinical trial was conducted in 126 hospitals in 6 countries between April 26, 2017, and April 14, 2023, with 30-day follow-up and blinded adjudication of the primary outcome. The analysis included 3144 of 3504 MINT participants (89.7%) with acute MI, a hemoglobin (Hb) level less than 10 g/dL at randomization, and a first Hb measurement available on the day of or the day following hospital admission., Intervention: The MINT trial randomized participants to a restrictive (Hb <7-8 g/dL) or liberal (Hb <10 g/dL) RBC transfusion strategy. Acute anemia was defined as having a first Hb value greater than 13 g/dL (men) or 12 g/dL (women), or as having a decrease greater than or equal to 2 g/dL between the first Hb measurement and measurement at randomization. Other Hb levels were categorized as chronic anemia., Main Outcomes and Measures: The primary outcome was a composite of death or recurrent MI up to 30 days after randomization. Secondary outcomes were death, recurrent MI, cardiac death, heart failure, pulmonary complications, and major bleeding events. Intention-to-treat analysis was performed., Results: Among 3144 included participants (mean [SD] age, 72.3 [11.6] years; 1715 [54.5%] male; 1307 [41.6%] with type 1 MI), 1078 [34.3%]) had acute anemia. Acute anemia was associated with an increased risk of death or recurrent MI (adjusted risk ratio, 1.25; 95% CI, 1.05-1.48). The effect of a restrictive RBC transfusion strategy compared with a liberal strategy was similar for participants with either acute or chronic anemia for all outcomes., Conclusions and Relevance: In this secondary analysis of the MINT trial, acute anemia was associated with less favorable post-MI outcomes than chronic anemia but did not modify the effects of the randomized transfusion strategy. In patients with anemia and MI, the acuity of anemia should not influence the choice of transfusion trigger., Trial Registration: ClinicalTrials.gov Identifier: NCT02981407.

Background: The optimal hemoglobin threshold to guide red blood cell (RBC) transfusion for patients with acute myocardial infarction (MI) and anemia is uncertain., Objective: To estimate the efficacy of 4 individual hemoglobin thresholds (<10 g/dL [<100 g/L], <9 g/dL [<90 g/L], <8 g/dL [<80 g/L], and <7 g/dL [<70 g/L]) to guide transfusion in patients with acute MI and anemia., Design: Prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial using target trial emulation methods. (ClinicalTrials.gov: NCT02981407)., Setting: 144 clinical sites in 6 countries., Participants: 3492 MINT trial participants with acute MI and a hemoglobin level below 10 g/dL., Intervention: Four transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Protocol exceptions were permitted for specified adverse clinical events., Measurements: Data from the MINT trial were leveraged to emulate 4 transfusion strategies and estimate per protocol effects on the composite outcome of 30-day death or recurrent MI (death/MI) and 30-day death using inverse probability weighting., Results: The 30-day risk for death/MI was 14.8% (95% CI, 11.8% to 18.4%) for a <10-g/dL strategy, 15.1% (CI, 11.7% to 18.2%) for a <9-g/dL strategy, 15.9% (CI, 12.4% to 19.0%) for a <8-g/dL strategy, and 18.3% (CI, 14.6% to 22.0%) for a <7-g/dL strategy. Absolute risk differences and risk ratios relative to the <10-g/dL strategy for 30-day death/MI increased as thresholds decreased, although 95% CIs were wide. Findings were similar and imprecise for 30-day death., Limitation: Unmeasured confounding may have persisted despite adjustment., Conclusion: The 30-day risks for death/MI and death among patients with acute MI and anemia seem to increase progressively with lower hemoglobin concentration thresholds for transfusion. However, the imprecision around estimates from this target trial analysis precludes definitive conclusions about individual hemoglobin thresholds., Primary Funding Source: National Heart, Lung, and Blood Institute., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0571.

Chimeric antigen receptor (CAR) T cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T cell therapies against solid tumors., Competing Interests: M.A.K.-D. discloses research/grants from Bristol Myers Squibb, Novartis, and Pharmacyclics, and a consultancy for Kite Pharma., (© 2024 The Author(s).)

Context: Limited data provides evidence-based insights on the association between comprehensive metrics of high-density lipoproteins (HDL) and cognitive performance, especially in midlife women for whom benefit might be the greatest., Objective: To assess the associations of serum HDL metrics including HDL lipid content [HDL cholesterol, phospholipid (HDL-PL), triglyceride], proteins/subclasses [apolipoprotein A-1 (apoA-1); small, medium, large, total HDL particle (HDL-P); and HDL size], and cholesterol efflux capacity with cognitive performance in midlife women., Methods: This prospective cohort study was conducted among 503 midlife women (1234 observations) from the Study of Women's Health Across the Nation HDL ancillary study. Joint models were applied to examine associations of HDL metrics assessed at midlife (50.2 ± 2.9 years, baseline of the current study) and their changes over midlife (6.1 ± 3.9 years of duration) with subsequent cognitive performance [working memory (Digit Span Backward Test), processing speed (Symbol Digit Modalities Test), and episodic memory immediate and delayed recall (East Boston memory test)] assessed repeatedly (maximum 5 times) 1.5 ± 1 years later over 7.72 ± 4.10 years of follow up., Results: Higher total HDL-P and smaller HDL size at midlife were associated with a better subsequent immediate recall, delayed recall and/or processing speed. Greater increase in HDL-PL, apoA-1, medium HDL-P, and total HDL-P and less increase in HDL size over midlife were associated with a better subsequent immediate and/or delayed recall., Conclusions: Enhancing specific serum HDL metrics during midlife could be promising in cognitive restoration, particularly memory, the initial and predominant symptom of Alzheimer's disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Neighborhood poverty is associated with adiposity in women, though longitudinal designs, annually collected residential histories, objectively collected anthropometric measures, and geographically diverse samples of midlife women remain limited. Objective: To investigate whether longitudinal exposure to neighborhood concentrated poverty is associated with differences in body mass index (BMI) and waist circumference (WC) among 2,328 midlife women (age 42-52 years at baseline) from 6 U.S. cities enrolled in the Study of Women's Health Across the Nation (SWAN) from 1996 to 2007. Methods: Residential addresses and adiposity measures were collected at approximately annual intervals from the baseline visit through a 10-year follow-up. We used census poverty data and local spatial statistics to identify hot-spots of high concentrated poverty areas and cold-spots of low concentrated poverty located within each SWAN site region, and used linear mixed-effect models to estimate percentage differences (95% confidence interval [CI]) in average BMI and WC levels between neighborhood concentrated poverty categories. Results: After adjusting for individual-level sociodemographics, health-related factors, and residential mobility, compared to residents of moderate concentrated poverty communities, women living in site-specific hot-spots of high concentrated poverty had 1.5% higher (95% CI: 0.6, 2.3) BMI and 1.3% higher (95% CI: 0.5, 2.0) WC levels, whereas women living in cold-spots of low concentrated poverty had 0.7% lower (95% CI: -1.2, -0.1) BMI and 0.3% lower (95% CI: -0.8, 0.2) WC. Site-stratified results remained in largely similar directions to overall estimates, despite wide CIs and small sample sizes. Conclusions: Longitudinal exposure to neighborhood concentrated poverty is associated with slightly higher BMI and WC among women across midlife.

Objective: The shelter-in-place mandates enacted early in the COVID-19 pandemic resulted in changes in alcohol use and consequent outcomes. We assessed changes in six categories of season-specific alcohol-attributable mortality from before to during the early phases of the COVID-19 pandemic in the United States., Method: We used logistic regression models to assess alcohol-attributable mortality in the United States from 2017 through 2020 ( n = 11,632,725 decedents ages 18 and older). Outcomes included chronic fully alcohol-attributable deaths, poisonings, motor vehicle accidents, suicides, homicides, and falls. Exposure variables included year, season, the interaction between the year 2020 and season, rurality, the interaction between the year 2020 and rurality, decedent age, sex, race, ethnicity, marital status, and education., Results: Compared with 2019, season-specific mortality age-adjusted rates of chronic fully alcohol-attributable deaths, homicides, poisonings, and falls increased during the COVID-19 pandemic. Suicide rates decreased in most 2020 seasons relative to the same seasons in 2019. Motor vehicle deaths decreased in spring 2020 versus 2019. Relative to dying by any other cause, the odds of death by chronic fully alcohol-attributable causes and poisonings were higher across seasons in 2020 versus 2019. The odds of death by suicide were higher among residents of rural counties in spring 2020 versus 2019., Conclusions: There were distinct temporal changes in six types of alcohol-attributable deaths during the early phases of the COVID-19 pandemic.

Background: The MINT trial raised concern for harm from a restrictive versus liberal transfusion strategy in patients with acute myocardial infarction (MI) and anemia. Type 1 and type 2 MI are distinct pathophysiological entities that may respond differently to blood transfusion. This analysis sought to determine if the effects of transfusion varied among patients with a type 1 or a type 2 MI and anemia. We hypothesized that the liberal transfusion strategy would be of greater benefit in type 2 than in type 1 MI., Methods: We compared rates of death or MI at 30 days in patients with type 1 (n=1460) and type 2 (n=1955) MI and anemia who were randomly allocated to a restrictive (threshold of 7 to 8 g/dL) or a liberal (threshold of 10 g/dL) transfusion strategy., Results: The primary outcome of death or MI was observed in 16% of type 1 MI and 15.4% of type 2 MI patients. The rate of death or MI was higher in patients with type 1 MI randomized to a restrictive (18.2%) versus liberal (13.2%) transfusion strategy (RR 1.32, 95% CI 1.04 - 1.67) with no difference observed between the restrictive (15.8% ) and liberal (15.1% ) transfusion strategies in patients with type 2 MI (RR 1.05 95% CI 0.85-1.29). The test for a differential effect of transfusion strategy by MI type was not statistically significant (P- interaction = 0.16)., Conclusions: The concern for harm with a restrictive transfusion strategy in patients with acute MI and anemia raised in the MINT primary outcome manuscript may be more apparent in patients with type 1 than type 2 MI., Clinical Trial Registration: ClinicalTrials.gov number, NCT02981407.

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor-initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.

Purpose: To determine the differential impact of Medicaid expansion on all-cause mortality between Black, Latino/a, and White populations in rural and urban areas, and assess how expansion impacted mortality disparities between these groups., Methods: We employ a county-level time-varying heterogenous treatment effects difference-in-difference analysis of Medicaid expansion on all-cause age-adjusted mortality for those 64 years of age or younger from 2009 to 2019. For all counties within the 50 US States and the District of Columbia, we use restricted-access vital statistics data to estimate Average Treatment Effect on the Treated (ATET) for all combinations of racial and ethnic group (Black, Latino/a, White), rurality (rural, urban), and sex. We then assess aggregate ATET, as well as how the ATET changed as time from expansion increased., Findings: Medicaid expansion led to a reduction in all-cause age-adjusted mortality for urban Black populations, but not rural Black populations. Urban White populations experienced mixed effects dependent on years after expansion. Latino/a populations saw no appreciable impact. While no effect was observed for rural Black and Latino/a populations, rural White all-cause age-adjusted mortality unexpectedly increased due to Medicaid expansion. These effects reduced rural- and urban-specific Black-White mortality disparities but did not shrink the rural-urban mortality gap., Conclusions: The mortality-reducing impact of Medicaid expansion has been uneven across racial and ethnic groups and rural-urban status; suggesting that many populations-particularly rural individuals-are not seeing the same benefits as others. It is imperative that states work to ensure Medicaid expansion is being appropriately implemented in rural areas., (© 2024 The Author(s). The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

Objective: The clinical utility of high-density lipoprotein cholesterol (HDL-C) in risk classification is limited, especially in midlife women. Novel metrics of HDL may better reflect this risk. We clustered a comprehensive profile of HDL metrics into favorable and unfavorable clusters and assessed how these two clusters are related to future subclinical atherosclerosis (carotid intima media thickness [cIMT], interadventitial diameter [IAD], and carotid plaque presence) in midlife women., Methods: Four hundred sixty-one women (baseline age: 50.4 [2.7] years; 272 White, 137 Black, 52 Chinese) from the Study of Women's Health Across the Nation HDL ancillary study who had baseline measures of HDL cholesterol efflux capacity (HDL-CEC), lipid contents (HDL-phospholipids [HDL-PL] and HDL triglycerides [HDL-Tg]), and HDL particle (HDL-P) distribution and size, followed by carotid ultrasound (average 12.9 [SD: 2.6] years later), were included. Using latent cluster analysis, women were clustered into a favorable (high HDL-CEC, HDL-PL, large and medium HDL-P, less HDL-Tg and small HDL-P, larger size) or an unfavorable HDL cluster (low HDL-CEC, HDL-PL, large and medium HDL-P, more HDL-Tg, and small HDL-P, smaller size) and then linked to future subclinical atherosclerosis using linear or logistic regression., Results: The favorable HDL cluster was associated with lower cIMT, IAD, and odds of carotid plaque presence. These associations were attenuated by body mass index, except in Chinese women where the association with cIMT persisted (0.72 [0.63, 0.83])., Conclusions: The association between favorable HDL clusters and a better postmenopausal subclinical atherosclerosis profile is largely explained by body mass index; however, racial/ethnic differences may exist., Competing Interests: Financial disclosure/conflicts of interest: Maria M. Brooks is a Data and Safety Monitoring Board member for Cerus Corporation. The other authors have nothing to disclose., (Copyright © 2024 by The Menopause Society.)

Objective: High-density lipoprotein cholesterol (HDL-C) is one of 5 components [high blood pressure, glucose, triglycerides, waist circumference, low HDL-C], 3 of which, needed to diagnose metabolic syndrome (MetS). Evolving research shows that higher HDL-C is not necessarily cardioprotective in midlife women, supporting a need to re-evaluate HDL-C's contribution to risks related to MetS. We tested whether risk of future diabetes and higher carotid intima-media thickness (cIMT) differ by HDL-C status in midlife women diagnosed with MetS based on the other 4 components., Methods Midlife Women Were Classified Into 3 Groups: 1) no MetS, 2) MetS with HDL-C ≥ 50 mg/dL (MetS hiHDL), and 3) MetS with HDL-C < 50 mg/dL (MetS loHDL). cIMT was measured 13.8 ± 0.6 years post baseline. Incident diabetes was assessed yearly., Results: Among 2773 women (1350 (48 %) of them had cIMT), 2383 (86 %) had no MetS, 117 (4 %) had MetS hiHDL, 273 (10 %) had MetS loHDL. Compared with no MetS, both MetS- hiHDL and loHDL groups had higher cIMT and diabetes risk. Risk of having high cIMT did not differ between MetS loHDL vs. hiHDL groups. Adjusting for levels of MetS criteria other than HDL-C at baseline explained the associations of each of the two MetS groups with cIMT. Conversely, after adjustment, associations of MetS hiHDL and MetS loHDL with incident diabetes persisted., Conclusions: In midlife women, HDL-C status matters for predicting risk of incident diabetes but not higher cIMT beyond other MetS components., Competing Interests: We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work. Dr. Rebecca Thurston is a consultant and advisor for Astellas Pharma, consultant and received travel support from Bayer, and on the medical advisory board for Hello Therapeutics. All other coauthors have nothing to disclose., (© 2024 The Author(s).)

Background: Addressing health equity requires attention to upstream determinants of health, including environmental and social factors that act in tandem to increase communities' exposure to and vulnerability to toxicants. Cumulative risk assessment, which evaluates combined risks from environmental and social factors, is a useful approach for estimating potential drivers of health disparities. We developed a cumulative risk score of multiple indices of environmental and social conditions and assessed block group-level differences in New Castle County, Delaware., Methods: This cross-sectional study used choropleth maps to visualize the distribution of environmental, social, and cumulative risks and Moran's I statistics to assess spatial clustering of cumulative risk across the county and among individual block groups., Results: Findings indicate that environmental risk rarely occurs without social risk and that environmental and social risks co-occur in distinct areas, resulting in large-scale clustering of cumulative risk. Areas of higher cumulative risk had more Black residents and people of lower socioeconomic status., Conclusions: Replicable measures of cumulative risk can show how environmental and social risks are inequitably distributed by race and socioeconomic status, as seen here in New Castle County. Such measures can support upstream approaches to reduce health disparities resulting from histories of environmental racism., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

A central premise of the first demographic transition theory is that demographic change would occur more slowly in rural than urban areas. Few studies, however, have investigated whether rural areas remain holdouts during the second demographic transition. To address this gap, this study (1) examines trends among rural and urban families in Canada and the United States over a 30-year period and (2) determines whether compositional differences in demographic, socioeconomic, and religious factors explain current differences between rural and urban families. We find that rural Canadian women continue to have, on average, 0.6 more children than urban women. However, rural families do not trail behind urban families on any other indicator of family change. In fact, rural women in both countries are now significantly more likely to cohabit and roughly 10 percentage points more likely to have children outside of marriage than urban women. These differences are largely explained by lower levels of education and income among rural American women and fewer immigrants in rural Canada. Examining family change through a rural-urban lens fills important empirical gaps and yields novel insights into current debates on the fundamental causes of ongoing family change in high-income countries., (Copyright © 2024 The Authors.)

Background: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level., Methods: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days., Results: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49)., Conclusions: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.)., (Copyright © 2023 Massachusetts Medical Society.)

Objective: To describe vaginal microbiota classified by community state types (CST) in a diverse cohort of postmenopausal women and evaluate relationships among genitourinary syndrome of menopause (GSM) symptoms (vaginal dryness, vulvovaginal irritation, sexual pain, dysuria, urinary urgency), CSTs, estrogen, vaginal maturation index (VMI), and vaginal pH., Methods: In the Study of Women's Health Across the Nation, 1,320 women aged 60.4 to 72.5 years self-collected (2015-2017) vaginal samples analyzed for microbiota composition and structure (CSTs) using 16S rRNA gene amplicon sequencing, VMI, and pH. GSM symptoms were collected with self-administered questionnaires; interviewers elicited estrogen use and measured body mass index. Serum E2 and E1 were measured using high-performance liquid chromatography. We analyzed data using Pearson χ2 tests, analysis of variance, Kruskal-Wallis tests, and binomial logistic regression., Results: The most frequently occurring CST was low Lactobacillus species IV-C (49.8%); 36.4% of women had CSTs dominated by Lactobacillus species. More than half of the women with vaginal atrophy biomarkers (VMI <50 and pH >5) had CST IV-C0, whereas women using estrogen or with higher E1 and E2 levels had a higher prevalence of Lactobacillus crispatus -dominated CST I ( P values < 0.001). Sexual pain was associated with atrophy biomarkers and independently associated with Streptococcus species-dominated CST IV-C1 (odds ratio, 2.26; 95% confidence intervals, 1.20-4.23). For all other GSM symptoms, we found no consistent associations with E1 or E2 levels, atrophy biomarkers, or any CST., Conclusions: Although close relationships exist among estrogen, CSTs, VMI, and pH, sexual pain was the only GSM symptom associated with the structure of vaginal microbiota and atrophy biomarkers., Competing Interests: Financial disclosure/conflicts of interest: Dr Ravel is the cofounder of LUCA Biologics, a biotechnology company focusing on translating microbiome research into live biotherapeutics drugs for women's health. Dr Hess has served on the Astelles Data Safety Monitoring Board for the Fezolinetant program of research. Dr Brooks has served as a Data Safety and Monitoring Board member for Cerus Corporation and as a Data Safety and Monitoring Board member for Pfizer. The other authors have nothing to disclose., (Copyright © 2023 by The Menopause Society.)

Objective: Perimenopausal women experience a steep increase in low-density lipoprotein cholesterol (LDL-C) that is related to a higher risk of carotid plaque later in life. Low-density lipoprotein subclasses have been linked to cardiovascular diseases beyond LDL-C, promising a better risk stratification. We aim to characterize changes in LDL subclasses and assess their associations with presence of coronary artery calcium (CAC score ≥10) and carotid intima-media thickness (cIMT) over the menopausal transition (MT) and by menopause stage., Methods: Nuclear magnetic resonance spectroscopy LDL subclasses were measured for a maximum of five time points. Coronary artery calcification and cIMT were measured for a maximum of two time points. LOESS (locally weighted regression with scatter smoothing) plots, linear mixed-effects models, and generalized estimating equations were used for analyses., Results: The study included 471 women (baseline: age, 50.2 ± 2.7 years; 79.0% premenopausal/early perimenopausal), of whom 221 had data on CAC or cIMT. Low-density lipoprotein subclasses increased over the MT, whereas intermediate density-lipoprotein particles declined. In adjusted models, higher total LDL particles (LDL-P) and apolipoprotein B were associated with greater CAC prevalence and greater cIMT. Although none of the associations were modified by menopause stage, higher LDL-C, apolipoprotein B, and total LDL-P were associated with greater cIMT during the perimenopause or postmenopause stages, whereas higher LDL-C and small LDL-P were associated with greater CAC prevalence, mainly during perimenopause., Conclusions: During the MT, women experience significant increases in LDL subclasses found to be related to greater cIMT levels and CAC prevalence. Whether these changes could better predict future risk of hard cardiovascular disease events beyond LDL-C remains a research question to address., Competing Interests: Financial disclosure/conflicts of interest: M.M.B. serves as a Data and Safety Monitoring Board member for Cerus Corporation. S.C. received a payment for statistical consulting from the University of Pittsburgh. The other authors report no conflicts., (Copyright © 2023 by The Menopause Society.)

Introduction: Cardiovascular fat is a novel risk factor that may link to dementia. Fat volume and radiodensity are measurements of fat quantity and quality, respectively. Importantly, high fat radiodensity could indicate healthy or adverse metabolic processes., Methods: The associations of cardiovascular fat (including epicardial, paracardial, and thoracic perivascular adipose tissue [PVAT]) quantity and quality assessed at mean age of 51 with subsequent cognitive performance measured repeatedly over 16 years of follow-up were examined using mixed models among 531 women., Results: Higher thoracic PVAT volume was associated with a higher future episodic memory (β[standard error (SE)] = 0.08 [0.04], P = 0.033), while higher thoracic PVAT radiodensity with lower future episodic (β[SE] = -0.06 [0.03], P = 0.045) and working (β[SE] = -0.24 [0.08], P = 0.003) memories. The latter association is prominent at higher volume of thoracic PVAT., Discussion: Mid-life thoracic PVAT may have a distinct contribution to future cognition possibly due to its distinct adipose tissue type (brown fat) and anatomical proximity to the brain circulation., Highlights: Higher mid-life thoracic perivascular adipose tissue (thoracic PVAT) volume is related to a better future episodic memory in women. Higher mid-life thoracic PVAT radiodensity is related to worse future working and episodic memories. Negative association of high thoracic PVAT radiodensity with working memory is prominent at higher thoracic PVAT volume. Mid-life thoracic PVAT is linked to future memory loss, an early sign of Alzheimer's disease. Mid-life women's epicardial and paracardial fat are not related to future cognition., (© 2023 the Alzheimer's Association.)

Housing and residential outcomes in the United States are significantly stratified by ethnoracial group, but the extent to which disparities exist in affordable renting over time is less clear. In this study, I explore affordable housing disparities among White, Black, Hispanic, and Asian renters and test hypotheses regarding variation by education, local ethnoracial composition, and chosen measurement of affordability. Chiefly, I find that White households have higher rates of affordable housing than Black and Hispanic households with disparities remaining nearly identical between 2005 and 2019 and become larger when considering household's ability to afford other basic needs. Nevertheless, returns to education are not uniformly larger for White renters, in that Black and Asian renters experience larger marginal increases in residual income based affordable housing at higher levels of education. The effects of county ethnoracial composition effects are consistent with all groups-including White households-experiencing declining affordability when living in counties with large coethnic populations., Competing Interests: Declaration of competing interest The author declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To examine whether longitudinal exposure to neighborhood socioeconomic vulnerability influences blood pressure changes throughout midlife in a racially, ethnically, and geographically-diverse cohort of women transitioning through menopause., Methods: We used longitudinal data on 2738 women (age 42-52 at baseline) living in six United States cities from The Study of Women's Health Across the Nation. Residential histories, systolic blood pressures (SBP), and diastolic blood pressures (DBP) were collected annually for ten years. We used longitudinal latent profile analysis to identify patterns of neighborhood socioeconomic vulnerability occurring from 1996 to 2007 in participant neighborhoods. We used linear mixed-effect models to determine if a woman's neighborhood profile throughout midlife was associated with blood pressure changes., Results: We identified four unique profiles of neighborhood socioeconomic vulnerability - differentiated by residential socioeconomic status, population density, and vacant housing conditions - which remained stable across time. Women residing in the most socioeconomically vulnerable neighborhoods experienced the steepest increase in annual SBP growth by 0.93 mmHg/year (95% CI: 0.65-1.21) across ten-year follow-up., Conclusions: Neighborhood socioeconomic vulnerability was significantly associated with accelerated SBP increases throughout midlife among women., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC., Methods: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source., Results: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes., Conclusions: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Despite similar incidence rates among Black and White women, breast cancer mortality rates are 40% higher among Black women. More than half of the racial difference in breast cancer mortality can be attributed to triple negative breast cancer (TNBC), an aggressive subtype of invasive breast cancer that disproportionately affects Black women. Recent research has implicated neighborhood conditions in the etiology of TNBC. This study investigated the relationship between cumulative neighborhood-level exposures and TNBC risk., Methods: This single-institution retrospective study was conducted on a cohort of 3316 breast cancer cases from New Castle County, Delaware (from 2012 to 2020), an area of the country with elevated TNBC rates. Cases were stratified into TNBC and "Non-TNBC" diagnosis and geocoded by residential address. Neighborhood exposures included census tract-level measures of unhealthy alcohol use, metabolic dysfunction, breastfeeding, and environmental hazards. An overall cumulative risk score was calculated based on tract-level exposures., Results: Univariate analyses showed each tract-level exposure was associated with greater TNBC odds. In multivariate analyses that controlled for patient-level race and age, tract-level exposures were not associated with TNBC odds. However, in a second multivariate model that included patient-level variables and considered tract-level risk factors as a cumulative exposure risk score, each one unit increase in cumulative exposure was significantly associated with a 10% increase in TNBC odds. Higher cumulative exposure risk scores were found in census tracts with relatively high proportions of Black residents., Conclusions: Cumulative exposure to neighborhood-level risk factors that disproportionately affect Black communities was associated with greater TNBC risk., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)