Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.

OBJECTIVES: We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials. DESIGN: The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6. SETTING: The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States. PARTICIPANTS: The trials enrolled 27,347 postmenopausal women, aged 50-79 y. INTERVENTIONS: We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. OUTCOME MEASURES: Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial. RESULTS: Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68-1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86-2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57-1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69-1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified. CONCLUSIONS: Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results

Plasma Levels of Fetuin‐A and Risk of Coronary Heart Disease in US Women: The Nurses' Health Study

Background: Fetuin‐A may be involved in the etiology of coronary heart disease (CHD) through opposing pathways (ie, promoting insulin resistance and inhibiting ectopic calcification). We aimed to explicitly examine whether systemic inflammation, a factor leading to elevated vascular calcification, may modify the association between fetuin‐A and CHD risk. Method and Results During 16 years of follow‐up (1990–2006), we prospectively identified and confirmed 466 incident fatal or nonfatal CHD case in the Nurses' Health Study. For each case, 1 healthy control was selected using risk‐set sampling from 26 245 eligible participants. Cases and controls were matched for age, smoking status, fasting status, and date of blood draw. After multivariate adjustment for lifestyle factors, body mass index, diet, and blood lipids, fetuin‐A levels were not associated with CHD risk in the whole population: odds ratio (OR) (95% CI) comparing extreme quintiles of fetuin‐A was 0.79 (0.44 to 1.40). However, a significant inverse association was observed among participants with higher C‐reactive protein levels (Pinteraction=0.04). The OR (95% CI) comparing highest versus lowest quintiles of fetuin‐A was 0.50 (0.26 to 0.97; Ptrend=0.004) when C‐reactive protein levels were above population median (0.20 mg/dL), whereas among the remainder of the participants, the corresponding OR (95% CI) was 1.09 (0.58 to 2.05; Ptrend=0.75). Conclusions: In this population of US women, fetuin‐A levels were associated with lower CHD risk when C‐reactive protein levels were high, but null association was observed among participants with lower C‐reactive protein levels. This divergent pattern of association needs replication in future studies

Impact of cyclooxygenase inhibitors in the Women\u27s Health Initiative hormone trials: secondary analysis of a randomized trial

OBJECTIVES: We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women\u27s Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials. DESIGN: The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6. SETTING: The Women\u27s Health Initiative hormone trials were conducted at 40 clinical sites in the United States. PARTICIPANTS: The trials enrolled 27,347 postmenopausal women, aged 50-79 y. INTERVENTIONS: We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. OUTCOME MEASURES: Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial. RESULTS: Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68-1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86-2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57-1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69-1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified. CONCLUSIONS: Use of COX inhibitors did not significantly affect the Women\u27s Health Initiative hormone trial results

MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock

Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1−/− cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-α and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-α, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock

Vitamin D levels and menopause-related symptoms.

Objective: To determine whether vitamin D levels are associated with menopause-related symptoms in older women. Methods: A randomly selected subset of 1,407 women, among 26,104 potentially eligible participants of the Women’s Health Initiative Calcium and Vitamin D (CaD) trial of postmenopausal women aged 51-80 years, had 25-hydroxyvitamin D [25(OH)D] levels measured at the CaD trial baseline visit. Information about menopause-related symptoms at baseline was obtained by questionnaire and included overall number of symptoms and composite measures of sleep disturbance, emotional well-being, and energy/fatigue, as well as individual symptoms. After exclusions for missing data, 530 women [mean age 66.2 years (SD 6.8)] were included in these analyses. Results: There were borderline significant associations between 25(OH)D levels and total number of menopausal symptoms (p values ranging from 0.05 to 0.06 for fully adjusted models); however, the effect was clinically insignificant and disappeared with correction for multiple testing. There were no associations between 25(OH)D levels and composite measures of sleep disturbance, emotional well-being, or energy/fatigue (p’s > 0.10 for fully adjusted models). Conclusions: There was no evidence of a clinically important association between serum 25(OH)D levels and menopause-related symptoms in postmenopausal women

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Bimetallic MOFs (H3O)x[Cu(MF6)(pyrazine)2]·(4 − x)H2O (M = V4+, x = 0; M = Ga3+, x = 1): co-existence of ordered and disordered quantum spins in the V4+ system

The title compounds are bimetallic MOFs containing [Cu(pyz)2]2+ square lattices linked by MF6n− octahedra. In each, only the Cu2+ spins exhibit long-range magnetic order below 3.5 K (M = V4+) and 2.6 K (M = Ga3+). The V4+ spins remain disordered down to 0.5 K

New research directions on disparities in obesity and type 2 diabetes

Obesity and type 2 diabetes disproportionately impact U.S. racial and ethnic minority communities and lowâ income populations. Improvements in implementing efficacious interventions to reduce the incidence of type 2 diabetes are underway (i.e., the National Diabetes Prevention Program), but challenges in effectively scalingâ up successful interventions and reaching atâ risk populations remain. In October 2017, the National Institutes of Health convened a workshop to understand how to (1) address socioeconomic and other environmental conditions that perpetuate disparities in the burden of obesity and type 2 diabetes; (2) design effective prevention and treatment strategies that are accessible, feasible, culturally relevant, and acceptable to diverse population groups; and (3) achieve sustainable health improvement approaches in communities with the greatest burden of these diseases. Common features of guiding frameworks to understand and address disparities and promote health equity were described. Promising research directions were identified in numerous areas, including study design, methodology, and core metrics; program implementation and scalability; the integration of medical care and social services; strategies to enhance patient empowerment; and understanding and addressing the impact of psychosocial stress on disease onset and progression in addition to factors that support resiliency and health.This report discusses a workshop convened by the National Institutes of Health to understand how to (1) address socioeconomic and other environmental conditions that perpetuate disparities in the burden of obesity and type 2 diabetes; (2) design effective prevention and treatment strategies that are accessible, feasible, culturally relevant, and acceptable to diverse population groups; and (3) achieve sustainable health improvement approaches in communities with the greatest burden of these diseases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154507/1/nyas14270_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154507/2/nyas14270.pd

Gene-environment interactions and obesity traits among postmenopausal African-American and Hispanic women in the Women’s Health Initiative SHARe Study

Genome-wide association studies of obesity measures have identified associations with single nucleotide polymorphisms (SNPs). However, no large-scale evaluation of gene-environment interactions has been performed. We conducted a search of gene-environment (G×E) interactions in post-menopausal African-American and Hispanic women from the Women’s Health Initiative SNP Health Association Resource GWAS study. Single SNP linear regression on body mass index (BMI) and waist-to-hip circumference ratio (WHR) adjusted for multidimensional-scaling-derived axes of ancestry and age was run in race-stratified data with 871,512 SNPs available from African-Americans (N=8,203) and 786,776 SNPs from Hispanics (N=3,484). Tests of G×E interaction at all SNPs for recreational physical activity (met-hrs/wk), dietary energy intake (kcal/day), alcohol intake (categorical), cigarette smoking years, and cigarette smoking (ever vs. never) were run in African-Americans and Hispanics adjusted for ancestry and age at interview, followed by meta-analysis of G×E interaction terms. The strongest evidence for concordant G×E interactions in African-Americans and Hispanics was for smoking and marker rs10133840 (Q statistic P=0.70, beta=−0.01, P=3.81×10−7) with BMI as the outcome. The strongest evidence for G×E interaction within a cohort was in African-Americans with WHR as outcome for dietary energy intake and rs9557704 (SNP×kcal =−0.04, P=2.17×10−7). No results exceeded the Bonferroni–corrected statistical significance threshold

The Women's Health Initiative: The Food Environment, Neighborhood Socioeconomic Status, BMI, and Blood Pressure

Using data (n=60,775 women) from the Women’s Health Initiative Clinical Trial (WHI CT)— a national study of postmenopausal women aged 50 to 79 years — we analyzed cross-sectional associations between the availability of different types of food outlets in the 1.5 miles surrounding a woman’s residence, census tract neighborhood socioeconomic status (NSES), body mass index (BMI) and blood pressure (BP)