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1.
Lancet Respir Med ; 7(11): 964-974, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31562059

RESUMO

BACKGROUND: Pneumonia is the leading cause of death among children globally. Most pneumonia deaths in low-income and middle-income countries (LMICs) occur among children with HIV infection or exposure, severe malnutrition, or hypoxaemia despite antibiotics and oxygen. Non-invasive bubble continuous positive airway pressure (bCPAP) is considered a safe ventilation modality that might improve child pneumonia survival. bCPAP outcomes for high-risk African children with severe pneumonia are unknown. Since most child pneumonia hospitalisations in Africa occur in non-tertiary district hospitals without daily physician oversight, we aimed to examine whether bCPAP improves severe pneumonia mortality in such settings. METHODS: This open-label, randomised, controlled trial was done in the general paediatric ward of Salima District Hospital, Malawi. We enrolled children aged 1-59 months old with WHO-defined severe pneumonia and either HIV infection or exposure, severe malnutrition, or an oxygen saturation of less than 90%. Children were randomly assigned 1:1 to low-flow nasal cannula oxygen or nasal bCPAP. Non-physicians administered care; the primary outcome was hospital survival. Primary analyses were by intention-to-treat and interim and adverse events analyses per protocol. This trial is registered with ClinicalTrials.gov, number NCT02484183, and is closed. FINDINGS: We screened 1712 children for eligibility between June 23, 2015, and March 21, 2018. The data safety and monitoring board stopped the trial for futility after 644 of the intended 900 participants were enrolled. 323 children were randomly assigned to oxygen and 321 to bCPAP. 35 (11%) of 323 children who received oxygen died in hospital, as did 53 (17%) of 321 who received bCPAP (relative risk 1·52; 95% CI 1·02-2·27; p=0·036). 13 oxygen and 17 bCPAP patients lacked hospital outcomes and were considered lost to follow-up. Suspected adverse events related to treatment occurred in 11 (3%) of 321 children receiving bCPAP and 1 (<1%) of 323 children receiving oxygen. Four bCPAP and one oxygen group deaths were classified as probable aspiration episodes, one bCPAP death as probable pneumothorax, and six non-death bCPAP events included skin breakdown around the nares. INTERPRETATION: bCPAP treatment in a paediatric ward without daily physician supervision did not reduce hospital mortality among high-risk Malawian children with severe pneumonia, compared with oxygen. The use of bCPAP within certain patient populations and non-intensive care settings might carry risk that was not previously recognised. bCPAP in LMICs needs further evaluation before wider implementation for child pneumonia care. FUNDING: Bill & Melinda Gates Foundation, International AIDS Society, Health Empowering Humanity.

2.
Am J Obstet Gynecol ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31283904

RESUMO

BACKGROUND: Multiparity is associated with a greater risk of incident cardiovascular disease. However, the relationship of parity with cardiovascular health, as measured by the American Heart Association Life's Simple 7 metrics, is uncertain. OBJECTIVE: We aimed to examine the association between parity and ideal cardiovascular health among 3,430 women, aged 45-84 years, free of clinical cardiovascular disease enrolled in the Multi-Ethnic Study of Atherosclerosis. STUDY DESIGN: The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study that recruited middle aged to older women and men from six centers in the United States between 2000 and 2002. The study population comprised 38% White, 28% Black, 23% Hispanic and 11% Chinese Americans. Parity (total number of live births) was self-reported and categorized as 0, 1-2, 3-4 and ≥5. The Life's Simple 7 metrics, defined according to American Heart Association criteria include health behaviors (smoking, physical activity, body mass index, diet) and health factors, (blood pressure, total cholesterol and blood glucose). We categorized each metric into ideal (2-points), intermediate (1-point) and poor (0-points). A total cardiovascular health score of 0-8 was considered inadequate; 9-10, average, and 11-14, optimal. We used multinomial logistic regression to examine the cross-sectional association between parity and cardiovascular health score, adjusted for socio-demographics, field site, hormone therapy and menopause. RESULTS: The mean (SD) age was 62 (10) years. The mean (SD) cardiovascular health score was lower with higher parity [8.9 (2.3), 8.7 (2.3), 8.5 (2.2), and 7.8 (2.0) for 0, 1-2, 3-4 and ≥5 live births, respectively]. In comparison to inadequate cardiovascular health scores, the adjusted odds of average cardiovascular health scores were significantly lower for all parity categories relative to nulliparity [prevalence Odds Ratios (OR) for parity of 1-2, 0.64 (95% CI 0.49-0.83); 3-4, 0.65 (0.49-0.86); ≥5, 0.64 (0.45-0.91)]. Women with ≥5 live births had a lower prevalence of optimal cardiovascular health scores [OR 0.50 (0.30-0.83)]. In the fully adjusted models, the association between parity and each Life's Simple 7 metric was only statistically significant for body mass index. Women with ≥5 live births had lower prevalence of ideal body mass index [OR 0.52 (0.35-0.80)]. In addition, the test for interaction showed that the association between parity and cardiovascular health was not modified by race/ethnicity (P=0.81 for average cardiovascular health scores and 0.20 for optimal cardiovascular health scores). CONCLUSION: Multiparity was associated with poorer cardiovascular health, especially for women with ≥5 live births. More research is required to explore the mechanisms by which parity may worsen cardiovascular health.

3.
J Clin Endocrinol Metab ; 104(10): 4600-4606, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31157875

RESUMO

PURPOSE: Based on the 2018 American College of Cardiology/American Heart Association cholesterol guidelines, the number of individuals eligible for statin therapy to reduce atherosclerotic cardiovascular disease risk has greatly expanded. Statins inhibit cholesterol biosynthesis, which can impair gonadal steroidogenesis. We evaluated the effect of statins on endogenous sex hormones in a large epidemiological study. METHODS: A total of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants underwent the baseline examination. Of these, 6171 had measurements of serum sex hormones available: dehydroepiandrosterone (DHEA), SHBG, estradiol, and total and bioavailable testosterone. Multivariable linear regression models were used to assess the relationship of statin use with each sex hormone. RESULTS: A total of 345 women (17.4%) and 464 men (14.7%) were statin users (mean age, 67 years; 41% white, 29% black, 11% Chinese, and 19% Hispanic). Among the users vs nonusers of statins, the mean SHBG was 3.54 nmol/L (P < 0.01) lower in women and 3.37 nmol/L (P < 0.001) lower in men; the mean DHEA was 1.06 nmol/L (P < 0.05) lower in women and 0.70 nmol/L (P < 0.01) lower in men, after adjustment for potential confounders. With further propensity score adjustment, the mean DHEA and SHBG levels were 0.67 nmol/L (P < 0.05) and 3.49 nmol/L (P < 0.001) lower, respectively, for statin users vs nonusers. No statistically significant association was noted between estradiol, total testosterone, and bioavailable testosterone and statin use. CONCLUSION: Statin users have lower levels of SHBG and DHEA. This is especially relevant owing to the increasing use of statin therapy.

4.
J Womens Health (Larchmt) ; 28(7): 900-909, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31170017

RESUMO

Background: The relationship of endogenous sex hormones (SH) with vascular endothelial function and with cardiovascular disease (CVD) is incompletely understood. We examined the associations between SH and endothelial function measured by brachial artery flow-mediated dilation (FMD). Materials and Methods: We included 1368 postmenopausal women and 1707 men, free of clinical CVD, participating in MESA Visit 1 (2000-2002). Serum SH [total testosterone, SH binding globulin (SHBG), dehydroepiandrosterone (DHEA), estradiol] were measured; free testosterone was calculated. The percent FMD difference (%FMD) was measured by high-resolution ultrasound. Using multivariable-adjusted linear regression, we tested the cross-sectional associations of SH (log transformed, compared per one SD increment) with %FMD. Results: The mean age of women and men were 64.2 and 61.4 years, respectively. Among women, after adjusting for demographics, CVD risk factors, and hormone therapy, higher SHBG was associated with greater %FMD [ß = 0.215% (95% CI 0.026-0.405)], whereas higher free testosterone was associated with a smaller %FMD [-0.209% (-0.402, -0.017)]. Estradiol and DHEA were not associated with %FMD in women after multivariable adjustment. There was an age interaction, with higher free testosterone and lower SHBG associated with worse FMD in women <65 years of age, but not in those ≥65 years (p = 0.04). We did not see similar associations in men. Conclusions: A more androgenic SH profile of higher free testosterone and lower SHBG was associated with worse %FMD in postmenopausal women. Changes in SH with aging and menopause may result in vascular changes in women. Further studies are needed to assess longitudinal changes in SH levels and their association with vascular function.

5.
PLoS One ; 14(4): e0211726, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30969969

RESUMO

BACKGROUND: Brachial artery reactivity (BAR) is usually determined as the maximum brachial artery diameter (BAD) following release of an occluding pressure cuff compared to a BAD before cuff inflation. BAD early after cuff deflation can also serve as baseline for estimating total brachial artery reactivity (TBAR). We investigate whether TBAR is associated with first time coronary heart disease events. METHODS: Participants of the Multi-Ethnic Study of Atherosclerosis (n = 5499) consisting of whites, African-Americans, Chinese and Hispanics were followed longitudinally for a mean of 12.5 years. Brachial artery ultrasound was performed following five minutes of cuff occlusion at the forearm. TBAR was estimated from BAD following cuff release as the difference between maximum and minimum brachial artery diameters divided by the minimum diameter multiplied by 100%. TBAR was added to multivariable Cox proportional hazards models with Framingham risk factors as predictors and time to first coronary heart disease event as outcome. RESULTS: Average TBAR was 9.7% (9.7 SD). Mean age was 61.7 years, 50.9% women. Increased TBAR was associated with lower risk of CHD events with a hazard rate of 0.78 per SD increase (95% C.I. 0.67, 0.91; p = 0.001). A TBAR below the median of 7.87% (Inter Quartile Range: 4.16%, 13.0%) was associated with a 31% lower risk of coronary heart disease event (Hazard Ratio: 0.69; 95% C.I.: 0.55, 0.87). CONCLUSION: TBAR is an independent predictor of first time coronary heart disease events and is exclusively measured after release of a blood pressure occlusion cuff.

6.
J Am Heart Assoc ; 8(9): e010810, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31017036

RESUMO

Background Identifying associations between serum metabolites and visceral adipose tissue ( VAT ) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity-related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT . Methods and Results Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross-sectional linear regression of individual-level data from participants in MESA (Multi-Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted 1H nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted 1H nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid-lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT ( P=4.88×10-20-1.16×10-3). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched-chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT ( P=1.90×10-35-8.46×10-7), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations. Conclusions We identified and replicated a metabolite panel associated with VAT in 2 community-based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity.

7.
Psychosom Med ; 81(4): 352-362, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30855555

RESUMO

OBJECTIVE: Depression in patients with cardiovascular disease is associated with increased risk of adverse clinical outcomes. Investigators have searched for potential biobehavioral explanations for this increased risk. Platelet activation and response to serotonin is an attractive potential mechanism. The aim of the study was to examine platelet serotonin signaling in a group of patients with coronary artery disease (CAD) and comorbid depression to define the relationship between platelet serotonin signaling and cardiovascular complications. METHODS: A total of 300 patients with CAD were enrolled (145 with acute coronary syndrome and 155 with stable CAD). Depression was assessed using the Structured Clinical Interview for DSM-IV as well as Beck Depression Inventory II in a dichotomous and continuous manner. Platelet serotonin response was measured by serotonin augmented aggregation, direct platelet serotonin activation, platelet serotonin receptor density, and platelet serotonin uptake. Cardiovascular outcomes were assessed at 12-month follow-up. RESULTS: One third of enrolled participants had at least minimal depressive symptoms and 13.6% had major depressive disorder. Depressed cardiovascular patients had significantly higher incidence of major (odds ratio = 3.43, 95% confidence interval = 1.49-7.91, p = .004) and minor (odds ratio = 2.42, 95% confidence interval = 1.41-4.13, p = .001) adverse cardiac events. Platelet serotonin response was not significantly different in patients with depression. Participants with major depressive disorder had higher serotonin receptor density (997.5 ± 840.8 vs 619.3 ± 744.3 fmol/ug, p = .009) primarily found in ACS patients. Depressed patients with minor adverse cardiac events had increased platelet response to serotonin. CONCLUSIONS: Depressed cardiovascular patients had higher serotonin receptor density and significantly higher incidence of major and minor cardiac adverse events. Future studies with larger sample sizes including patients with more severe depression are needed to expand on the present hypothesis-generating findings.

8.
Circulation ; 139(5): 620-635, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30586737

RESUMO

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. RESULTS: We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

9.
Front Genet ; 9: 466, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30369944

RESUMO

Background: Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). Methods and Results: We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing (P < 4.13 × 10-7). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, FLJ16686). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near PARP8 (rs2961831, P = 6.39 × 10-9). In the replication study, we found a signal at rs4607517 near GCK/YKT6 (P = 0.01). Variants near candidate diabetes genes (especially GCK and KCNQ1) were also nominally associated with HOMA-IR and cHOMA-B. Conclusion: We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at KCNQ2, CTNAA2, and KCNQ1with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30297127

RESUMO

BACKGROUND: Sex differences in the incidence and manifestation of cardiovascular disease (CVD) suggest the involvement of sex hormones in disease pathogenesis. Coronary artery calcium (CAC) and its progression, measured by non-contrast cardiac computed tomography, are markers of subclinical atherosclerosis and predict CVD, even among low-risk women. We hypothesized that sex hormone levels were associated with CAC progression among women in the Multi-Ethnic Study of Atherosclerosis. METHODS: We studied 2759 post-menopausal women (age 65 ± 9 years), free of baseline CVD, with baseline serum sex hormones and CAC measured at Exam 1 (2000-2002). Of this sample, 2427 had ≥1 follow-up CAC measurement through Exam 5 (2010-2012). Using mixed effects linear regression methods, we tested change in log[CAC+1] score by log[sex hormone] levels (continuous, comparing the 90th versus 10th percentiles). Models adjusted for demographics, lifestyle factors, cardiovascular risk factors, hormone therapy, and years since menopause. RESULTS: At baseline, we found no associations between sex hormones and prevalent CAC. Over a median of 4.7 years, in fully-adjusted models, women with higher free testosterone levels had relatively greater CAC progression [Ratio 1.26 (95% CI 1.01-1.56)], whereas higher sex hormone binding globulin (SHBG) was associated with lower progression risk [0.80 (0.64-0.99). No associations were seen for total testosterone, estradiol, or dehydroepiandrosterone. CONCLUSION: A more androgenic hormone profile of higher free testosterone and lower SHBG is associated with a greater CAC progression up to 10-years in post-menopausal women. Sex hormone levels may help identify women at increased risk for CVD who may benefit from additional risk-reducing strategies.

11.
J Clin Endocrinol Metab ; 103(12): 4599-4608, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30265320

RESUMO

Context: Previous studies have suggested less cardioprotective benefit of aspirin in adults with diabetes, raising concerns about "aspirin resistance" and potentially reduced effectiveness for prevention of cardiovascular disease (CVD). Objective: To examine differences in platelet response to aspirin by diabetes status. Design, Setting, Participants: We examined platelet response before and after aspirin (81 mg/day for 14 days) in 2113 adults (175 with diabetes, 1,938 without diabetes), in the Genetic Study of Aspirin Responsiveness cohort, who had family history of early-onset CVD. Main Outcome Measures: In vivo platelet activation (urinary thromboxane B2), in vitro platelet aggregation to agonists (arachidonic acid, adenosine diphosphate, collagen), and platelet function analyzer-100 closure time. Results: Although adults with diabetes had higher in vivo platelet activation before aspirin, the reduction in in vivo platelet activation after aspirin was similar in those with vs without diabetes. Likewise, the reduction in multiple in vitro platelet measures was similar after aspirin by diabetes status. In regression analyses adjusted for age, sex, race, BMI, smoking, platelet counts, and fibrinogen levels, in vivo platelet activation remained higher in adults with vs without diabetes after aspirin (P = 0.04), but this difference was attenuated after additional adjustment for preaspirin levels (P = 0.10). No differences by diabetes status were noted for any of the in vitro platelet measures after aspirin in fully adjusted models that also accounted for preaspirin levels. Conclusions: In vitro platelet response to aspirin does not differ by diabetes status, suggesting no intrinsic differences in platelet response to aspirin. Instead, factors extrinsic to platelet function should be investigated to give further insights into aspirin use for primary prevention in diabetes.

12.
J Clin Endocrinol Metab ; 103(11): 4304-4314, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137406

RESUMO

Context: Sex hormones may influence sex differences in cardiovascular disease (CVD). N-terminal pro-B-type natriuretic peptide (NT-proBNP), a predictor of CVD, is higher in women than men, which may relate to sex hormones. Objective: To evaluate whether total testosterone (T), bioavailable T, free T, estradiol, dehydroepiandrosterone (DHEA), and SHBG are associated with NT-proBNP. Design: Cohort study. Participants: Cross-sectional sample included 2371 postmenopausal women and 2688 men free of CVD, of which 2041 women and 2348 men were included longitudinally. Main Outcome Measures: NT-proBNP at baseline (2000 to 2002) and one or more repeat NT-proBNPs (through 2012). Analyses adjusted for CVD risk factors. Results: Women had higher NT-proBNP than men (median 79.9 vs 38.5 pg/mL). Cross-sectionally, higher bioavailable T, free T, DHEA, and lower SHBG levels were independently associated with lower NT-proBNP among both women and men (all P < 0.05). Higher total T in women and estradiol in men were also associated with lower NT-proBNP (both P < 0.05). Longitudinally, in women, higher total T, bioavailable T, free T, DHEA, and lower estradiol and SHBG were associated with greater 10-year increase in NT-proBNP (all P < 0.05). In men, higher free T and estradiol were associated with greater NT-proBNP increase (both P < 0.05). Conclusions: A more androgenic sex hormone pattern was inversely associated with NT-proBNP cross-sectionally and may contribute to sex differences in NT-proBNP. Longitudinally, a more androgenic sex hormone pattern was associated with greater increase in NT-proBNP in women, which may reflect a mechanism for CVD risk after menopause.

13.
PLoS One ; 13(7): e0200486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044860

RESUMO

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

14.
J Am Coll Cardiol ; 72(1): 1-11, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29957219

RESUMO

BACKGROUND: Pre-eclampsia with severe features (PEC) is a pregnancy-specific syndrome characterized by severe hypertension and end-organ dysfunction, and is associated with short-term adverse cardiovascular events, including heart failure, pulmonary edema, and stroke. OBJECTIVES: The authors aimed to characterize the short-term echocardiographic, clinical, and laboratory changes in women with PEC, focusing on right ventricular (RV) systolic pressure (RVSP) and echocardiographic-derived diastolic, systolic, and speckle tracking parameters. METHODS: In this prospective observational study, the authors recruited 63 women with PEC and 36 pregnant control patients. RESULTS: The PEC cohort had higher RVSP (31.0 ± 7.9 mm Hg vs. 22.5 ± 6.1 mm Hg; p < 0.001) and decreased global RV longitudinal systolic strain (RVLSS) (-19.6 ± 3.2% vs. -23.8 ± 2.9% [p < 0.0001]) when compared with the control cohort. For left-sided cardiac parameters, there were differences (p < 0.001) in mitral septal e' velocity (9.6 ± 2.4 cm/s vs. 11.6 ± 1.9 cm/s), septal E/e' ratio (10.8 ± 2.8 vs. 7.4 ± 1.6), left atrial area size (20.1 ± 3.8 cm2 vs. 17.3 ± 2.9 cm2), and posterior and septal wall thickness (median [interquartile range]: 1.0 cm [0.9 to 1.1 cm] vs. 0.8 cm [0.7 to 0.9 cm], and 1.0 cm [0.8 to 1.2 cm] vs. 0.8 cm [0.7 to 0.9 cm]). Eight women (12.7%) with PEC had grade II diastolic dysfunction, and 6 women (9.5%) had peripartum pulmonary edema. CONCLUSIONS: Women with PEC have higher RVSP, higher rates of abnormal diastolic function, decreased global RVLSS, increased left-sided chamber remodeling, and higher rates of peripartum pulmonary edema, when compared with healthy pregnant women.

15.
Artigo em Inglês | MEDLINE | ID: mdl-29874848

RESUMO

We investigated the effect of candidate variants in AS3MT (arsenic (III) methyltransferase) with urinary arsenic metabolites and their principal components in a subset of 264 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Urinary arsenic species, including inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), and arsenobetaine (Ab), were measured using high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS) and corrected for organic sources from seafood consumption by regressing Ab on arsenic species using a validated method. Principal components of arsenic metabolism were also used as independent phenotypes. We conducted linear regression of arsenic traits with allelic dosage of candidate single nucleotide polymorphisms (SNPs) rs12768205 (G > A), rs3740394 (A > G), and rs3740393 (G > C) measured using Illumina MetaboChip. Models were stratified by non-Hispanic white vs. all other race/ethnicity and adjusted for age, sex, arsenic exposure, study site, and population stratification. Consistent with previous studies, rs12768205 showed evidence for strongest association (non-Hispanic white: iAs% -0.14 (P 0.83), MMA% -0.66 (0.49), DMA% 0.81(0.49); other race/ethnicity: 0.13 (0.71), -1.21 (0.09), 1.08 (0.20)). No association, however, passed the strict Bonferroni p-value. This was a novel study among an ethnically diverse population exposed to low arsenic levels.

16.
Diabetes Metab ; 2018 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-29875064

RESUMO

AIM: Type 2 diabetes (T2DM) in a first-degree relative is a risk factor for incident diabetes. Americans of African ancestry (AA) have higher rates of T2DM than Americans of European ancestry (EA). Thus, we aimed to determine whether the presence, number and kinship of affected relatives are associated with race-specific T2DM incidence in a prospective study of participants from the Genetic Study of Atherosclerosis Risk (GeneSTAR), who underwent baseline screening including a detailed family history. METHODS: Nondiabetic healthy siblings (n=1405) of patients with early-onset coronary artery disease (18-59 years) were enrolled (861 EA and 544 AA) and followed for incident T2DM (mean 14±6 years). RESULTS: Baseline age was 46.2±7.3 years and 56% were female. T2DM occurred in 12.3% of EA and 19.1% of AA. Among EA, 32.6% had ≥1 affected first-degree relatives versus 53.1% in AA, P<0.0001. In fully adjusted Cox proportional hazard analyses, any family history was related to incident T2DM in EA (HR=2.53, 95% CI: 1.58-4.06) but not in AA (HR=1.01, 0.67-1.53). The number of affected relatives conferred incremental risk of T2DM in EA with HR=1.82 (1.08-3.06), 4.83 (2.15-10.85) and 8.46 (3.09-23.91) for 1, 2, and ≥3 affected, respectively. In AA only ≥3 affected increased risk (HR=2.45, 1.44-4.19). Specific kinship patterns were associated with incident T2DM in EA but not in AA. CONCLUSIONS: The presence of any first-degree relative with T2DM does not discriminate risk in AA given the high race-specific prevalence of diabetes. Accounting for the number of affected relatives may more appropriately estimate risk for incident diabetes in both races.

17.
J Am Coll Cardiol ; 71(22): 2555-2566, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29852978

RESUMO

BACKGROUND: Higher androgen and lower estrogen levels are associated with cardiovascular disease (CVD) risk factors in women. However, studies on sex hormones and incident CVD events in women have yielded conflicting results. OBJECTIVES: The authors assessed the associations of sex hormone levels with incident CVD, coronary heart disease (CHD), and heart failure (HF) events among women without CVD at baseline. METHODS: The authors studied 2,834 post-menopausal women participating in the MESA (Multi-Ethnic Study of Atherosclerosis) with testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG) levels measured at baseline (2000 to 2002). They used Cox hazard models to evaluate associations of sex hormones with each outcome, adjusting for demographics, CVD risk factors, and hormone therapy use. RESULTS: The mean age was 64.9 ± 8.9 years. During 12.1 years of follow-up, 283 CVD, 171 CHD, and 103 HF incident events occurred. In multivariable-adjusted models, the hazard ratio (95% confidence interval [CI]) associated with 1 SD greater log-transformed sex hormone level for the respective outcomes of CVD, CHD, and HF were as follows: total testosterone: 1.14 (95% CI: 1.01 to 1.29), 1.20 (95% CI: 1.03 to 1.40), 1.09 (95% CI: 0.90 to 1.34); estradiol: 0.94 (95% CI: 0.80 to 1.11), 0.77 (95% CI: 0.63 to 0.95), 0.78 (95% CI: 0.60 to 1.02); and testosterone/estradiol ratio: 1.19 (95% CI: 1.02 to 1.40), 1.45 (95% CI: 1.19 to 1.78), 1.31 (95% CI: 1.01 to 1.70). Dehydroepiandrosterone and SHBG levels were not associated with these outcomes. CONCLUSIONS: Among post-menopausal women, a higher testosterone/estradiol ratio was associated with an elevated risk for incident CVD, CHD, and HF events, higher levels of testosterone associated with increased CVD and CHD, whereas higher estradiol levels were associated with a lower CHD risk. Sex hormone levels after menopause are associated with women's increased CVD risk later in life.

18.
Artigo em Inglês | MEDLINE | ID: mdl-29795237

RESUMO

Differences in residential location as well as race/ethnicity and dietary habits may result in differences in inorganic arsenic (iAs) exposure. We investigated the association of exposure to iAs with race/ethnicity, geography, and dietary intake in a random sample of 310 White, Black, Hispanic, and Chinese adults in the Multi-Ethnic Study of Atherosclerosis from 6 US cities with inorganic and methylated arsenic (ΣAs) measured in urine. Dietary intake was assessed by food-frequency questionnaire. Chinese and Hispanic race/ethnicity was associated with 82% (95% CI: 46%, 126%) and 37% (95% CI: 10%, 70%) higher urine arsenic concentrations, respectively, compared to White participants. No differences were observed for Black participants compared to Whites. Urine arsenic concentrations were higher for participants in Los Angeles, Chicago, and New York compared to other sites. Participants that ate rice ≥2 times/week had 31% higher urine arsenic compared to those that rarely/never consumed rice. Participants that drank wine ≥2 times/week had 23% higher urine arsenic compared to rare/never wine drinkers. Intake of poultry or non-rice grains was not associated with urinary arsenic concentrations. At the low-moderate levels typical of the US population, exposure to iAs differed by race/ethnicity, geographic location, and frequency of rice and wine intake.

19.
J Eval Clin Pract ; 24(4): 713-717, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29797761

RESUMO

PURPOSE: "Attending rotations" on intensive care unit (ICU) services have been in place in most teaching hospitals for decades. However, the ideal frequency of patient care handoffs is unknown. Frequent attending physician handoffs could result in delays in care and other complications, while too few handoffs can lead to provider burnout and exhaustion. Therefore, we sought to determine the correlation between frequency of attending shifts with ICU charges, 30-day readmission rates, and mortality rates. METHODS: We performed a retrospective cohort study at a large, urban, academic community hospital in Baltimore, MD. We included patients admitted into the cardiac or medical ICUs between September 1, 2012, and December 10, 2015. We tracked the number of attending shifts for each patient and correlated shifts with financial outcomes as a primary measure. RESULTS: For any given ICU length of stay, we found no distinct association between handoff frequency and charges, 30-day readmission rates, or mortality rates. CONCLUSIONS: Despite frequent handoffs in care, there was no objective evidence of care compromise or differences in cost. Further validation of these observations in a larger cohort is justified.

20.
AJR Am J Roentgenol ; 211(1): W52-W63, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29792743

RESUMO

OBJECTIVE: The purpose of this study is to determine the diagnostic performance of MRI and MR arthrography for depicting ligamentum teres lesions. MATERIALS AND METHODS: A literature search was performed. Original studies reporting the diagnostic accuracy of MRI examinations for the depiction of ligamentum teres lesions were included. RESULTS: Eight studies entailing 1456 MRI examinations were included (frequency of median ligamentum teres injury, 25.9%; interquartile range, 14.1-45.3%). Two studies reported the results of unenhanced MRI examinations, and their diagnostic performance could not be estimated. Sensitivity, specificity, and diagnostic odds ratio (DOR) of all MRI examinations were 64.7%, 86.9%, and 12.2, respectively, whereas the sensitivity, specificity, and DOR of MR arthrography examinations were 82.2%, 88.6%, and 35.9, respectively. The heterogeneity (I2) for all MRI and MR arthrography examinations was 92.3% and 88.2%, respectively. Five blinded MR arthrography studies with 643 MR arthrography examinations found an appropriate threshold effect for summary ROC construction (AUC, 0.95). The summary estimate of these studies yielded a sensitivity of 87.8%, a specificity of 91%, and DOR of 73.1. The heterogeneity (I2) for this group was 64.3%. In patients with low pretest probability (25%), MR arthrography enabled the exclusion of ligamentum teres lesion (postprobability for a negative result, 4%; negative likelihood ratio, 0.13). CONCLUSION: MR arthrography can depict ligamentum teres lesions with high accuracy. However, its diagnostic performance for differentiating various types of ligamentum teres lesions (partial, complete ligamentum teres tears, and hypertrophic ligamentum teres), as well as the diagnostic performance of unenhanced MRI for the depiction of ligamentum teres lesions, is yet to be determined because of the paucity of reported data in the literature.

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