Brachial Artery Constriction during Brachial Artery Reactivity Testing Predicts Major Adverse Clinical Outcomes in Women with Suspected Myocardial Ischemia: Results from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study

Background:Limited brachial artery (BA) flow-mediated dilation during brachial artery reactivity testing (BART) has been linked to increased cardiovascular risk. We report on the phenomenon of BA constriction (BAC) following hyperemia.Objectives:To determine whether BAC predicts adverse CV outcomes and/or mortality in the women's ischemic Syndrome Evaluation Study (WISE). Further, as a secondary objective we sought to determine the risk factors associated with BAC.Methods:We performed BART on 377 women with chest pain referred for coronary angiography and followed for a median of 9.5 years. Forearm ischemia was induced with 4 minutes occlusion by a cuff placed distal to the BA and inflated to 40mm Hg > systolic pressure. BAC was defined as >4.8% artery constriction following release of the cuff. The main outcome was major adverse events (MACE) including all-cause mortality, non-fatal MI, non-fatal stroke, or hospitalization for heart failure.Results:BA diameter change ranged from -20.6% to +44.9%, and 41 (11%) women experienced BAC. Obstructive CAD and traditional CAD risk factors were not predictive of BAC. Overall, 39% of women with BAC experienced MACE vs. 22% without BAC (p=0.004). In multivariate Cox proportional hazards regression, BAC was a significant independent predictor of MACE (p=0.018) when adjusting for obstructive CAD and traditional risk factors.Conclusions:BAC predicts almost double the risk for major adverse events compared to patients without BAC. This risk was not accounted for by CAD or traditional risk factors. The novel risk marker of BAC requires further investigation in women. © 2013 Sedlak et al

Comparison of SWAN and WISE Menopausal Status Classification Algorithms

Background: Classification of menopausal status is important for epidemiological and clinical studies as well as for clinicians treating midlife women. Most epidemiological studies, including the Study of Women's Health Across the Nation (SWAN), classify women based on self-reported bleeding history. Methods: The Women's Ischemia Syndrome Evaluation (WISE) study developed an algorithm using menstrual and reproductive history and serum hormone levels to reproduce the menopausal status classifications assigned by the WISE hormone committee. We applied that algorithm to women participating in SWAN and examined characteristics of women with concordant and discordant SWAN and WISE classifications. Results: Of the 3215 SWAN women with complete information at baseline (1995–1997), 2466 (76.7%) received concordant classifications (kappa = 0.52); at the fifth annual follow-up visit, of the 1623 women with complete information, 1154 (72.7%) received concordant classifications (kappa = 0.57). At each time point, we identified subgroups of women with discordant SWAN and WISE classifications. These subgroups, ordered by chronological age, showed increasing trends for menopausal symptoms and follicle-stimulating hormone (FSH) and a decreasing trend for estrogen (p < 0.001). Conclusions: The WISE algorithm is a useful tool for studies that have access to blood samples for hormone data unrelated to menstrual cycle phase, with or without an intact uterus, and no resources for adjudication. Future studies may want to combine aspects of the SWAN and WISE algorithms by adding hormonal measures to the series of bleeding questions in order to determine more precisely where women are in the perimenopausal continuum.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63232/1/jwh.2006.15.1184.pd

Adrenergic gene polymorphisms and cardiovascular risk in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation

<p>Abstract</p> <p>Background</p> <p>Adrenergic gene polymorphisms are associated with cardiovascular and metabolic phenotypes. We investigated the influence of adrenergic gene polymorphisms on cardiovascular risk in women with suspected myocardial ischemia.</p> <p>Methods</p> <p>We genotyped 628 women referred for coronary angiography for eight polymorphisms in the α_1A-, β₁-, β₂- and β₃-adrenergic receptors (<it>ADRA1A</it>, <it>ADRB1, ADRB2</it>, <it>ADRB3</it>, respectively), and their signaling proteins, G-protein β 3 subunit (<it>GNB3</it>) and G-protein α subunit (<it>GNAS</it>). We compared the incidence of death, myocardial infarction, stroke, or heart failure between genotype groups in all women and women without obstructive coronary stenoses.</p> <p>Results</p> <p>After a median of 5.8 years of follow-up, 115 women had an event. Patients with the <it>ADRB1 </it>Gly389 polymorphism were at higher risk for the composite outcome due to higher rates of myocardial infarction (adjusted hazard ratio [HR] 3.63, 95% confidence interval [95%CI] 1.17–11.28; Gly/Gly vs. Arg/Arg HR 4.14, 95%CI 0.88–19.6). The risk associated with <it>ADRB1 </it>Gly389 was limited to those without obstructive CAD (n = 400, P_interaction= 0.03), albeit marginally significant in this subset (HR 1.71, 95%CI 0.91–3.19). Additionally, women without obstructive CAD carrying the <it>ADRB3 </it>Arg64 variant were at higher risk for the composite endpoint (HR 2.10, 95%CI 1.05–4.24) due to subtle increases in risk for all of the individual endpoints. No genetic associations were present in women with obstructive CAD.</p> <p>Conclusion</p> <p>In this exploratory analysis, common coding polymorphisms in the β₁- and β₃-adrenergic receptors increased cardiovascular risk in women referred for diagnostic angiography, and could improve risk assessment, particularly for women without evidence of obstructive CAD.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00000554.</p

The epidemic of extended-spectrum-beta-lactamase-producing Escherichia coli ST131 is driven by a single highly pathogenic subclone, H30-Rx

The Escherichia coli sequence type 131 (ST131) clone is notorious for extraintestinal infections, fluoroquinolone resistance, and extended-spectrum beta-lactamase (ESBL) production, attributable to a CTX-M-15-encoding mobile element. Here, we applied pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing to reconstruct the evolutionary history of the ST131 clone. PFGE-based cluster analyses suggested that both fluoroquinolone resistance and ESBL production had been acquired by multiple ST131 sublineages through independent genetic events. In contrast, the more robust whole-genome-sequence-based phylogenomic analysis revealed that fluoroquinolone resistance was confined almost entirely to a single, rapidly expanding ST131 subclone, designated H30-R. Strikingly, 91% of the CTX-M-15-producing isolates also belonged to a single, well-defined clade nested within H30-R, which was named H30-Rx due to its more extensive resistance. Despite its tight clonal relationship with H30Rx, the CTX-M-15 mobile element was inserted variably in plasmid and chromosomal locations within the H30-Rx genome. Screening of a large collection of recent clinical E. coli isolates both confirmed the global clonal expansion of H30-Rx and revealed its disproportionate association with sepsis (relative risk, 7.5; P < 0.001). Together, these results suggest that the high prevalence of CTX-M-15 production among ST131 isolates is due primarily to the expansion of a single, highly virulent subclone, H30-Rx. IMPORTANCE We applied an advanced genomic approach to study the recent evolutionary history of one of the most important Escherichia coli strains in circulation today. This strain, called sequence type 131 (ST131), causes multidrug-resistant bladder, kidney, and bloodstream infections around the world. The rising prevalence of antibiotic resistance in E. coli is making these infections more difficult to treat and is leading to increased mortality. Past studies suggested that many different ST131 strains gained resistance to extended-spectrum cephalosporins independently. In contrast, our research indicates that most extended-spectrum-cephalosporin-resistant ST131 strains belong to a single highly pathogenic subclone, called H30-Rx. The clonal nature of H30-Rx may provide opportunities for vaccine or transmission prevention-based control strategies, which could gain importance as H30-Rx and other extraintestinal pathogenic E. coli subclones become resistant to our best antibiotics

The epidemic of extended-spectrum-β-lactamase-producing Escherichia coli ST131 is driven by a single highly pathogenic subclone, H30-Rx

The Escherichia coli sequence type 131 (ST131) clone is notorious for extraintestinal infections, fluoroquinolone resistance, and extended-spectrum beta-lactamase (ESBL) production, attributable to a CTX-M-15-encoding mobile element. Here, we applied pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing to reconstruct the evolutionary history of the ST131 clone. PFGE-based cluster analyses suggested that both fluoroquinolone resistance and ESBL production had been acquired by multiple ST131 sublineages through independent genetic events. In contrast, the more robust whole-genome-sequence-based phylogenomic analysis revealed that fluoroquinolone resistance was confined almost entirely to a single, rapidly expanding ST131 subclone, designated H30-R. Strikingly, 91% of the CTX-M-15-producing isolates also belonged to a single, well-defined clade nested within H30-R, which was namedH30-Rx due to its more extensive resistance. Despite its tight clonal relationship with H30Rx, the CTX-M-15 mobile element was inserted variably in plasmid and chromosomal locations within the H30-Rx genome. Screening of a large collection of recent clinical E. coli isolates both confirmed the global clonal expansion of H30-Rx and revealed its disproportionate association with sepsis (relative risk, 7.5; P \u3c 0.001). Together, these results suggest that the high prevalence of CTX-M-15 production among ST131 isolates is due primarily to the expansion of a single, highly virulent subclone, H30-Rx

Safety of Coronary Reactivity Testing in Women With No Obstructive Coronary Artery Disease Results From the NHLBI-Sponsored WISE (Women's Ischemia Syndrome Evaluation) Study

ObjectivesThis study evaluated the safety of coronary reactivity testing (CRT) in symptomatic women with evidence of myocardial ischemia and no obstructive coronary artery disease (CAD).BackgroundMicrovascular coronary dysfunction (MCD) in women with no obstructive CAD portends an adverse prognosis of a 2.5% annual major adverse cardiovascular event (MACE) rate. The diagnosis of MCD is established by invasive CRT, yet the risk of CRT is unknown.MethodsThe authors evaluated 293 symptomatic women with ischemia and no obstructive CAD, who underwent CRT at 3 experienced centers. Microvascular function was assessed using a Doppler wire and injections of adenosine, acetylcholine, and nitroglycerin into the left coronary artery. CRT-related serious adverse events (SAEs), adverse events (AEs), and follow-up MACE (death, nonfatal myocardial infarction [MI], nonfatal stroke, or hospitalization for heart failure) were recorded.ResultsCRT-SAEs occurred in 2 women (0.7%) during the procedure: 1 had coronary artery dissection, and 1 developed MI associated with coronary spasm. CRT-AEs occurred in 2 women (0.7%) and included 1 transient air microembolism and 1 deep venous thrombosis. There was no CRT-related mortality. In the mean follow-up period of 5.4 years, the MACE rate was 8.2%, including 5 deaths (1.7%), 8 nonfatal MIs (2.7%), 8 nonfatal strokes (2.7%), and 11 hospitalizations for heart failure (3.8%).ConclusionsIn women undergoing CRT for suspected MCD, contemporary testing carries a relatively low risk compared with the MACE rate in these women. These results support the use of CRT by experienced operators for establishing definitive diagnosis and assessing prognosis in this at-risk population. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00832702

Bio-informatics assessment schema (BIAS) to improve myocardial perfusion image diagnostic and prognostic value: the NHLBI-sponsored women's ischemia syndrome evaluation (WISE) study

Introduction: When assessing myocardial perfusion image (MPI) data for diagnosis or prediction of prognosis it is common to evaluate the technology using a Receiver-Operator Characteristic (ROC) curve. The diagonal response represents the knowledge prior to conducting the test (i.e. the diagonal represents random chance). We present an approach termed Bio-Informatics Assessment Schema (BIAS) that provides an elevated baseline from which to evaluate the MPI reading, i.e. indicating that at baseline, more data is available than random chance. Here we describe how the BIAS formulae are generated for cardiovascular magnetic resonance image (CMRI) data applied to the Women's Ischemia Syndrome Evaluation (WISE) Study

Glacial to Holocene swings of the Australian–Indonesian monsoon

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Geoscience 4 (2011): 540–544, doi:10.1038/ngeo1209.The Australian-Indonesian monsoon is an important component of the climate system in the tropical Indo-Pacific region. However, its past variability, relation with northern and southern high latitude climate and connection to the other Asian monsoon systems are poorly understood. Here we present high-resolution records of monsoon-controlled austral winter upwelling during the past 22,000 years, based on planktic foraminiferal oxygen isotope and faunal composition in a sedimentary archive collected offshore southern Java. We show that glacial-interglacial variations in the Australian-Indonesian winter monsoon were in phase with the Indian summer monsoon system, consistent with their modern linkage through cross-equatorial surface winds. Likewise, millennial-scale variability of upwelling shares similar sign and timing with upwelling variability in the Arabian Sea. On the basis of element composition and grain-size distribution as precipitation-sensitive proxies in the same archive, we infer that (austral) summer monsoon rainfall was highest during the Bølling-Allerød period and the past 2,500 years. Our results indicate drier conditions during Heinrich Stadial 1 due to a southward shift of summer rainfall and a relatively weak Hadley Cell south of the Equator. We suggest that the Australian-Indonesian summer and winter monsoon variability were closely linked to summer insolation and abrupt climate changes in the northern hemisphere.This study was funded by the German Bundesministerium für Bildung und Forschung (PABESIA) and the Deutsche Forschungsgemeinschaft (DFG, HE 3412/15-1). DWO’s participation was funded by the U.S. National Science Foundation