Rationale: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined.Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA.Methods: Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (>3). Replication of a multivariable model was performed with data from the SARP-1 1 2 cohort.Measurements and Main Results: Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval],

Background Severe asthma is a complex heterogeneous disease associated with older age and obesity. The presence of eosinophilic (type 2) inflammation in some but not all patients with severe asthma predicts responsiveness to current treatments, but new treatment approaches will require better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation - which occurs in subgroups of obese and older patients - modifies asthma to make it worse. Interleukin 6 (IL6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the relationship between IL6, metabolic dysfunction, and asthma severity. Methods We generated a reference range in health for plasma IL6 in a cohort of healthy controls (n=93). We compared the clinical characteristics of asthmatics with plasma IL6 levels below and above the upper limit of normal (“IL6 low” and “IL-high” asthma) in two asthma cohorts - predominantly non-severe asthmatics recruited at the University of California San Francisco (UCSF)(n=249) and predominantly severe asthmatics recruited by the Severe Asthma Research Program (SARP)(n=387). Findings The upper 95th centile value for plasma IL6 in the healthy cohort was 3·1pg/mL, and 14% of UCSF cohort and 26% of the SARP cohort had plasma IL6 levels above this upper limit. The “IL6-high” patients in both asthma cohorts had a significantly higher body mass index and a higher prevalence of metabolic disease than the IL6-low patients (all p values < 0.01). IL6-high patients also had significantly lower lung function and more frequent asthma exacerbations than IL6-low patients (all p values < 0·01). Although 75% of IL6-high asthmatics were obese, 63% of obese patients were IL6-low. Among obese patients, the forced expired volume in one second (FEV1) was significantly lower in IL6-high than in IL6-low patients (mean FEV1 70·8 [S.D. 19·5] vs. 78·1 [19·7] % predicted, p = 0·002), and the percentage of patients reporting an asthma exacerbation in the past 1-2 years was higher in IL6-high than in IL6-low patients (66 vs. 48%, p = 0·003). Among non-obese asthmatics, FEV1% and asthma exacerbation outcomes were also significantly worse in IL6-high than in IL6-low patients (mean FEV1 66·4 [SD 23·1] vs. 83·2 [20·4] % predicted, p< 0·01; 59 vs. 34 %, p=0·008). Interpretation Systemic IL6 inflammation and clinical features of metabolic dysfunction - occurring most commonly among a subset of obese asthmatics but also in a small subset of non-obese patients - is associated with more severe asthma. IL6 inhibitors or treatments that improve metabolic dysfunction represent rational clinical trials to pursue for a subset of patients with severe asthma, and plasma IL6 is a biomarker that could guide patient stratification.

Recent advances in omics technologies have led to unprecedented efforts characterizing the molecular changes that underlie the development and progression of a wide array of complex human diseases, including cancer. As a result, multi-omics analyses—which take advantage of these technologies in genomics, transcriptomics, epigenomics, proteomics, metabolomics, and other omics areas—have been proposed and heralded as the key to advancing precision medicine in the clinic. In the field of precision oncology, genomics approaches, and, more recently, other omics analyses have helped reveal several key mechanisms in cancer development, treatment resistance, and recurrence risk, and several of these findings have been implemented in clinical oncology to help guide treatment decisions. However, truly integrated multi-omics analyses have not been applied widely, preventing further advances in precision medicine. Additional efforts are needed to develop the analytical infrastructure necessary to generate, analyze, and annotate multi-omics data effectively to inform precision medicine-based decision-making.

Background-The estrogen receptor-␣ (ER-␣) IVS1-401 polymorphism identifies a group of women (Ϸ20%) who have augmented effects of hormone replacement therapy (HRT) on levels of HDL cholesterol. This study sought to determine if this augmentation extends to HRT regulation of E-selectin and C-reactive protein (CRP) and to explore possible mechanisms by which this polymorphism might influence estrogen action. Methods and Results-Serum levels of soluble E-selectin and CRP were measured at baseline and 1 year in 264 postmenopausal women randomized to treatment with oral conjugated equine estrogen (0.625 mg/d), estrogen plus progestin (medroxyprogesterone acetate 2.5 mg/d), or placebo. Women with the ER-␣ IVS1-401 C/C genotype receiving HRT had nearly a 2-fold greater reduction in E-selectin compared with C/T or T/T women (P for interactionϭ0.02). In contrast, there was no augmentation of the HRT-associated increase in CRP among the C/C women compared with C/T or T/T women (P for interactionϭ0.54). Of luciferase reporter constructs containing sequences spanning the IVS1-401 T/C polymorphism, expression of the construct containing the C allele was enhanced Ͼ10-fold, with cotransfection of a constitutively expressed B-myb vector. In contrast, B-myb resulted in only a 2.5-fold increase in expression of the T allele construct. Key Words: receptors Ⅲ genetics Ⅲ women Ⅲ coronary disease D uring the past several years, 5 randomized clinical trials have reported no effect of hormone replacement therapy (HRT) on clinical or anatomic progression of established atherosclerotic vascular disease. [1][2][3][4][5] One possible explanation for these results is that the benefits of HRT on lipids and endothelial function were offset by previously unrecognized or underemphasized proinflammatory effects. However, among inflammation-related proteins, the effects of oral HRT are somewhat divergent, with consistent evidence of reductions in circulating levels of several soluble adhesion molecules, most notably E-selectin, 6,7 and consistent evidence of increases in C-reactive protein (CRP). 8 -10 Ultimately, the cardiovascular effects of HRT may depend in large measure on the relative balance of these beneficial and adverse effects of HRT on inflammation. Recently, data have emerged indicating that the human estrogen receptor-␣ (ER-␣) IVS1-401 T/C and other closely linked polymorphisms may augment estrogen action with respect to regulation of HDL cholesterol. 11 The purpose of this study was to determine the extent to which this drug-gene interaction influences HRT regulation of E-selectin and CRP and to explore potential mechanisms for augmented estrogen action with this polymorphism. Conclusions-Women MethodsWe used the specimens collected from participants in the Estrogen Replacement and Atherosclerosis (ERA) trial, an angiographic end point trial of unopposed estrogen (conjugated equine estrogen 0.625 mg/d), estrogen plus progestin (medroxyprogesterone acetate [MPA] 2.5 mg/d orally), or placebo in 309 women with established coronary dis...