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Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4

OBJECTIVE We examined users' preferences for and engagement with text messages delivered as part of an emergency department (ED)-based intervention to improve antihypertensive medication adherence. METHODS We recruited ED patients with elevated blood pressure for a pilot randomized trial evaluating a medication adherence intervention with text messages. Intervention participants chose text content and frequency, received texts for 45 days, and completed a feedback survey. We defined engagement via responses to texts. We examined participant characteristics associated with text preferences, engagement, and feedback. RESULTS Participants (N = 101) were 57% female and 46% non-White. Most participants (71%) chose to receive both reminder and informational texts; 94% chose reminder texts once per day and 97% chose informational texts three times per week. Median text message response rate was 56% (IQR 26-80%). Participants who were Black (p

Among acute heart failure (AHF) inpatients, right ventricular dysfunction (RVD) predicts clinical outcomes independent of left ventricular (LV) dysfunction. Prior studies have not accounted for congestion severity, show conflicting findings on echocardiography (echo) timing, and excluded emergency department (ED) patients. We describe for the first time the epidemiology, predictors, and outcomes of RVD in AHF starting with earliest ED treatment.Point-of-care echo and 10-point lung ultrasound (LUS) were obtained in 84 prospectively enrolled AHF patients at two EDs, ≤1 h after first intravenous diuresis, vasodilator, and/or positive pressure ventilation (PPV). Echo and LUS were repeated at 24, 72, and 168 h, unless discharged sooner (n = 197 exams). RVD was defined as17 mm tricuspid annulus plane systolic excursion (TAPSE), our primary measure. To identify correlates of RVD, a multivariable linear mixed model (LMM) of TAPSE through time was fit. Possible predictors were specified a priori and/or with p ≤ 0.1 difference between patients with/without RVD. Data were standardized and centered to facilitate comparison of relative strength of association between predictors of TAPSE. Survival curves for a 30-day death or AHF readmission primary outcome were assessed for RVD, LUS severity, and LVEF. A multivariable generalized linear mixed model (GLMM) for the outcome was used to adjust RVD for LVEF and LUS.46% (n = 39) of patients at ED arrival showed RVD by TAPSE (median 18 mm, interquartile range 13-23). 18 variables with p ≤ 0.1 unadjusted difference with/without RVD, and 12 a priori predictors of RVD were included in the multivariable LMM model of TAPSE through time (RIn this observational study, RVD was common in AHF, and predicted by congestion on LUS, LVEF, RVSP, and comorbidities from ED arrival through discharge. 30-day death or AHF-rehospitalization was associated with RVD at ED arrival and ΔLUS severity, but not LVEF.

Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, −5.7%; adjusted 95% CI, −8.8% to −2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.

With the Pfizer-BioNTech, Moderna, and now Johnson and Johnson COVID-19 vaccines readily available to the general population, the appearance of vaccine-induced axillary adenopathy on imaging has become more prevalent. We are presenting follow up to the first reported four cases of vaccine induced unilateral axillary adenopathy on imaging to our knowledge, which demonstrate expected self-resolving adenopathy. Our hope is that by providing this follow-up and reviewing current management guidelines, clinicians as well as patients will appreciate that this is an expected, benign, and self-resolving finding. In addition, we hope to quell any vaccine hesitancy brought about by recent mainstream media attention to this topic and ultimately empower patients to receive both the COVID-19 vaccine and undergo routine screening mammography, as both are vital to their health.

Rationale: Standard physiologic assessments of extubation readiness in patients with acute hypoxemic respiratory failure (AHRF) may not reflect lung injury resolution and could adversely affect cli...

Background Combined post- and precapillary pulmonary hypertension (CpcPH) portends poor outcomes in pulmonary hypertension related to left heart disease (PH-LHD). While recent evidence does not support the use of targeted pulmonary arterial hypertension (PAH) therapy in PH-LHD, there is a lack of clinical data on their use in CpcPH. We evaluated the outcomes in patients with CpcPH treated with PAH therapies. Methods Retrospectively, 50 patients meeting hemodynamic criteria of CpcPH and started on PAH-targeted drugs were identified. Fifty age- and gender-matched PAH patients were chosen as controls. We evaluated the change in 6-minute walk distance, World Health Organization functional class (FC), tricuspid annular plane systolic excursion, BNP or NT-proBNP, and pulmonary artery systolic pressure at 3, 6, 12, and 24 months of follow-up. Results After adjusting for age and gender, there was no improvement in World Health Organization FC in CpcPH over 2 years (odds ratio of change to FC I/II 1.01, 95% CI: 0.98-1.04). There was no significant improvement in 6-minute walk distance (β coefficient 0.21, 95% CI: −0.98 to 1.4), reduction in BNP/NT-proBNP (β coefficient −12.16, 95% CI: −30.68 to 6.37), increase in tricuspid annular plane systolic excursion (β coefficient 0.074, 95% CI: 0.010-0.139), or decrease in pulmonary artery systolic pressure (0.996, 95% CI: 0.991-1.011) in CpcPH with therapy. There was higher mortality in CpcPH compared to PAH on treatment (24% vs 4%, P = .003). Conclusions There were no improvements in symptoms, exercise capacity, or echocardiographic parameters with PAH-targeted therapy in CpcPH. Further studies into potential treatments benefiting this population are needed.

Rationale: Some reports indicate longitudinal variability in sputum differential cell counts, whereas others describe stability. Highly variable sputum eosinophil percentages are associated with greater lung function loss than persistently elevated eosinophil percentages, but elevated neutrophils are linked to more severe asthma.Objectives: To examine sputum granulocyte stability or variability longitudinally and associations with important clinical characteristics.Methods: The SARP III (Severe Asthma Research Program III) cohort underwent comprehensive phenotype characterization at baseline and annually over 3 years. Adult subjects with acceptable sputum levels were assigned to one of three longitudinal sputum groups: eosinophils predominantly 2 SDs determined from independent, repeated baseline eosinophil percentages). Subjects were similarly assigned to one of three longitudinal neutrophil groups with a 50% cut point.Measurements and Main Results: The group with predominantly

Objectives Hypertension is one of the most common chronic illnesses among adults in the United States. While poor hypertension control is a risk factor for many emergent conditions, asymptomatic hypertension is rarely an emergency. Despite this, patients may present to the emergency department (ED) with a chief complaint of hypertension, and there may be significant variability in the management of these patients. Our objective was to characterize national trends in ED visits for chief complaint of hypertension between 2006 and 2015. Methods We used the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2006 to 2015 to examine ED visits for chief complaint of hypertension. We examined trends in demographics, diagnostic resource utilization, and clinical management of these patients. Results Between 2006 and 2015, visits with hypertension as the primary chief complaint represented 0.6% of all ED visits, or 6,215,787 national-level ED visits. Of these, 63.9% received a primary diagnosis of hypertension. While there was no significant growth in these visits over the study period, 79.3% of visits received any form of diagnostic testing, with 35.5% of patients receiving an antihypertensive medication. Increasing blood pressure and non-white race were associated with increased odds of receiving antihypertensive medications. Conclusions Despite clinical policies and guidelines recommending against routine diagnostic testing for asymptomatic hypertension, roughly 4 out of 5 ED visits received diagnostic testing, and more than 1 out of 3 received medications. These visits may represent an opportunity for improvement to reduce overutilization, as well as for innovative approaches as EDs expand their role in care coordination across settings.

Combined elevated sputum eosinophils+neutrophils in asthma associated with lowest lung function, greater healthcare utilization, and longitudinally, further spirometric loss, implicating cell-cell interactions or overlapping inflammatory pathways while increased eosinophils or neutrophils alone show less effect.

Author(s): Gordon, Richard D.; Kwon, Nancy S.; Levy, Phillip D.; Madsen, Tracy E.; Greenberg, Marna Rayl | Abstract: On behalf of the ACEP Research CommitteeIntroduction: To study diversity of researchers and barriers to success among Emergency Medicine Foundation (EMF) grant recipients in the last 10 years.Methods: EMF grant awardees were approached to complete a brief survey, which included demographics, queries related to contributions to the literature, success in obtaining grants, and any perceived barriers they encountered.Results: Of the 342 researchers contacted by email, a total of 147 completed the survey for a response rate of 43%. The respondents were predominately mid to late career white-male-heterosexual-Christian with an average age of 44 years (range 25-69 years of age). With regards to training and education, the majority of respondents (50%) were either Associate or Professor clinical rank (8% instructor/resident/fellow and 31% Assistant). Sixty-two percent of the respondents reported perceived barriers to career advancement since completion of residency. The largest perceived barrier to success was medical specialty (26%), followed by gender (21%) and age (16%).Conclusion: Our survey of EMF grant recipients in the last 10 years shows a considerable lack of diversity. The most commonly perceived barriers to career advancement by this cohort were medical specialty, gender, and age. An opportunity exists for further definition of barriers and development of mechanisms to overcome them, with a goal of increased success for those that are underrepresented.

Significance Although resistance to glucocorticoids is a major clinical problem, the underlying mechanisms are unknown. It is known that glucocorticoid use can suppress adrenal androgen production. In population studies, animal models, and cell culture experiments, androgens are associated with several benefits in asthma, but neither androgen use in glucocorticoid-resistant asthma nor the genetic determinants of androgen responsiveness have been studied in humans. A missense-encoding variant in HSD3B1 is known to regulate conversion from adrenal precursors to potent androgens and clinical outcomes in prostate cancer. This is the first genetic evidence to our knowledge that implicates an androgen synthesis variant in resistance to glucocorticoids for asthma or any other inflammatory disease. Furthermore, this study demonstrates an adverse consequence of adrenal androgen suppression with glucocorticoid therapy., Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.

Although lithium is widely used in current practice to treat bipolar disorder (BD) and treatment-resistant major depressive disorder (MDD) among older adults, little is known about its efficacy and tolerability in this population, which is generally excluded from randomized clinical trials. The objective of this study was to evaluate the efficacy and tolerability of long-term use of lithium among older adults with BD and MDD.Data from the Cohort of individuals with Schizophrenia and mood disorders Aged 55 years or more (CSA) were used. Two groups of patients with BD and MDD were compared: those who were currently receiving lithium versus those who were not. The effects of lithium on psychiatric (i.e., depressive symptoms severity, perceived clinical severity, rates of psychiatric admissions in the past-year), geriatric (overall and cognitive functioning) and physical outcomes (i.e., rates of non-psychiatric medical comorbidities and general hospital admissions in the past-year) were evaluated. All analyses were adjusted for age, sex, duration of disorder, diagnosis, smoking status, alcohol use, and use of antipsychotics, antiepileptics or antidepressants.Among the 281 older participants with BD or MDD, 15.7% were taking lithium for a mean duration of 12.5(SD = 11.6) years. Lithium use was associated with lower intensity of depressive symptoms, reduced perceived clinical global severity and lower benzodiazepine use (all p 0.05), without being linked to greater rates of medical comorbidities, except for hypothyroidism.Data were cross-sectional and data on lifetime history of psychotropic medications was not assessed.Our results suggest that long-term lithium use may be efficient and relatively well-tolerated in older adults with BD or treatment-resistant MDD.

This article describes our experience developing a novel mobile health unit (MHU) program in the Detroit, Michigan, metropolitan area. Our main objectives were to improve healthcare accessibility, quality and equity in our community during the novel coronavirus pandemic. While initially focused on SARS-CoV-2 testing, our program quickly evolved to include preventive health services. The MHU program began as a location-based SARS-CoV-2 testing strategy coordinated with local and state public health agencies. Community needs motivated further program expansion to include additional preventive healthcare and social services. MHU deployment was targeted to disease “hotspots” based on publicly available SARS-CoV-2 testing data and community-level information about social vulnerability. This formative evaluation explores whether our MHU deployment strategy enabled us to reach patients from communities with heightened social vulnerability as intended. From 3/20/20-3/24/21, the Detroit MHU program reached a total of 32,523 people. The proportion of patients who resided in communities with top quartile Centers for Disease Control and Prevention Social Vulnerability Index rankings increased from 25% during location-based “drive-through” SARS-CoV-2 testing (3/20/20-4/13/20) to 27% after pivoting to a mobile platform (4/13/20-to-8/31/20; p = 0.01). The adoption of a data-driven deployment strategy resulted in further improvement; 41% of the patients who sought MHU services from 9/1/20-to-3/24/21 lived in vulnerable communities (Cochrane Armitage test for trend, p

Many clinicians are wary of administering 30 cc/kg of intravenous fluid (IVF) to septic patients with reduced left-ventricular ejection fraction (rLVEF), fearing volume overload. Prior studies have used history of heart failure, rather than LVEF measured at presentation, thereby potentially distorting the relationship between rLVEF, IVF, and adverse outcomes. Our goal was to assess the relationship between IVF volume and outcomes in patients with, versus without, rLVEF.This was a prospective observational study performed at an urban Emergency Department (ED). Included patients were adults with suspected sepsis, defined as being treated for infection plus either systolic blood pressure 90 mm/Hg or lactate2 mmol/L. All patients had LVEF assessed by ED echocardiogram, prior to receipt of1 l IVF.We enrolled 73 patients, of whom 33 had rLVEF, defined as40%. Patients with rLVEF were older, had greater initial lactate, more ICU admission, and more vasopressor use. IVF volume was similar between LVEF groups at 3-h (2.2 (IQR 0.8) vs 2.0 (IQR 2.4) liters) while patients with rLVEF were more likely to achieve 30 cc/kg (61% (CI 44-75) vs 45% (CI 31-60). In the reduced versus not-reduced LVEF groups, hospital days, ICU days, and ventilator days were similar: 8 (IQR 7) vs 6.5 (8.5) days, 7 (IQR 7) vs 5 (4) days, and 4 (IQR 8) vs. 5 (10) days, respectively.Septic patients with rLVEF at presentation received similar volume of IVF as those without rLVEF, without an increase in adverse outcomes attributable to volume overload. While validation is needed, our results suggest that limiting IVF administration in the setting of rLVEF is not necessary.

Background: We conducted a secondary analysis of changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 over 30 days in a randomized trial of self-care coaching versus structured usual care in patients with acute heart failure who were discharged from the emergency department. Methods: Patients in 15 emergency departments completed the KCCQ-12 at emergency department discharge and at 30 days. We compared change in KCCQ-12 scores between the intervention and usual care arms, adjusted for enrollment KCCQ-12 and demographic characteristics. We used linear regression to describe changes in KCCQ-12 summary scores and logistic regression to characterize clinically meaningful KCCQ-12 subdomain changes at 30 days. Results: There were 350 patients with both enrollment and 30-day KCCQ summary scores available; 166 allocated to usual care and 184 to the intervention arm. Median age was 64 years (interquartile range, 55–70), 37% were female participants, 63% were Black, median KCCQ-12 summary score at enrollment was 47 (interquartile range, 33–64). Self-care coaching resulted in significantly greater improvement in health status compared with structured usual care (5.4-point greater improvement, 95% CI, 1.12–9.68; P =0.01). Improvements in health status in the intervention arm were driven by improvements within the symptom frequency (adjusted odds ratio, 1.62 [95% CI, 1.01–2.59]) and quality of life (adjusted odds ratio, 2.39 [95% CI, 1.46–3.90]) subdomains. Conclusions: In this secondary analysis, patients with acute heart failure who received a tailored, self-care intervention after emergency department discharge had clinically significant improvements in health status at 30 days compared with structured usual care largely due to improvements within the symptom frequency and quality of life subdomains of the KCCQ-12. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02519283.

Elevated blood pressure remains the single biggest risk factor contributing to the global burden of disease and mortality. May Measurement Month is an annual global screening campaign aiming to improve awareness of blood pressure at the individual and population level. Adults ({greater than or equal to}18 years) recruited through opportunistic sampling were screened at sites in 92 countries during May 2019. Ideally three blood pressure readings were measured for each participant, and data on lifestyle factors and co-morbidities were collected. Hypertension was defined as a systolic BP {greater than or equal to} 140 mmHg, and/or a diastolic BP {greater than or equal to} 90 mmHg (mean of the second and third readings) or taking antihypertensive medication. When necessary, multiple imputation was used to estimate participants' mean blood pressure. Mixed-effects models were used to evaluate associations between blood pressure and participant characteristics. Of 1,508,130 screenees 482,273 (32.0%) had never had a blood pressure measurement before and 513,337 (34.0%) had hypertension, of whom 58.7% were aware and 54.7% were on antihypertensive medication. Of those on medication, 57.8% were controlled to

Sepsis is a critical illness characterized by dysregulated inflammatory responses lacking counter-regulation. Specialized proresolving mediators are agonists for antiinflammation and for promoting resolution, and they are protective in preclinical sepsis models. Here, in human sepsis, we mapped resolution circuits for the specialized proresolving mediators resolvin D1 and resolvin D2 in peripheral blood neutrophils and monocytes, their regulation of leukocyte activation and function ex vivo, and their relationships to measures of clinical severity. Neutrophils and monocytes were isolated from healthy subjects and patients with sepsis by inertial microfluidics and resolvin D1 and resolvin D2 receptor expression determined by flow cytometry. The impact of these resolvins on leukocyte activation was determined by isodielectric separation and leukocyte function by stimulated phagolysosome formation. Leukocyte proresolving receptor expression was significantly higher in sepsis. In nanomolar concentrations, resolvin D1 and resolvin D2 partially reversed sepsis-induced changes in leukocyte activation and function. Principal component analyses of leukocyte resolvin receptor expression and responses differentiated sepsis from health and were associated with measures of sepsis severity. These findings indicate that resolvin D1 and resolvin D2 signaling for antiinflammation and resolution are uncoupled from leukocyte activation in early sepsis and suggest that indicators of diminished resolution signaling correlate with clinical disease severity.

Background Despite advances in asthma care, disparities persist. Black patients are disproportionally affected by asthma and also have poorer outcomes compared with white patients. Objective We sought to determine associations between black and white patients and asthma-related health care use, accounting for complex relationships. Methods This study was completed as part of the National Heart, Lung, and Blood Institute's Severe Asthma Research Program, a prospective observational cohort. Between November 2012 and February 2015, it enrolled 579 participants 6 years and older with 1 year of observation time and complete data. Inverse probability of treatment weighting was used to balance racial groups with respect to community and family socioeconomic variables and environmental exposure variables. The primary outcome was emergency department (ED) use for asthma. Secondary outcomes included inhaled corticosteroid use, outpatient physician's office visits for asthma, and asthma–related hospitalization. Results Black patients had greater odds of ED use over 1 year (odds ratio, 2.19; 95% CI, 1.43-3.35) but also differed in the majority (>50%) of baseline variables measured. After statistical balancing of the racial groups, the difference between black and white patients with respect to ED use no longer reached the level of significance. Instead, in secondary analyses black patients were less likely to see an outpatient physician for asthma management (adjusted odds ratio, 0.57; 95% CI, 0.38-0.85). Conclusions The disparity in ED use was eliminated after consideration of multiple variables. Social and environmental policies and interventions tailored to black populations with a high burden of asthma are critical to reduction (or elimination) of these disparities.

Rationale: Corticosteroids (CSs) are the most effective asthma therapy, but responses are heterogeneous and systemic CSs lead to long-term side effects. Therefore, an improved understanding of the contributing factors in CS responses could enhance precision management. Although several factors have been associated with CS responsiveness, no integrated/cluster approach has yet been undertaken to identify differential CS responses. Objectives: To identify asthma subphenotypes with differential responses to CS treatment using an unsupervised multiview learning approach. Methods: Multiple-kernel k-means clustering was applied to 100 clinical, physiological, inflammatory, and demographic variables from 346 adult participants with asthma in the Severe Asthma Research Program with paired (before and 2-3 weeks after triamcinolone administration) sputum data. Machine-learning techniques were used to select the top baseline variables that predicted cluster assignment for a new patient. Measurements and Main Results: Multiple-kernel clustering revealed four clusters of individuals with asthma and different CS responses. Clusters 1 and 2 consisted of young, modestly CS-responsive individuals with allergic asthma and relatively normal lung function, separated by contrasting sputum neutrophil and macrophage percentages after CS treatment. The subjects in cluster 3 had late-onset asthma and low lung function, high baseline eosinophilia, and the greatest CS responsiveness. Cluster 4 consisted primarily of young, obese females with severe airflow limitation, little eosinophilic inflammation, and the least CS responsiveness. The top 12 baseline variables were identified, and the clusters were validated using an independent Severe Asthma Research Program test set. Conclusions: Our machine learning-based approaches provide new insights into the mechanisms of CS responsiveness in asthma, with the potential to improve disease treatment.

Background: Offset and leg length (LL) restoration are critical for the achievement of a stable, well-functioning hip following total hip arthroplasty (THA). Several techniques are described in the literature, including a hip calibration gauge. We question whether meticulous preoperative planning of a specific surgical technique in combination with the utilisation of a calibration gauge can provide an accurate offset and LL restoration. Methods: Retrospective review of 101 unilateral THAs via a posterior approach by a single surgeon. Preoperative radiographic LL and offset were radiographically calculated. Intraoperatively prior to hip dislocation a calibration gauge was used to measure LL and offset with a pin inserted into the iliac crest acting as a static referencing point. All had pelvis x-ray performed 6 weeks postoperatively. A literature review was conducted to establish average postoperative LL/offset values for statistical comparison. Results: The average absolute postoperative leg-length discrepancy (LLD) was 2.51 mm compared to preoperatively 3.54 mm ( p = 0.018). A total of 93.1% and 100% had LLD of ⩽5 mm and ⩽10 mm, respectively. The mean postoperative offset difference was 2.39 mm. The investigated LLD and offset results were comparable with literature data of studies utilising an intraoperative measuring device. LLD was significantly decreased when compared to a free-hand technique (LLD 4.42 mm, p < 0.001). Conclusion: The technique utilising preoperative templating, intraoperative offset verification together with the use of hip calibration gauge yielded accurate LLD and offset restoration as in the literature. Precise offset restoration, which often is a neglected issue, can lead to better abductor vector restoration, hip function and less pain.

We have previously reported the deregulatory impact of ethanol on global DNA methylation of brain-derived neural stem cells (NSC). Here, we conducted a genome-wide RNA-seq analysis in differentiating NSC exposed to different modes of ethanol exposure. RNA-seq results showed distinct gene expression patterns and canonical pathways induced by ethanol exposure and withdrawal. Short-term ethanol exposure caused abnormal up-regulation of synaptic pathways, while continuous ethanol treatment profoundly affected brain cells’ morphology. Ethanol withdrawal restored the gene expression profile of differentiating NSC without rescuing impaired expression of epigenetics factors. Ingenuity Pathway Analysis (IPA) analysis predicated that ethanol may impact synaptic functions via GABA receptor signalling pathway and affects neural system and brain morphology. We identified Sptbn2, Dcc, and Scn3a as candidate genes which may link alcohol-induced neuronal morphology to brain structural abnormalities, predicted by IPA analysis. Cross-examination of Scn3a and As3mt in differentiated NSC from two different mouse strains (BL6 and CD1) showed a consistent pattern of induction and reduction, respectively. Collectively, our study identifies genetic networks, which may contribute to alcohol-mediated cellular and brain structural dysmorphology, contributing to our knowledge of alcohol-mediated damage to central nervous system, paving the path for better understanding of FASD pathobiology.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value, While coffee and tea consumption has been associated with risk of diseases, their mechanisms of action remain elusive. Here the authors present a large EWAS on coffee and tea consumption in cohorts of European and African-American ancestries, finding that coffee consumption is associated with differential DNA methylation levels at multiple CpGs.

Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to

The prognostic importance of Emergency Heart Failure Mortality Risk Grade (EHMRG) score in assessing short term mortality in Congestive Heart Failure (CHF) patients has been validated in the past, however, few studies have examined acuity patterns in the CHF population across healthcare settings. We aim to understand acuity patterns of CHF patients across a large health system for better resource utilization.Retrospective chart review of adult patients with acute CHF in a large Metropolitan health system was performed in 3 community and 3 academic hospitals between January 2014 and January 2016. We collected demographic data, setting type, and calculated EHMRG score. Descriptive analysis of each hospital and mixed-effects negative binomial models were created to see patterns of acuity versus hospital volume.A total of 3312 Emergency Department (ED) visits among 2490 unique patients were included. Academic and community hospitals had 2168 patients and 1144 patients, respectively. Hospitals with higher volume treated a large amount of lower acuity patients. Academic hospitals had 30% of CHF ED visits in the lowest EHMRG quantile versus 20% at community hospital (p 0.0001). Compared to EHMRG quantile 5b, hospital volume was 17%, 8% and 5% higher in quantile 1, 2, and 3 with a p-value less than 0.05 (IRR = 1.17; 1.08;1.05), respectively, but were not significant compared to quantile 4 and 5a. Revisit rates were lower in academic hospitals; admission rates were lower in community hospitals.Academic hospitals had a higher number of Acute Heart Failure (AHF) patients, larger number of low acuity patients, higher admission rates, but less revisit rates to the ED as compared to community hospitals. We suggest acuity specific interventions will help decrease admission and revisit rates.

Countries all over the world implemented lockdowns to counteract COVID-19. These lockdowns heavily limited people's exercise possibilities. At the same time, experts advocated to remain physically active to prevent future health problems. Based on an online survey, this study examines adults' exercise levels and patterns during the COVID-19 lockdown in Belgium. Ordinal logistic regression analyses of 13,515 valid and population-weighted responses indicate a general increase in exercise frequencies, as well as in sedentary behavior. Except for people aged 55+, previously low active adults self-reported to exercise more during the lockdown. Among the people who were already high active before COVID-19, those above 55 years old, those with low education, those used to exercise with friends or in a sport club, and those who were not using online tools to exercise, self-reported to exercise less during the lockdown. Having less time, sitting more, and missing the familiar way and competitive element of exercising were the main reasons for a self-reported exercise reduction. Given the health risks associated with physical inactivity, results imply that governments should consider how those who were not reached can be encouraged to exercise during a lockdown. After all, additional COVID-19 lockdowns might be implemented in the future.

Background Emergency department ( ED ) visits for hypertension are rising, but the importance of elevated blood pressure ( BP ) measured during the ED visit is controversial. We evaluated the relationship between ED BP and mean BP over the subsequent year. Methods and Results We performed a retrospective cohort study from January 1, 2010 to December 31, 2013 of 8105 adult patients who made 1 visit to an academic medical center ED with ≥2 ED BP s and ≥2 BP s measured in the subsequent year. The primary exposure was lowest ED systolic BP . The primary outcome was mean systolic BP ≥140 mm Hg over the year following the index ED visit. Diastolic BP was examined as a secondary exposure and outcome. Multiple logistic regression was performed adjusting for several covariates, with interaction terms for hypertension diagnosis, ED disposition, pain‐related ED chief complaint, and sex. Patients whose lowest ED systolic BP was 140 to 159 mm Hg had an adjusted odds ratio of having a mean SBP ≥140 mm Hg in the subsequent year of 10.9 (95% CI , 7.6–15.6). Patients without diagnosed hypertension and ED BP 140/90 to 159/99 mm Hg were more likely to have elevated BP in the following year. Hospitalization increased the likelihood of persistently elevated systolic BP but not diastolic BP . There was no effect modification by pain‐related ED complaint. Conclusions When ED BP is consistently elevated, BP is highly likely to remain elevated in the subsequent year, regardless of pain, and particularly among patients without diagnosed hypertension. Further research is needed to determine the optimal management of elevated ED BP .

Multiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use; however, there is little data identifying clinical characteristics of MS associated with worse COVID-19 outcomes. Therefore, we conducted a multicenter prospective cohort study looking at the outcomes of 40 MS patients with confirmed COVID-19. Severity of COVID-19 infection was based on hospital course, where a mild course was defined as the patient not requiring hospital admission, moderate severity was defined as the patient requiring hospital admission to the general floor, and most severe was defined as requiring intensive care unit admission and/or death. 19/40(47.5%) had mild courses, 15/40(37.5%) had moderate courses, and 6/40(15%) had severe courses. Patients with moderate and severe courses were significantly older than those with a mild course (57[50–63] years old and 66[58.8–69.5] years old vs 48[40–51.5] years old, P = 0.0121, P = 0.0373). There was differing prevalence of progressive MS phenotype in those with more severe courses (severe:2/6[33.3%]primary-progressing and 0/6[0%]secondary-progressing, moderate:1/14[7.14%] and 5/14[35.7%] vs mild:0/19[0%] and 1/19[5.26%], P = 0.0075, 1 unknown). Significant disability was found in 1/19(5.26%) mild course-patients, but was in 9/15(60%, P = 0.00435) of moderate course-patients and 2/6(33.3%, P = 0.200) of severe course-patients. Disease-modifying therapy prevalence did not differ among courses (mild:17/19[89.5%], moderate:12/15[80%] and severe:3/6[50%], P = 0.123). MS patients with more severe COVID-19 courses tended to be older, were more likely to suffer from progressive phenotype, and had a higher degree of disability. However, disease-modifying therapy use was not different among courses., Highlights • In a multicenter study of 40 multiple sclerosis (MS) patients, different phenotypes and level of disability were associated with COVID-19 severity. • Poorer outcomes were associated with more severe MS disability. • The use of DMT for MS was not associated with worse outcome.

Rationale: Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers. Objectives: To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers. Methods: Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers. Measurements and Main Results: Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV(1) and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/μl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/μl increase in baseline eosinophil number. Conclusions: Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.

OBJECTIVE. The purpose of this study is to compare the performance of 2D synthetic mammography (SM) to that of full-field digital mammography (FFDM) in the detection of microcalcifications and to e...

Objective Pulmonary function tests (PFTs) are important for assessing respiratory function in amyotrophic lateral sclerosis (ALS) patients. However, weakness of oral and glottal closure, due to concomitant bulbar dysfunction, may result in unreliable PFT values stemming from leakage of air around the breathing tube and through the glottis. In this study, we assessed whether standard thoracic electrical impedance tomography (EIT) could serve as a surrogate measure for PFTs. Approach Thoracic EIT was performed simultaneously with standard PFTs on seven ALS patients without clinical bulbar weakness (six men and one woman, mean age of 63 years) and ten healthy volunteers (seven men and three women, mean age of 57 years). A raw impedance metric along with more standard EIT measures were computed and correlated with the normalized forced vital capacity (FVC). Additionally, test/re-test metrics and EIT images were analyzed. Main results The impedance metric was found to be robust and sensitive to lung activity. We also identified qualitative EIT differences between healthy volunteers and ALS patients, with the ALS images showing greater heterogeneity. Significant correlations with FVC were found for both impedance and EIT metrics in ALS patients (r2 = 0.89) and for the impedance metric only in healthy volunteers (r2 = 0.49). Significance This suggests that EIT, using our novel impedance metric, has the potential to serve as an alternative technology to standard PFTs for assessing pulmonary function in patients with ALS, offering new metrics of disease status for those with bulbar weakness.

Objectives The UK & Ireland Implanters' registry is a multicenter registry which reports on real-world experience with novel transcatheter heart valves. Background The 34 mm Evolut R transcatheter aortic valve is a self-expanding and fully recapturable transcatheter aortic valve, designed to treat patients with a large aortic annulus. Methods Between January 2017 and April 2018, clinical, procedural and 30-day outcome data were prospectively collected from all patients receiving the 34 mm Evolut R valve across 17 participating centers in the United Kingdom and Ireland. The primary efficacy outcome was the Valve Academic Research Consortium-2(VARC-2)-defined endpoint of device success. The primary safety outcome was the VARC-2-defined composite endpoint of early safety at 30 days. Results A total of 217 patients underwent attempted implant. Mean age was 79.5 ± 8.8 years and Society of Thoracic Surgeons Predicted Risk of Mortality Score 5.2% ± 3.4%. Iliofemoral access was used in 91.2% of patients. Device success was 79.7%. Mean gradient was 7.0 ± 4.6 mmHg and effective orifice area 2.0 ± 0.6 cm2 . Paravalvular regurgitation was more than mild in 7.2%. A new permanent pacemaker was implanted in 15.7%. Early safety was demonstrated in 91.2%. At 30 days, all-cause mortality was 3.2%, stroke 3.7%, and major vascular complication 2.3%. Conclusions Real-world experience of the 34 mm Evolut R transcatheter aortic valve demonstrated acceptable procedural success, safety, valve function, and incidence of new permanent pacemaker implantation.

Rapid HIV testing programs in emergency departments (EDs) have been shown to promote early diagnosis and linkage to specialty care. However, sensitivity of the subject-matter and stigmatization of disclosing associated risk factors may make patients reluctant to consent to testing in this setting. This study sought to determine whether men are more likely to refuse rapid HIV testing in the ED as compared to women and to analyze the influence of tester gender on the response. This retroactive study utilized demographic and testing information from a rapid HIV testing program housed within two urban EDs for a 5-month period. Gender and age were collected for both testers and patients, along with patient consent outcome. A total of 5358 patients (males = 2230; females = 3128) were approached and offered an HIV test by one of 19 testers during the study period. From the sample population, male and female patient refusal rates were similar (30.0% vs 29.1%, respectively). Female testers approached 57.8% (n = 3,095) of the patients; however, they had a significantly higher refusal rate compared to male testers (35.6% vs 21.4%; p

This study examined whether insulin-like growth factor binding protein-7 (IGFBP7) would aid in the diagnosis and prognosis of acute heart failure (HF) beyond N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration.IGFBP7 is associated with impaired ventricular relaxation and worse prognosis.The ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial that enrolled subjects presenting with dyspnea. Six-month prognosis for death or repeat hospitalization was obtained.Among 1,449 patients, 274 (18.9%) were diagnosed with acute HF. Those with IGFBP7 concentrations in the highest quartile were older, male, had hypertension and HF, had lower estimated glomerular filtration rate (eGFR) and lowest ejection fraction (41 ± 20%; all p 0.001). Independent predictors of IGFBP7 were age, male sex, history of diabetes, history of HF, and eGFR. Median concentrations of NT-proBNP (2,844 ng/ml vs. 99 ng/ml) and IGFBP7 (146.1 ng/ml vs. 86.1 ng/ml) were higher in those with acute HF (both; p 0.001). Addition of IGFBP7 to NT-proBNP concentrations improved discrimination, therefore increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p 0.001 for differences). Addition of IGFBP7 to a complete model of independent predictors of acute HF improved model calibration. IGFBP7 significantly reclassified acute HF diagnosis beyond NT-proBNP (net reclassification index: +0.25). Higher logAmong patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk.

OBJECTIVES The objective was to determine the national lumbar puncture (LP) practice patterns relative to the incidence of central nervous system (CNS) infections among children presenting to the emergency department (ED) with complex febrile seizures (CFS). METHODS This was a retrospective study of ED visits for CFS from 2007 to 2014 in patients aged 0 to 5 years using a national sample. Primary outcomes include the frequency of LP, incidence of CNS infections, and ED disposition. RESULTS Of 28,810 ED visits for CFS (44.4% female; mean age = 1.39 years), LP was performed in 7,445 (25.8%, 95% confidence interval [CI] 23.5%-28.2%). There was no significant difference in the proportion due to hospital teaching status or geographical region. The proportion decreased from 31.4% to 17.8% over the study period (Rao-Scott statistic = 5.85, p

Background Squeaking is an on-going complication with a variable incidence of 0.5%-20.7%. The mechanism of squeaking has not been understood completely and is most likely multifactorial in nature. Previously, we have reported on a squeaking rate of 7.3% at 2 years. Our current results show a substantial increase in the squeaking incidence from 7.3% to 17.4% with the DeltaMotion articulation at the 5-year follow-up. Methods Two hundred six total hip arthroplasties with a large ceramic-on-ceramic bearing were performed on 195 patients by 2 senior authors. The minimum duration of follow-up was 5 years (range 5-6.2). Results The mean Harris Hip Score remained stable at 91.7 at 5 years compared to 92 after 2 years. However, we observed an increase in the squeaking rate from 7.3% after 2 years to 17.4% after 5 years. As in previous studies, we did not find significant differences between the silent and squeaking group in relation to age, height, weight, and femoral head diameter. In contrast, others reported no significant differences regarding range of motion and gender between the silent and the squeaking hip group at 2 years of follow-up, whereas at 5 years, the squeaking group showed a significantly higher combined range of motion and a higher relative risk of squeaking in women compared to the silent group. Conclusion While large diameter ceramic bearings may produce squeaking, especially in female patients, our mid-term clinical results of a large ceramic-on-ceramic bearing in total hip arthroplasty are encouraging. Nevertheless, long-term follow-up is recommended.

Background Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. Methods To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6–18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. Results From pre−/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. Conclusions These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. Trial registration ClinicalTrials.gov registration number: NCT01748175. Electronic supplementary material The online version of this article (10.1186/s12890-018-0612-x) contains supplementary material, which is available to authorized users.

Objective Sexual minority men (SMM) in the United States continue to experience adverse health problems and psychosocial burdens. However, there is limited psychometric research seeking to quantify the life worries of this population. Informed by syndemic theory, the Life Worries Scale (LWS) was developed to measure the concerns of young SMM. Method Analyses of the scale were undertaken using baseline data (n = 665) from an ongoing cohort study of emerging adult, SMM. Results Exploratory factor analyses (EFA) of an initial set of 24 Likert-type items, followed by confirmatory factor analysis (CFA) and an exploratory structural equation model (ESEM), indicated a structure consisting of 6 domains of worries: financial stability, social stability, self esteem, loneliness, physical appearance, and physical health. These 6 subscales were highly correlated and also demonstrated high levels of internal consistency. Differences in life worries were noted across demographic states, specifically HIV serostatus, sexual attraction, housing status, and self-rated health. High levels of association were also detected between all 6 subscales with both depression and PTSD, while significant correlations were detected between suicidality and both self esteem and loneliness related worries. Conclusions The results of our analyses provide evidence for the strong psychometric characteristics of the LWS. This newly developed instrument should be utilized in research to examine the extent to which life worries explain health outcomes and risk behaviors in sexual minority males, and may be potentially extended for use in other populations. (PsycINFO Database Record

Background: Systemic hemodynamic characteristics of patients with suspected acute ischemic stroke are poorly described. The objective of this study was to identify baseline hemodynamic characteristics of emergency department (ED) patients with suspected acute stroke. Methods: This was a planned analysis of the stroke cohort from a multicenter registry of hemodynamic profiling of ED patients. The registry prospectively collected non-invasive hemodynamic measurements of patients with suspicion for acute stroke within 12. h of symptom onset. K-means cluster analysis identified hemodynamic phenotypes of all suspected stroke patients, and we performed univariate hemodynamic comparisons based on final diagnoses. Results: There were 72 patients with suspected acute stroke, of whom 38 (53%) had a final diagnosis of ischemic stroke, 10 (14%) had hemorrhagic stroke, and 24 (33%) had transient ischemic attack (TIA). Analysis defined three phenotypic clusters based on low or normal cardiac index (CI) and normal or high systemic vascular resistance index (SVRI). Patients with TIA had lower mean CI (2.3. L/min/m2) compared to hemorrhagic or ischemic stroke patients (p.

Introduction TRV027, a 'biased' ligand of the angiotensin II type 1 receptor (AT1R), did not affect a composite clinical outcome at 30 days in a phase 2b acute heart failure (AHF) trial (BLAST-AHF).Methods Post-hoc analyses from BLAST-AHF (n = 618) examined the effects of TRV027 by baseline systolic blood pressure (SBP) on changes in renal function and 180-day outcomes. Interactions between baseline SBP and select endpoints were identified utilizing a subpopulation treatment effect pattern plots (STEPP) analysis, then grouping of patients by SBP tertile: = 127 to = 140 mmHg.Results A trend towards increased creatinine in the first 3 days was noted in the lower SBP tertile, while in those in the higher two tertiles, TRV027, especially the 1 mg/h dose, reduced creatinine at days 5 and 30. Beneficial effects on 180-day all-cause mortality and cardiovascular (CV) death or readmission were observed in the two higher SBP tertiles (SBP >= 127 mmHg) in the TRV027 1 mg/h dose group (all-cause mortality HR 0.39, 95% CI 0.14-1.06, p = 0.056; CV death or HF/RF rehospitalization HR 0.53, 95% CI 0.28-1.01, p = 0.049), while more adverse outcomes were observed in patients in the lower SBP tertile.Conclusions This post-hoc analysis of the BLAST-AHF study suggests contrasting effects of TRV027 by baseline SBP, with trends towards lower 180-day event rates in patients enrolled with higher baseline SBP, especially when given lower doses of TRV027.

Objectives The objectives were to reassess use of amino-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations for diagnosis and prognosis of acute heart failure (HF) in patients with acute dyspnea. Background NT-proBNP facilitates diagnosis, prognosis, and treatment in patients with suspected or proven acute HF. As demographics of such patients are changing, previous diagnostic NT-proBNP thresholds may need updating. Additionally, value of in-hospital NT-proBNP prognostic monitoring for HF is less understood. Methods In a prospective, multicenter study in the United States and Canada, patients presenting to emergency departments with acute dyspnea were enrolled, with demographic, medication, imaging, and clinical course information collected. NT-proBNP analysis will be performed using the Roche Diagnostics Elecsys proBNPII immunoassay in blood samples obtained at baseline and at discharge (if hospitalized). Primary end points include positive predictive value of previously established age-stratified NT-proBNP thresholds for the adjudicated diagnosis of acute HF and its negative predictive value to exclude acute HF. Secondary end points include sensitivity, specificity, and positive and negative likelihood ratios for acute HF and, among those with HF, the prognostic value of baseline and predischarge NT-proBNP for adjudicated clinical end points (including all-cause death and hospitalization) at 30 and 180 days. Results A total of 1,461 dyspneic subjects have been enrolled and are eligible for analysis. Follow-up for clinical outcome is ongoing. Conclusions The International Collaborative of N-terminal pro–B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department study offers a contemporary opportunity to understand best diagnostic cutoff points for NT-proBNP in acute HF and validate in-hospital monitoring of HF using NT-proBNP.

Purpose Implementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing GeNomics In PracTicE (IGNITE) Network’s efforts to promote: 1) a broader understanding of genomic medicine implementation research; and 2) the sharing of knowledge generated in the network. Methods To facilitate this goal the IGNITE Network Common Measures Working Group (CMG) members adopted the Consolidated Framework for Implementation Research (CFIR) to guide their approach to: identifying constructs and measures relevant to evaluating genomic medicine as a whole, standardizing data collection across projects, and combining data in a centralized resource for cross network analyses. Results CMG identified ten high-priority CFIR constructs as important for genomic medicine. Of those, eight didn’t have standardized measurement instruments. Therefore, we developed four survey tools to address this gap. In addition, we identified seven high-priority constructs related to patients, families, and communities that did not map to CFIR constructs. Both sets of constructs were combined to create a draft genomic medicine implementation model. Conclusion We developed processes to identify constructs deemed valuable for genomic medicine implementation and codified them in a model. These resources are freely available to facilitate knowledge generation and sharing across the field.

Introduction: While moderate to severely elevated blood pressure (BP) is present in nearly halfof all emergency department (ED) patients, the incidence of true hypertensive emergencies inED patients is low. Administration of bolus intravenous (IV) antihypertensive treatment to lowerBP in patients without a true hypertensive emergency is a wasteful practice that is discouragedby hypertension experts; however, anecdotal evidence suggests this occurs with relatively highfrequency. Accordingly, we sought to assess the frequency of inappropriate IV antihypertensivetreatment in ED patients with elevated BP absent a hypertensive emergency. Methods: We performed a retrospective cohort study from a single, urban, teaching hospital.Using pharmacy records, we identified patients age 18-89 who rec eived IV antihypertensivetreatment in the ED. We defined treatment as inappropriate if documented suspicion for anindicated cardiovascular condition or acute end-organ injury was lacking. Data abstractionincluded adverse events and 30-day readmission rates, and analysis was primarily descriptive. Results: We included a total of 357 patients over an 18-month period. The mean age was 55;51% were male and 93% black, and 127 (36.4%) were considered inappropriately treated.Overall, labetalol (61%) was the most commonly used medication, followed by enalaprilat(18%), hydralazine (18%), and metoprolol (3%). There were no significant differences betweenappropriate and inappropriate BP treatment groups in terms of clinical characteristics oradverse events. Hypotension or bradycardia occurred in three (2%) patients in the inappropriatetreatment cohort and in two (1%) patients in the appropriately treated cohort. Survival todischarge and 30-day ED revisit rates were equivalent. Conclusion: More than one in three patients who were given IV bolus antihypertensive treatmentin the ED received such therapy inappropriately by our definitio n, suggesting that significantresources could perhaps be saved through education of providers and development of clearlydefined BP treatment protocols. [West J Emerg Med. 2017;18(5)957-962.]

Aims: Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel ` biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies.Methods and results: BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2: 1: 2: 1, overweighting both placebo, and the 5mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027.Conclusion: In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.

Acute idiopathic hyperammonemia in an adult patient is a life-threatening condition often resulting in a rapid progression to irreversible cerebral edema and death. While ammonia-scavenging therapies lower blood ammonia levels, in comparison, clearance of waste nitrogen from the brain may be delayed. Therefore, we used magnetic resonance spectroscopy (MRS) to monitor cerebral glutamine levels, the major reservoir of ammonia, in a gastric bypass patient with hyperammonemic coma undergoing therapy with N-carbamoyl glutamate and the ammonia-scavenging agents, sodium phenylacetate and sodium benzoate. Improvement in mental status mirrored brain glutamine levels, as coma persisted for 48h after plasma ammonia normalized. We hypothesize that the slower clearance for brain glutamine levels accounts for the delay in improvement following initiation of treatment in cases of chronic hyperammonemia. We propose MRS to monitor brain glutamine as a noninvasive approach to be utilized for diagnostic and therapeutic monitoring purposes in adult patients presenting with idiopathic hyperammonemia.

Background Diagnosing acute heart failure (AHF) in undifferentiated dyspneic emergency department (ED) patients can be challenging. We prospectively studied a validated diagnostic prediction model for AHF that uses patient age, clinician pretest probability for AHF, and N-terminal pro–B-type natriuretic peptide (NT-proBNP) as a continuous value to determine its utility and performance. Methods and Results This was a multicenter randomized controlled trial of undifferentiated dyspneic patients with an indeterminate pretest probability of AHF as assessed by the treating emergency physician (EP). After recording its components, the calculated model results with validated treatment threshold guidelines were provided to EPs for patients randomized to the intervention arm. Final diagnoses with the use of 60-day follow-up information were adjudicated by 2 independent cardiologists. The primary outcomes were accuracy of the model and of physician diagnosis comparing intervention and standard care arms. A total of 197 patients were randomized and had outcome data recorded; 41% were determined to have had heart failure. Final EP diagnostic accuracy was 76% (sensitivity 68.2%, specificity 83.9%) with no significant difference between exposed versus blinded arms (accuracy 77% vs 74%; P = .77). Area under the model receiver operating characteristic curve was 0.93. Using the model treatment thresholds would have redirected 48% of patients with 95% accuracy. Conclusions This study prospectively validated the diagnostic accuracy of our AHF model in a significant proportion of indeterminate dyspneic ED patients, but provision of this information did not improveEP diagnostic accuracy. Future studies should determine how such a clinical prediction tool could be effectively integrated into routine practice and improve early management of suspected AHF patients in the ED.

Introduction The technical objective of total knee arthroplasty (TKA) is to restore normal mechanical parameters to the knee. Patient-specific instrumentation (PSI) was developed to streamline the operative process and improve accuracy. PSI produces individualized cutting guides based on three-dimensional models of the patient's anatomy acquired from computed-tomography (CT) or magnetic-resonance imaging (MRI). However, the superiority of one modality over the other remains unclear. Therefore, we aimed to compare the accuracy of patient-specific cutting guides produced from MRI or CT imaging methods in TKA. Methods Electronic databases were systematically searched using relevant keywords and MeSH terms for original-data English-language publications comparing the accuracy of CT and MRI-based PSI cutting guides in TKA. Data was extracted from the text, tables and figures of studies and meta-analysed. Results MRI-based PSI cutting guides produced a lower proportion of coronal plane outliers (>3°) with regard to overall limb mechanical axis (OR 2.75, p = 0.01). There were no significant differences between the two in terms of sagittal femoral and tibial component placement, or coronal femoral and tibial placement, or femoral component axial rotation. Tibial rotation was not analysed in the literature. Conclusions MRI-based patient-specific cutting guides produced a lower proportion of outliers in the overall coronal alignment of the limb compared to CT, with no significant difference between the two in terms of femoral or tibial component placement. Future studies should investigate the differences in resource usage and operative time between the two to inform surgeons' decision making when choosing an ideal imaging modality for PSI TKA. Study design Meta-analysis. Level of evidence III, systematic review of cohort and comparative studies.

The purpose of this study was to compare health care resource utilization among patients who were given intravenous nitroglycerin for acute heart failure (AHF) in the emergency department (ED) by intermittent bolus, continuous infusion, or a combination of both.We retrospectively identified 395 patients that received nitroglycerin therapy in the ED for the treatment of AHF over a 5-year period. Patients that received intermittent bolus (n=124) were compared with continuous infusion therapy (n=182) and combination therapy of bolus and infusion (n=89). The primary outcomes were the frequency of intensive care unit (ICU) admission and hospital length of stay (LOS).On unadjusted analysis, rates of ICU admission were significantly lower in the bolus vs infusion and combination groups (48.4% vs 68.7% vs 83%, respectively; P.0001) and median LOS (interquartile range) was shorter (3.7 [2.5-6.2 days]) compared with infusion (4.7 [2.9-7.1 days]) and combination (5.0 [2.9-6.7 days]) groups; P=.02. On adjusted regression models, the strong association between bolus nitroglycerin and reduced ICU admission rate remained, and hospital LOS was 1.9 days shorter compared with infusion therapy alone. Use of intubation (bolus [8.9%] vs infusion [8.8%] vs combination [16.9%]; P=.096) and bilevel positive airway pressure (bolus [26.6%] vs infusion [20.3%] vs combination [29.2%]; P=.21) were similar as was the incidence of hypotension, myocardial injury, and worsening renal function.In ED patients with AHF, intravenous nitroglycerin by intermittent bolus was associated with a lower ICU admission rate and a shorter hospital LOS compared with continuous infusion.

To identify and measure recently described chemical mediators, termed specialized pro-resolving mediators that actively regulate the resolution of acute-inflammation, and correlate measurements with clinical outcomes.Herein, deidentified plasma was collected from sepsis patients (n = 22 subjects) within 48 hours of admission to the ICU and on days 3 and 7 thereafter and subjected to lipid mediator profiling.Brigham and Women's Hospital Medical Intensive Care Unit.Patients in the medical ICU with sepsis.In all patients, we identified more than 30 bioactive mediators and pathway markers in peripheral blood using established criteria for arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid metabolomes. These included inflammation initiating mediators leukotriene B4 and prostaglandin E2 and pro-resolving mediators resolvin D1, resolvin D2, and protectin D1. In sepsis nonsurvivors, we found significantly higher inflammation-initiating mediators including prostaglandin F2α and leukotriene B4 and pro-resolving mediators, including resolvin E1, resolvin D5, and 17R-protectin D1 than was observed in surviving sepsis subjects. This signature was present at ICU admission and persisted for 7 days. Further analysis revealed increased respiratory failure in nonsurvivors. Higher inflammation-initiating mediators (including prostaglandin F2α) and select proresolving pathways were associated with the development of acute respiratory distress syndrome, whereas other traditional clinical indices were not predictive of acute respiratory distress syndrome development.These results provide peripheral blood lipid mediator profiles in sepsis that correlate with survival and acute respiratory distress syndrome development, thus suggesting plausible novel biomarkers and biologic targets for critical illness.