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To assess hotspot micro-vessel flow velocity waveforms in human papillomavirus (HPV) cervical infections using transvaginal power Doppler ultrasound (TV-PDU) and to explore the associations of these sonographic parameters with HPV condyloma and low-grade squamous intraepithelial lesions (LSIL) of the cervix. A total of 39 patients with cervical HPV infections with abnormal cytology and colposcopy results (26 cases of LSIL; 13 cases of HPV condyloma) were enrolled to assess the vascular classification of the cervix and micro-vessel flow velocity using TV-PDU before treatment; 40 individuals with a pathologically normal cervix were used as the control group; seven parameters were measured, including vascular grading classification (Class I, Class II, and Class III), lowest pulsatility index (PI), resistance index (RI), peak systolic velocity (PS), end-diastolic velocity (ED), time average maximum velocity (TAMV), and the vascular index (VI = PS/ED). According to vascular classification, most LSILs were class I (69.2%, 18/26), followed by class II (26.9%, 7/26) and class III (3.8%, 1/26). Most HPV condylomas were class I (92.3%, 12/13), and one was class II (7.7%, 1/13). PI, RI, VI (p < 0.0001), and the PSs (p < 0.05) were significantly lower in these cases than in the controls. The ED and TAMV were not significantly different between the patients and controls (p = 0.4985 and p = 0.1564). No sonographic parameter was significantly different between LSIL and HPV condyloma. The mean PI, RI, and VI were significantly lower in LSIL than in the controls. For HPV condyloma, a PI of 1.07 had an 84.6% sensitivity, 85.0% specificity, and an AUC of 88.8%; for LSIL, a PI of 1.08 had a 100% sensitivity, 85% specificity, and an AUC of 94.2%; for HPV infection (HPV condyloma + LSIL), a PI of 1.08 had a 94.9% sensitivity, 85% specificity, and an AUC of 92.4%. Hotspot vascular classification and micro-vessel flow velocity waveforms may provide a potential practical method for the auxiliary diagnosis of cervical HPV infection. The PI may represent a valuable index for distinguishing the micro-vessel flow velocity waveforms in LSIL and HPV condyloma. Since the case numbers were limited in the current study, further validation is needed.

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development., Author summary Upon the emergence of new infectious disease, animal model becomes a pivotal tool for study of disease mechanism and development of therapeutics. In this study, we propose a versatile approach that allows rapid generation of mouse model for novel infectious disease once the receptor of the pathogen is identified. We demonstrated this approach by generating a mouse model for COVID-19 in a month’s time. These mice were capable of recapitulating severe COVID-19 in patients, and successfully applied in the development of a therapeutic antibody cocktail for the disease. This not only suggests the usefulness of this mouse model for the research on COVID-19, but also exhibit the utility of the proposed approach for establishing animal model for infectious disease.

Background Informed consent forms are intended to facilitate research enrollment decisions. However, the technical language in institutional templates can be unfamiliar and confusing for decision-makers. Standardized language describing financial implications of participation, namely compensation for injury and costs of care associated with participating, can be complex and could be a deterrent for potential participants. This standardized language may also be misleading in the context of comparative effectiveness trials of standard care interventions, in which costs and risk of injury associated with participating may not differ from regular medical care. In addition, the revised U.S. Common Rule contains a new requirement to present key information upfront; the impact of how this requirement is operationalized on comprehension and likelihood of enrollment for a given study is unknown. Methods Two online surveys assessed the impact of (1) changes to compensation for injury language (standard vs. tailored language form) and (2) changes to the key information page (using the tailored compensation language form with standard key information vs. modified key information vs. modified key information plus financial information) on both likelihood of enrollment in and understanding of a hypothetical comparative effectiveness trial. Results Likelihood of enrolling was not observed to be different between the standard and tailored language forms in Study 1 (73 vs. 75%; p = 0.6); however, the tailored language group had a higher frequency of understanding the compensation for injury process specific to the trial (25 vs. 51%; p p = 0.6); however, understanding of randomization differed by form (44 vs. 59 vs. 46%; p = 0.002). Conclusions These findings suggest that refining consent forms to clarify key information and tailoring compensation for injury language to the nature of the study, especially in the context of comparative effectiveness trials, may help to improve study comprehension but may not impact enrollment.

Background: Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory and sympathetic function, responsible for maintenance of symptoms. Treatment options including medications and psychotherapies have limitations. We previously showed that transcutaneous Vagus Nerve Stimulation (tcVNS) blocks inflammatory (interleukin (IL)-6) responses to stress in PTSD. The purpose of this study was to assess the effects of tcVNS on PTSD symptoms and inflammatory responses to stress. Methods: Twenty patients with PTSD were randomized to double blind active tcVNS (N=9) or sham (N=11) stimulation in conjunction with exposure to personalized traumatic scripts immediately followed by active or sham tcVNS and measurement of IL-6 and other biomarkers of inflammation. Patients then self administered active or sham tcVNS twice daily for three months. PTSD symptoms were measured with the PTSD Checklist (PCL) and the Clinician Administered PTSD Scale (CAPS), clinical improvement with the Clinical Global Index (CGI) and anxiety with the Hamilton Anxiety Scale (Ham-A) at baseline and one-month intervals followed by a repeat of measurement of biomarkers with traumatic scripts. After three months patients self treated with twice daily open label active tcVNS for another three months followed by assessment with the CGI. Results: Traumatic scripts increased IL-6 in PTSD patients, an effect that was blocked by tcVNS (p

Introduction People of Ashkenazi Jewish (AJ) ancestry are more likely than unselected populations to have a BRCA1/2 pathogenic variant, which cause a significantly increased risk of breast, ovarian and prostate cancer. Three specific BRCA1/2 pathogenic variants, referred to as BRCA-Jewish founder mutations (B-JFM), account for >90% of BRCA1/2 pathogenic variants in people of AJ ancestry. Current practice of identifying eligible individuals for BRCA testing based on personal and/or family history has been shown to miss at least 50% of people who have one of these variants. Here we describe the protocol of the JeneScreen study—a study established to develop and evaluate two different population-based B-JFM screening programmes, offered to people of Jewish ancestry in Sydney and Melbourne, Australia. Methods and analysis To rmeasure the acceptability of population-based B-JFM screening in Australia, two screening programmes using different methodologies have been developed. The Sydney JeneScreen programme provides information and obtains informed consent by way of an online tool. The Melbourne JeneScreen programme does this by way of community sessions attended in person. Participants complete questionnaires to measure clinical and psychosocial outcomes at baseline, and for those who have testing, 2 weeks postresult. Participants who decline testing are sent a questionnaire regarding reasons for declining. Participants with a B-JFM are sent questionnaires 12-month and 24-month post-testing. The questionnaires incorporate validated scales, which measure anxiety, decisional conflict and regret, and test-related distress and positive experiences, and other items specifically developed or adapted for the study. These measures will be assessed for each programme and the two population-based B-JFM screening methods will be compared. Ethics and dissemination Institutional Human Research Ethics Committee approval was obtained from the South Eastern Area Health Service Human Research Ethics Committee: HREC Ref 16/125. Following the analysis of the study results, the findings will be disseminated widely through conferences and publications, and directly to participants in writing.

The link between posttraumatic stress disorder (PTSD) and ischemic heart disease remains elusive owing to a shortage of longitudinal studies with a clinical diagnosis of PTSD and objective measures of cardiac compromise.We performed positron emission tomography in 275 twins who participated in two examinations approximately 12 years apart. At both visits, we obtained a clinical diagnosis of PTSD, which was classified as long-standing (both visit 1 and visit 2), late onset (only visit 2), and no PTSD (no PTSD at both visits). With positron emission tomography, we assessed myocardial flow reserve (MFR), which, in absence of significant coronary stenoses, indexes coronary microvascular function. We compared positron emission tomography data at visit 2 across the three categories of longitudinally assessed PTSD and examined changes between the two visits.Overall, 80% of the twins had no or minimal obstructive coronary disease. Yet, MFR was depressed in twins with PTSD and was progressively lower across groups with no PTSD (2.13), late-onset PTSD (1.97), and long-standing PTSD (1.93) (p = .01). A low MFR (a ratio2.0) was present in 40% of the twins without PTSD, in 56% of those with late-onset PTSD, and in 72% of those with long-standing PTSD (p.001). Associations persisted in multivariable analysis, when examining changes in MFR between visit 1 and visit 2, and within twin pairs. Results were similar by zygosity.Longitudinally, PTSD is associated with reduced coronary microcirculatory function and greater deterioration over time. The association is especially noted among twins with chronic, long-standing PTSD and is not confounded by shared environmental or genetic factors.

BackgroundThe COVID-19 pandemic adversely affected the socially vulnerable and minority communities in the U.S. initially, but the temporal trends during the year-long pandemic remain unknown.ObjectiveWe examined the temporal association between the county-level Social Vulnerability Index (SVI), a percentile-based measure of social vulnerability to disasters, its subcomponents and race/ethnic composition with COVID-19 incidence and mortality in the U.S. in the year starting in March 2020.MethodsCounties (n=3091) with ≥ 50 COVID-19 cases by March 6th, 2021 were included in the study. Associations between SVI (and its subcomponents) and county level racial composition with the incidence and death per capita were assessed by fitting a negative-binomial mixed-effects model. This model was also used to examine potential time varying associations between weekly number of cases/deaths and SVI or racial composition. Data was adjusted for percentage of population aged ≥65 years, state level testing rate, comorbidities using the average Hierarchical Condition Category (HCC) score, and environmental factors including average fine particulate matter (PM2.5), temperature and precipitation.ResultsHigher SVI, indicative of greater social vulnerability, was independently associated with higher COVID-19 incidence (adjusted incidence rate ratio [IRR] per-10 percentile increase:1.02, (95% CI 1.02, 1.03, pConclusionExcept for the winter “third wave” when majority White communities had the highest incidence of cases, counties with greater social vulnerability and proportionately higher minority populations, experienced worse COVID-19 outcomes.Article Summary/Strengths & LimitationsExamined full 12 months of county-level data in the US delineating the temporal trends in the association between social vulnerability index and COVID-19 outcomesInvestigated COVID-19 outcomes in predominantly Black and Hispanic communities in comparison to White communities in the USAnalysis is ecological, descriptive, and on the county-level rather than on an individual levelAnalysis adjusted for confounders including county level age ≥ 65, comorbidities, and environmental factorsAnalysis limited to the US

Rationale: Excessive vasoconstriction in response to mental stress may be a potential mechanism by which acute psychological stress leads to adverse cardiac events. Objectives: We investigated whether excessive digital vasoconstriction during acute mental stress predicts adverse cardiovascular outcomes among patients with coronary artery disease. Methods and Results: Five hundred forty-nine patients with stable coronary artery disease (age 63±9, 76% male, 29% black) underwent mental stress testing with a standardized public speaking stressor and followed prospectively for cardiovascular end points. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated and dichotomized by the median value into low and high sPAT ratio groups. Upon 3-year follow-up, Fine and Gray’s subdistribution hazard ratios were used to examine the association between sPAT ratio and the composite end point of cardiovascular death, myocardial infarction, revascularization, and hospitalization for heart failure. The median sPAT ratio was 0.68 (interquartile range, 0.48–0.88), indicating 32% vasoconstriction with mental stress. Men were more likely to have low sPAT ratio than women (odds ratio, 1.79; P =0.007) while those on β-blockers were less likely to have low sPAT ratio (odds ratio, 0.52; P =0.003). After adjusting for demographic and cardiovascular risk factors, medications, and rate-pressure product change during mental stress, those with low sPAT ratio were at significantly higher risk of adverse outcomes (subdistribution hazard ratio, 1.77 [95% CI, 1.12–2.80]). Conclusions: Greater peripheral vasoconstriction with mental stress, denoted by a low sPAT ratio, is associated with a higher risk of adverse cardiovascular outcomes in patients with coronary artery disease.

Previous studies have shown lower cardiovascular risk with higher high-density lipoprotein cholesterol (HDL-C) levels. However, recent data in the general population have shown increased risk of adverse outcomes at very high HDL-C concentrations.To study the association between very high HDL-C levels (80 mg/dL) and mortality in patients with coronary artery disease (CAD) and to investigate the association of known HDL-C genotypes with high HDL-C level outcomes.This prospective, multicenter, cohort study, conducted from 2006 to present in the UK and from 2003 to present in Atlanta, Georgia, recruited patients with CAD from the UK Biobank (UKB) and the Emory Cardiovascular Biobank (EmCAB), respectively. Patients without confirmed CAD were excluded from the study. Data analyses were conducted from May 10, 2020, to April 28, 2021.High HDL-C levels (80 mg/dL).The primary outcome was all-cause death. The secondary outcome was cardiovascular death.A total of 14 478 participants (mean [SD] age, 62.1 [5.8] years; 11 034 men [76.2%]) from the UKB and 5467 participants (mean [SD] age, 63.8 [12.3] years; 3632 men [66.4%]) from the EmCAB were included in the study. Over a median follow-up of 8.9 (IQR, 8.0-9.7) years in the UKB and 6.7 (IQR, 4.0-10.8) years in the EmCAB, a U-shaped association with outcomes was observed with higher risk in those with both low and very high HDL-C levels compared with those with midrange values. Very high HDL-C levels (80 mg/dL) were associated with increased risk of all-cause death (hazard ratio [HR], 1.96; 95% CI, 1.42-2.71; P .001) and cardiovascular death (HR, 1.71; 95% CI, 1.09-2.68; P = .02) compared with those with HDL-C levels in the range of 40 to 60 mg/dL in the UKB after adjustment for confounding factors. These results were replicated in the EmCAB. These associations persisted after adjustment for the HDL-C genetic risk score within the UKB. Sensitivity analyses demonstrated that the risk of all-cause mortality in the very high HDL-C group was higher among men than women in the UKB (HR, 2.63; 95% CI, 1.75-3.95; P.001 vs HR, 1.39; 95% CI, 0.82-2.35; P = .23).Results of this cohort study suggest that very high HDL-C levels are paradoxically associated with higher mortality risk in individuals with CAD. This association was independent of the common polymorphisms associated with high HDL-C levels.

Poor sleep quality is related to old age among the general population, but few studies have focused on postpartum women of advanced maternal age. The present study aimed to describe and compare sleep quality between women younger or older than 35 years of age at 3 months postpartum, and to examine the related factors.A cross-sectional survey was conducted with 160 postpartum women who had given birth at a teaching hospital in Taiwan. The participants were assigned to two groups according to age (≥35 years, n=80; and 20-34 years, n=80). Sleep quality was measured using the Pittsburgh Sleep Quality Index with a cut-off score of 5.The prevalence of poor sleep quality at 3 months postpartum was higher in older mothers (61.6%) than in younger mothers (38.4%, p0.01). Multiple logistic regression revealed that poor sleep quality was positively correlated with the severity of postpartum physical symptoms, lack of exercise, and room-sharing with infants. After adjustment for those variables, older mothers were three times more likely to have poor sleep quality than younger mothers (odds ratio=3.08; 95% confidence interval 1.52-6.23).Health care providers should pay attention to sleep problems among postpartum women, especially mothers of advanced maternal age. In particular, health care providers should evaluate sleep quality among postpartum women, instruct them not to share the bed with their infants at night, perform exercise, and manage their postpartum physical symptoms to improve the sleep quality.

Introduction: Mental stress-induced myocardial ischemia (MSI) is a risk marker for adverse outcomes among coronary artery disease (CAD) that is more prevalent among patients with posttraumatic stress disorder (PTSD). Hypothesis: CAD patients with PTSD who develop MSI experience a higher risk of adverse cardiovascular events compared with those who do not develop MSI. Methods: We studied 995 individuals with stable CAD who participated in two contemporary cohort studies with similar protocols, the Mental Stress Ischemia Prognosis Study (MIPS), and the Myocardial Infarction and Mental Stress Study (MIMS). Provocation of myocardial ischemia with a standardized mental stress test (speech task) was assessed with single-photon emission computed tomography. PTSD was assessed with the structured clinical interviews for DSM-IV. Participants were categorized into four groups based on their MSI and PTSD status. The primary endpoint was a composite outcome of cardiovascular death or nonfatal myocardial infarction (MI), stroke, or heart failure hospitalization. Cox regression models were used to investigate the interaction of PTSD and MSI on the study endpoint in the two samples pooled with meta-analysis. Results: In total, 603 participants in MIPS and 392 in MIMS were included. MSI occurred in 16% of the patients in MIPS and 17% in MIMS. Over a 5-year median follow-up, there were 126 outcome events in MIPS and 117 in MIMS. In Cox regression models with adjustment for demographic and clinical risk factors, participants with both MSI and PTSD had a higher risk for the study endpoint, compared to those with neither. In contrast, participants with PTSD or MSI but not both were not at a higher risk ( p interaction=0.01). Separate analyses in the two studies were consistent. Conclusions: There is a synergistic association of PTSD and MSI on adverse outcomes in CAD patients. These findings support the confluence of chronic mental health vulnerability with acute stress responses in defining elevated risk in CAD patients.patients.

Introduction: Poor quality neighborhoods are independent risk factors for cardiovascular disease (CVD) but are understudied in Blacks, who face large CVD health disparities. Arterial stiffness (AS) precedes development of hypertension and adverse CVD events but the effect of neighborhood on AS among Blacks remain unknown. Objective: We compared the association between neighborhood environment and AS among Blacks in Jackson, MS and Atlanta, GA. Methods: We studied 1592 Blacks (age 58 ± 10, 38% male) living in Jackson, MS from the Jackson Heart Study (JHS) and 451 Blacks (age 53 ± 10, 39% male) living in Atlanta, GA from the Morehouse/Emory Center for Health Equity (MECA) study, without known CVD. Neighborhood problems (includes measures of aesthetic quality, walking environment, food access), social cohesion (includes activity with neighbors), and violence/safety were assessed using validated questionnaires. AS was measured as pulse wave velocity (PWV) using MRI in JHS and as PWV and augmentation index (AIx) using applanation tonometry (Sphygmocor Inc) in MECA. Multivariable linear regression models were used to examine the association between neighborhood characteristics and AS, adjusting for potential confounders. Results: Improved social characteristics, measured as social cohesion in JHS (β = -0.32 [-0.63, - 0.02], p=0.04) and activity with neighbors (β = -0.23 [-0.40, - 0.05] p=0.01) in MECA, were associated with lower PWV in both cohorts and lower AIx (β = -1.74 [-2.92, - 0.56], p=0.004) in MECA, after adjustment for CVD risk factors and income. Additionally, in MECA better food access (β = -1.18 [-2.35, - 0.01], p=0.05) was associated with lower AIx, and in JHS, lower neighborhood problems (β = -0.33 [-0.64, - 0.02], p=0.04) and lower violence (β = -0.30 [-0.61, 0.002], p=0.05) were associated with lower PWV (Fig). Conclusion: Neighborhood social characteristics show an independent association with vascular health of Blacks, findings that were reproducible in two distinct American cities.

Untreated blunt cerebrovascular injuries (BCVIs) are associated with high rates of death and disability due to stroke. We assessed alignment of clinical practice at our centre with current recommendations for management of BCVIs and examined rates of new and recurrent in-hospital stroke.We retrospectively reviewed the BC Trauma Registry to identify all adult (age18 yr) patients with trauma with BCVIs at the largest level 1 trauma centre in British Columbia, Canada, from Apr. 1, 2013, to Mar. 31, 2018. We evaluated the registry, hospital databases and patient charts to assess alignment with guidelines for early initiation of appropriate antithrombotic therapy and follow-up imaging, and to ascertain short-term outcomes.A total of 186 patients met the inclusion criteria. Just over half of BCVIs (97 [52.2%]) were Biffl grade 1-2. The majority of patients were treated with acetylsalicylic acid monotherapy (144/162 [88.9%]) or low-molecular-weight heparin (2/162 [1.2%]). Although guidelines recommend repeat imaging at 7-10 days to reassess the injury and guide duration of therapy, only 61/171 patients (35.7%) underwent repeat imaging within 7 days. Neuroimaging within 3 months after injury showed brain infarction in 29 patients (15.6%).Antithrombotic therapy was initiated in the majority of eligible patients with BCVIs, but completion of follow-up imaging and documentation of clear outpatient care plans were suboptimal. This finding shows the need for routine multidisciplinary management to facilitate standardization of care for this complex population.

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

The relationship between restless legs syndrome (RLS) and cardiovascular disease remains enigmatic in the general population, and its prognostic value in patients with coronary artery disease (CAD) is unknown. In this study, the frequency of RLS-like symptoms was assessed using a validated instrument in 3,266 patients undergoing cardiac catheterization (mean age 64 years, 62% male, 23% Black, and 74% with obstructive CAD). Patients were followed for primary end points of cardiovascular death or incident myocardial infarction. Fine and Gray hazard models explored the association between RLS and incident events after adjustment for demographic and clinical risk factors. In the total cohort, 29% of patients reported mild (rare or sometimes) symptoms, and 15% of patients had moderate/severe (often to almost always) symptoms of RLS. Female sex (odds ratio [OR] 2.11, 95% confidence interval (CI), 1.68 to 2.57), body mass index (OR 1.12 per 5 kg/m

Podocytes are highly differentiated epithelial cells that are crucial for maintaining the glomerular filtration barrier in the kidney. Podocyte injury followed by depletion is the major cause of pathological progression of kidney diseases. Although cell therapy has been considered a promising alternative approach to kidney transplantation for the treatment of kidney injury, the resultant therapeutic efficacy in terms of improved renal function is limited, possibly owing to significant loss of engrafted cells. Herein, hybrid three‐dimensional (3D) cell spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells were designed to mimic the glomerular microenvironment and as a cell delivery vehicle to replenish the podocyte population by cell transplantation. After creating a native glomerulus‐like condition, the expression of multiple genes encoding growth factors and basement membrane factors that are strongly associated with podocyte maturation and functionality was significantly enhanced. Our in vivo results demonstrated that intrarenal transplantation of podocytes in the form of hybrid 3D cell spheroids improved engraftment efficiency and replenished glomerular podocytes. Moreover, the proteinuria of the experimental mice with hypertensive nephropathy was effectively reduced. These data clearly demonstrated the potential of hybrid 3D cell spheroids for repairing injured kidneys.

Supplemental Digital Content is available in the text., Objective: The underlying pathobiology of the paradoxical relationship between obesity and adverse outcomes in coronary artery disease (CAD) is unclear. Our objective was to determine the association between obesity and circulating progenitor cell (CPC) counts—a measure of intrinsic regenerative capacity—in asymptomatic individuals and patients with CAD and its impact on the obesity paradox. Approach and Results: CPCs were enumerated by flow cytometry as CD45med+ cells expressing CD34+, CD133+, and CXCR4+ epitopes in 672 asymptomatic individuals (50 years of age; 28% obese) and 1277 patients with CAD (66 years of age; 39% obese). The association between obesity and CPCs was analyzed using linear regression models. The association of obesity and CPCs with cardiovascular death/myocardial infarction events over 3.5-year follow-up in patients with CAD was studied using Cox models. Obesity was independently associated with 16% to 34% higher CPC counts (CD34+, CD34+/CD133+, and CD34+/CXCR4+) in asymptomatic individuals. This association was not attenuated by systemic inflammation, insulin resistance, or secretion but partly attenuated by cardiorespiratory fitness and body composition. In patients with CAD, obesity was associated with 8% to 12% higher CPC counts and 30% lower risk of adverse outcomes. Compared with nonobese patients, only obese patients with high CPC counts (CD34+ cells ≥median, 1806 cells/mL) were at a lower risk (hazard ratio, 0.52 [95% CI, 0.31–0.88]), whereas those with low counts (

Background Prior studies have shown that women have worse 3‐month survival after receiving a left ventricular assist device compared with men. Currently used prognostic scores, including the Heartmate II Risk Score, do not account for the increased residual risk in women. We used the IMACS (International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support) registry to create and validate a sex‐specific risk score for early mortality in left ventricular assist device recipients. Methods and Results Adult patients with a continuous‐flow LVAD from the IMACS registry were randomly divided into a derivation cohort (DC; n=9113; 21% female) and a validation cohort (VC; n=6074; 21% female). The IMACS Risk Score was developed in the DC to predict 3‐month mortality, from preoperative candidate predictors selected using the Akaike information criterion, or significant sex × variable interaction. In the DC, age, cardiogenic shock at implantation, body mass index, blood urea nitrogen, bilirubin, hemoglobin, albumin, platelet count, left ventricular end‐diastolic diameter, tricuspid regurgitation, dialysis, and major infection before implantation were retained as significant predictors of 3‐month mortality. There was significant ischemic heart failure × sex and platelet count × sex interaction. For each quartile increase in IMACS risk score, men (odds ratio [OR], 1.86; 95% CI, 1.74–2.00; P P P Conclusions A sex‐specific risk score provides excellent risk prediction in LVAD recipients.

Patient safety is the core goal of medical institutions. The present study focuses on the patient safety culture and staff well-being admit the COVID-19 pandemic. In a large metropolitan hospital group, 337 employees who had participated in the quality improvement interventions completed an anonymous questionnaire of patient safety culture and personal well-being. The multiple regression analyses indicated that managerial role, seniority, female gender and direct contact with a patient were significantly related to the positive attitude on overall or certain dimensions of safety culture. Multivariate analysis also found that dimensions of teamwork climate, safety climate, job satisfaction and stress recognition as patient safety culture predicted staff exhaustion. Finally, comparing with the available institutional historic data in 2018, the COVID group scored higher on the working condition dimension of patient safety culture, but lower on the stress recognition dimension. The COVID group also scored higher on exhaustion. In the post-pandemic era, there seems to be an improvement on certain aspect of the patient safety culture among hospital staff, and the improvement is more prevalent for managers. However, exhaustion is also a poignant problem for all employees. These findings can inform hospital decision-makers in planning and implementing future improvements of patient safety culture and promoting employee well-being and resilience. Our findings also reveal directions for future research.

Cardiovascular disease (CVD) is the number one killer of adults in the U.S., with marked ethnic/racial disparities in prevalence, risk factors, associated health behaviors, and death rates. In this study, we recruited and randomized Blacks with poor cardiovascular health in the Atlanta Metro area to receive an intervention comparing two approaches to engagement with a behavioral intervention technology for CVD. Generalized Linear Mixed Models results from a 6-month intervention indicate that 53% of all participants experienced a statistical improvement in Life’s Simple 7 (LS7), 54% in BMI, 61% in blood glucose, and 53% in systolic blood pressure. Females demonstrated a statistically significant improvement in BMI and diastolic blood pressure and a reduction in self-reported physical activity. We found no significant differences in changes in LS7 or their constituent parts but found strong evidence that health coaches can help improve overall LS7 in participants living in at-risk neighborhoods. In terms of clinical significance, our result indicates that improvements in LS7 correspond to a 7% lifetime reduction of incident CVD. Our findings suggest that technology-enabled self-management can be effective for managing selected CVD risk factors among Blacks.

Introduction: Impaired vascular function in blacks contributes to a higher risk of heart failure (HF) compared to other race/ethnicities. Hypothesis: Black patients with HF with reduced ejection fraction (HFrEF) will have worse digital microvascular function measured using peripheral arterial tonometry (PAT). High resolution metabolomics profiling will identify novel biomarkers of vascular function. Methods: PAT was used to estimate the reactive hyperemia index (RHI) in blacks and whites with HFrEF (N=154, age: 53.7 ± 13.0 yrs, 48.7% female, 61.0% black) and healthy controls (N=200, age: 43.2 ± 14.0 yrs, 47.0% female, 27.0% black). Linear regression was used to determine if race was associated with RHI after adjustment for traditional CV risk factors. High-resolution plasma metabolomics profiling and pathway analysis, followed by metabolite confirmation with mass spectrometry were used to derive a metabolomics score (MS) from metabolites that were significantly associated with RHI, different between blacks and whites, and attenuated the association of black race with RHI. Results: Black subjects were younger in both the HFrEF and control cohorts. Blacks with HFrEF were more likely to have nonischemic HF and hypertension, more likely to be on hydralazine-nitrates and diuretics. RHI was lower in blacks than whites both in subjects with HFrEF (1.8 ± 0.5 vs. 2.0 ± 0.5, P=0.02) and in healthy controls (2.1 ± 0.5 vs. 2.4 ± 0.5, P=0.003). Black race was independently associated with lower RHI (adjusted β=-0.221, P=0.03). MS comprising metabolites representative of cardiac cachexia (3-Methyl-Histidine, L-Histidine, Creatinine), vascular collagen turnover (4-hydroxyproline), purine metabolism and oxidative stress (uric acid) attenuated the association of black race with RHI by 49.8%. Conclusion: Integration of vascular phenotyping with metabolomic profiling reveals a novel MS that attenuates the association of black race with impaired microvascular function.

Introduction: Arterial stiffness is a precursor for development of hypertension and premature cardiovascular disease (CVD). Physical activity has been associated with lower arterial stiffness among largely White populations, but the types of activity required and whether these findings apply to Blacks remain unknown. We examined whether physical activity levels were associated with arterial stiffness among Blacks in two independent cohorts. Methods: In the Morehouse-Emory Cardiovascular (MECA) Center for Health Equity, 458 Black adults (age 53 ± 10, 39% male) without known CVD living in Atlanta, GA were recruited. Arterial stiffness was measured as pulse wave velocity (PWV) using applanation tonometry (Sphygmocor Inc). Total and domain specific physical activity (work, active living, household, and sport/exercise) were assessed by self-report using the Jackson Heart Study Physical Activity Questionnaire. Multiple linear regression models were used to investigate differences after adjusting for age, gender, blood pressure, diabetes, and smoking. Change in the Framingham Risk Score (FRS) was tested as a potential mediator. Findings were validated in the Emory-Morehouse Partnership to Reduce Cardiovascular Health Disparities (META-Health) --another independent cohort of Black adults (n=60, age 50 ± 10, 25% male). Results: Lower arterial stiffness was associated with higher self-reported levels of sport/exercise (Beta = -0.54 [-1.03, -0.05], p=0.03, highest versus lowest quartile), but not work, active living, household-related physical activities, or the overall physical activity scores. 26.9% of this improvement appeared to be mediated through changes in FRS factors. These findings were confirmed in an independent group of Blacks in META-Health where higher levels of sport/exercise remained associated with lower arterial stiffness (Beta = -1.46 [-2.80, -0.12], p=0.03, highest versus lowest quartile). Conclusion: Higher sport/exercise related physical activity is associated with lower arterial stiffness in Blacks, an association that is only partially attributable to a lower traditional CVD risk factor burden.

Introduction: Prior studies have shown that females have worse 3-month survival post-LVAD. Currently used prognostic scores including the Heartmate II Risk Score (HMRS), were developed in >75% male cohorts, and may not account for the increased residual risk in females. Hypothesis: A sex-specific risk score will predict post-LVAD mortality in females, and perform better than HMRS. Methods: Adult CF-LVAD patients from the ISHLT Mechanically Assisted Circulatory Support (IMACS) registry (Implant years: Jan 2013 - Sep 2017, age: 56 ± 13 yrs, 21% female, 36% centrifugal pumps) were randomly divided into derivation (DC, n=9113, 21% female) and validation cohorts (VC, n=6074, 21% female). Primary outcome of interest was 3-month mortality. IMACS risk score (IMACS-RS) was developed in the DC, from pre-operative candidate predictors selected using Akaike Information Criterion, or significant sex*variable interaction. Results: There were 1,466 deaths (9.7%) within 3 months after implant. In the DC, age, cardiogenic shock at implant, Body Mass Index, Blood Urea Nitrogen, bilirubin, hemoglobin, albumin, platelet count, LV End Diastolic Diameter, Tricuspid Regurgitation, dialysis and major infection pre-implant were retained as significant predictors of 3-month mortality. There was a significant ischemic HF*sex and platelet count*sex interaction. For each quartile increase in IMACS-RS, females had 93% increased odds (p Conclusions: A sex-specific risk score provides excellent risk prediction in LVAD patients. Future prognostic studies in advanced HF should present sex-specific secondary outcomes.

While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. "gene burden") and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = [Formula: see text], Mobitz Type II AV block (p = [Formula: see text]) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.

Objective Exacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device. Methods Using a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n = 25) using noninvasive sensing modalities. Participants received either sham (n = 12) or active tcVNS (n = 13) after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated. Results Relative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted β = −5.7%; 95% CI: ±3.6%, effect size d = 0.43, p, Highlights • We studied the effects of tcVNS on physiological responses to stress in patients with posttraumatic stress disorder (PTSD). • TcVNS modulates physiologic reactivity to acute traumatic and mental stress. • Peripheral autonomic measures could serve as real-time measures to evaluate the therapy response in longitudinal settings.

Objective: Women with symptoms or signs of myocardial ischemia but no obstructive coronary artery disease (INOCA) often have coronary vascular dysfunction and elevated risk for adverse cardiovascular events. We hypothesized that u-hscTnI (ultra-high–sensitivity cardiac troponin I), a sensitive indicator of ischemic cardiomyocyte injury, is associated with coronary vascular dysfunction in women with INOCA. Approach and Results: Women (N=263) with INOCA enrolled in the WISE-CVD study (Women’s Ischemic Syndrome Evaluation–Coronary Vascular Dysfunction) underwent invasive coronary vascular function testing and u-hscTnI measurements (Simoa HD-1 Analyzer; Quanterix Corporation, Lexington, MA). Logistic regression models, adjusted for traditional cardiovascular risk factors were used to evaluate associations between u-hscTnI and coronary vascular function. Women with coronary vascular dysfunction (microvascular constriction and limited coronary epicardial dilation) had higher plasma u-hscTnI levels (both P =0.001). u-hscTnI levels were associated with microvascular constriction (odds ratio, 1.38 per doubling of u-hscTnI [95% CI, 1.03–1.84]; P =0.033) and limited coronary epicardial dilation (odds ratio, 1.37 per doubling of u-hscTnI [95% CI, 1.04–1.81]; P =0.026). u-hscTnI levels were not associated with microvascular dilation or coronary epicardial constriction. Conclusions: Our findings indicate that higher u-hscTnI is associated with coronary vascular dysfunction in women with INOCA. This suggests that ischemic cardiomyocyte injury in the setting of coronary vascular dysfunction has the potential to contribute to adverse cardiovascular outcomes observed in these women. Additional studies are needed to confirm and investigate mechanisms underlying these findings in INOCA. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00832702.

Background: Despite well-documented cardiovascular disparities between racial groups, within-race determinants of cardiovascular health among Black adults remain understudied. Factors promoting cardiovascular resilience among Black adults in particular warrant further investigation. Our objective was to examine whether individual psychosocial resilience and neighborhood-level cardiovascular resilience were associated with better cardiovascular health in Black adults, measured utilizing Life’s Simple 7 (LS7) scores. Methods: We assessed LS7 scores in 389 Black adults (mean age, 53±10 years; 39% men) living in Atlanta, Georgia. A composite score of individual psychosocial resilience was created by assessing environmental mastery, purpose in life, optimism, resilient coping, and depressive symptoms. Neighborhood-level cardiovascular resilience was separately determined by the census tract-level rates of cardiovascular mortality/morbidity events. Generalized linear mixed regression models were used to examine the association between individual psychosocial resilience, neighborhood cardiovascular resilience, and LS7 scores. Results: Higher individual psychosocial resilience was significantly associated with higher LS7 (β=0.38 [0.16–0.59] per 1 SD) after adjustment for sociodemographic factors. Similarly, higher neighborhood-level cardiovascular resilience was significantly associated with higher LS7 (β=0.23 [0.02–0.45] per 1 SD). When jointly examined, high individual psychosocial resilience (>median) was independently associated with higher LS7 (β=0.73 [0.31–1.17]), whereas living in high-resilience neighborhoods (>median) was not. The largest difference in LS7 score was between those with high and low psychosocial resilience living in low-resilience neighborhoods (8.38 [7.90–8.86] versus 7.42 [7.04–7.79]). Conclusions: Individual psychosocial resilience in Black adults is associated with better cardiovascular health.

Quantitative traits obtained from computed tomography (CT) scans performed in routine clinical practice have the potential to enhance translational research and genomic discovery when linked to electronic health record (EHR) and genomic data. For example, both liver fat and abdominal adipose mass are highly relevant to human disease; non-alcoholic fatty liver disease(NAFLD) is present in 30% of the US adult population, is strongly associated with obesity, and can progress to hepatic inflammation, cirrhosis, and hepatocellular carcinoma. We built a fully automated image curation and organ labeling technique using deep learning to identify liver, spleen, subcutaneous and visceral fat compartments in the abdomen and extract 12 quantitative imaging traits from 161,748 CT scans in 19,624 patients enrolled in the Penn Medicine Biobank (PMBB). The average liver fat, as defined by a difference in attenuation between spleen and liver, was −6.4 ± 9.1 Hounsfield units (HU). In 135 patients who had undergone both liver biopsy and imaging, receiver operating characteristic (ROC) analysis revealed an area under the curve(AUC) of 0.81 for hepatic steatosis. The mean fat volume within the abdominal compartment for subcutaneous fat was 4.9 ± 3.1 L and for visceral fat was 2.9 ± 2.1 L. We performed integrative analyses of liver fat with the phenome extracted from the EHR and found highly significant associations with chronic liver disease/cirrhosis, chronic non-alcoholic liver disease, diabetes mellitus, obesity, hypertension, renal failure, alcoholism, hepatitis C, use of therapeutic adrenal cortical steroids, respiratory failure and pancytopenia. Liver fat was significantly associated with two of the most robust genetic variants associated with NAFLD, namely rs738409 in PNPLA3 and rs58542926 in TM6SF2. Finally, we performed multivariate principle component analysis (PCA) to show the importance of each of the quantitative imaging traits to NAFLD and their interrelationships with the phenome. This work demonstrates the power of automated image quantitative trait analyses applied to routine clinical imaging studies to fuel translational scientific discovery.

Background We designed a novel ankle foot orthosis (AFO), namely, ideal training AFO (IT-AFO), with motion feedback on the hemiparetic lower limb to improve ambulation in individuals with stroke-related hemiplegia. We, therefore sought to compare the kinematic parameters of gait between IT-AFO with and without dynamic control and conventional anterior-type AFO or no AFO. Methods Gait parameters were measured using the RehaWatch® system in seven individuals with hemiplegia (mean 51.14 years). The parameters were compared across four conditions: no AFO, conventional anterior AFO, IT-AFO without dynamic control, and IT-AFO with dynamic control, with three trials of a 10-m walk test for each. Results The dorsiflexion angle increased during the swing phase when the IT-AFO was worn, and it was larger with dynamic control. These data can confirm drop foot improvement; however, the difference between the parameters with- and without-AFO control conditions was not significant in the swing phase. The IT-AFO with or without dynamic control enhanced the loading response to a greater extent between the hemiparetic and unaffected lower limbs than conventional AFO or no AFO. The duration of the stance phase on the hemiparetic lower limb was also longer when using IT-AFO with and without dynamic control than that when using conventional AFO, which improved asymmetry. User comfort and satisfaction was greater with IT-AFO than with the other conditions. Conclusions The IT-AFO with dynamic control improved gait pattern and weight shifting to the hemiparetic lower limb, reducing gait asymmetry. The difference with and without dynamic control of IT-AFO is not statistically significant, and it is limited by sample size. However, this study shows the potential of IT-AFO in applying positive motion feedback with gait training. Trial registration Taipei Medical University-Joint Institutional Review Board. N201510010. Registered 12 February 2015. http://ohr.tmu.edu.tw/main.php.

Objective Patients with CAD have substantial residual risk of mortality, and whether hitherto unknown small-molecule metabolites and metabolic pathways contribute to this risk is unclear. We sought to determine the predictive value of plasma metabolomic profiling in patients with CAD. Approach and results Untargeted high-resolution plasma metabolomic profiling of subjects undergoing coronary angiography was performed using liquid chromatography/mass spectrometry. Metabolic features and pathways associated with mortality were identified in 454 subjects using metabolome-wide association studies and Mummichog, respectively, and validated in 322 subjects. A metabolomic risk score comprising of log-transformed HR estimates of metabolites that associated with mortality and passed LASSO regression was created and its performance validated. In 776 subjects (66.8 years, 64% male, 17% Black), 433 and 357 features associated with mortality (FDR-adjusted q

Background: South Asians are a high-risk ethnic group for cardiovascular disease despite having lower levels of conventional cardiovascular risk factors such as obesity and smoking. Ethnic differences in pulse wave reflections, arterial stiffness, and subclinical atherosclerosis as measured using augmentation index (AIX), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) may reflect some of this excess risk. Methods: We conducted a cross-sectional analysis of pooled data from three community-based sources in Atlanta, Georgia, USA. Data on 530 South Asians collected from local health fairs was compared with data on 507 White and 192 African Americans from the Emory Predictive Health Initiative and 351 White and 382 African Americans from the Morehouse and Emory Team up to Eliminate Health Disparities Study. Results: Linear regression models adjusted for age, sex, smoking, MAP, fasting glucose, TC, HDL-C, creatinine, and body mass index were used to assess the relationship between ethnicity and vascular function measures. In fully adjusted models, South Asians had higher heart rate corrected AIX as compared with Whites and African Americans (by 5.47%, p

Vaccination has been used to control the spread of seasonal flu; however, the virus continues to evolve and escape from host immune response through mutation and increasing glycosylation. Efforts have been directed toward development of a universal vaccine with broadly protective activity against multiple influenza strains and subtypes. Here we report the design and evaluation of various chimeric vaccines based on the most common avian influenza H5 and human influenza H1 sequences. Of these constructs, the chimeric HA (cHA) vaccine with consensus H5 as globular head and consensus H1 as stem was shown to elicit broadly protective CD4(+) and CD8(+) T cell responses. Interestingly, the monoglycosylated cHA (cHA(mg)) vaccine with GlcNAc on each glycosite induced more stem-specific antibodies, with higher antibody-dependent cellular cytotoxicity (ADCC), and better neutralizing and stronger cross-protection activities against H1, H3, H5, and H7 strains and subtypes. Moreover, the cHA(mg) vaccine combined with a glycolipid adjuvant designed for class switch further enhanced the vaccine efficacy with more IFN-γ, IL-4, and CD8(+) memory T cells produced.

In this study, 15 wine cakes from various sources were collected for the investigation of whitening and moisturizing effects. The fatty acid and free amino acid contents of the wine cakes were analyzed. The results showed that flattened yellow wine cake had the highest free amino acid contents (630 mg/100 g) among all the wine cakes tested. In addition, the fatty acid content of the wine cakes was higher than that of Japanese sake wine. Since the fatty acids and amino acids of wine cake are similar to the natural moisturizing factors and the intercellular lipids in the human epidermis, the wine cakes could be applied as cosmetic humectants. The ethanolic extracts of wine cakes were subjected to tests for the inhibition cones of tyrosinase, the inhibition rates on tyrosinase activity, and inhibition of DOPA quinone synthesis via B16 melanoma cell. The inhibition zones of tyrosinase caused by grain sorghum wine cakes and yellow wine cakes were larger than that of arbutin. Reduction of the inhibition rate on tyrosinase activity was in the following order: dry grain sorghum wine cake, flattened yellow wine cake, wet grain sorghum wine cake, dry yellow wine cake and wet yellow wine cake. Moreover, in the tests for inhibition of DOPA quinone synthesis, higher inhibitions were shown for dry grain sorghum wine cake by 1.03-fold, wet grain sorghum wine cake by 0.74-fold, dry yellow wine cake by 0.62-fold, wet yellow wine cake by 0.94-fold, and sake wine cake by 0.79-told, when compared with arbutin. Our results of the three in vitro inhibition tests for tyrosinase activity indicated that grain sorghum wine cakes and yellow wine cakes can be developed for use as skin-whitening agents and humectants.

Background: Black patients have higher rates of hospitalization for acute heart failure than other race/ethnic groups. We sought to determine whether diuretic efficiency is associated with racial differences in risk for rehospitalization after acute heart failure. Methods: A post hoc analysis was performed on 721 subjects (age, 68±13 years; 22% black) enrolled in 3 acute heart failure clinical trials: ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure), DOSE-AHF (Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure), and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Repeated-measures ANOVA was used to test for a race×time effect on measures of decongestion. Diuretic efficiency was calculated as net fluid balance per total furosemide equivalents. In a subset of subjects, Cox regression was used to examine the association between race and rehospitalization according to plasma renin activity (PRA). Results: Compared with nonblack patients, black patients were younger and more likely to have nonischemic heart failure. During the first 72 to 96 hours, there was greater fluid loss ( P =0.001), decrease in NT-proBNP (N-terminal pro-B-type natriuretic peptide; P =0.002), and lower levels of PRA ( P P =0.014). However, adjustment for baseline PRA attenuated the association between black race and diuretic efficiency. Over a median follow-up of 68 (interquartile range, 56–177) days, there was an increased risk of all-cause and heart failure–specific rehospitalization in nonblack patients with increasing levels of PRA, while the risk of rehospitalization was relatively constant across levels of PRA in black patients. Conclusions: Higher diuretic efficiency in black patients with acute heart failure may be related to racial differences in activity of the renin-angiotensin-aldosterone system.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide that plays a key role in the neurobiology of the stress response, and prior studies suggest that its function is dysregulated in post-traumatic stress disorder (PTSD). Transcutaneous cervical vagus nerve stimulation (tcVNS) acts through PACAP and other neurobiological systems to modulate stress responses and/or symptoms of PTSD. In this pilot study, we examined the effects of tcVNS on PACAP in a three day chronic stress laboratory paradigm involving serial traumatic and mental stress exposures in healthy individuals with a history of exposure to psychological trauma (n ​= ​18) and patients with PTSD (n ​= ​12). Methods A total of 30 subjects with a history of exposure to psychological trauma experience were recruited (12 with PTSD diagnosis) for a three-day randomized double-blinded study of tcVNS or sham stimulation. Subjects underwent a protocol that included both personalized trauma recall and non-personalized mental stressors (public speaking, mental arithmetic) paired to tcVNS or sham stimulation over three days. Blood was collected at baseline and multiple time points after exposure to stressors. Linear mixed-effects models were used to assess changes in PACAP over time (in response to stressors) and its relation to active tcVNS or sham stimulation. Results PACAP blood levels increased over the course of three days for both active tcVNS and sham groups. This increase was statistically-significant in the sham group at the end of the second (Cohen’s drm ​= ​0.35, p ​= ​0.04), and third days (drm ​= ​0.41, p ​= ​0.04), but not in the active tcVNS group (drm ​= ​0.21, drm ​= ​0.18, and p ​> ​0.20). Conclusion These pilot findings suggest tcVNS may attenuate this neurobiological stress-response. Larger studies are needed to investigate gender and interaction effects.

Stress may contribute to progression of coronary heart disease (CHD) through inflammation, especially among women. Thus, we sought to examine whether increased inflammatory response to stress among patients with CHD is associated with a greater risk of cardiovascular events and whether this risk is higher in women. We examined inflammatory biomarkers known to increase with mental stress (speech task), including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and matrix metallopeptidase-9 (MMP-9) among 562 patients with stable CHD. Inflammatory response, the difference between post-stress and resting values, was examined as a predictor of major adverse cardiovascular events (MACE) using subdistribution hazards models for competing risks adjusting for demographics, cardiovascular risk factors, and medications. MACE was defined as a composite endpoint of cardiovascular death, myocardial infarction, unstable angina with revascularization, and heart failure. All biomarkers were standardized. The mean age was 63 years (range 34–79) and 24% were women. During a median follow-up of 3 years, 71 patients experienced MACE. Overall, there was no significant association between inflammatory response to stress and risk of MACE, but there were sex-based interactions for IL-6 (p = 0.001) and MCP-1 (p = 0.01). The risk of MACE increased 56% (HR: 1.56; 95% CI: 1.21, 2.01; p = 0.001) and 30% (HR: 1.30; 95% 1.09, 1.55; p = 0.004) for each standard deviation increase in IL-6 and MCP-1 response to mental stress for women, respectively, while there was no association among men. Increased inflammation in response to stress is associated with future adverse cardiovascular outcomes among women with CHD.

Background Cardiovascular disease incidence, prevalence, morbidity, and mortality have declined in the past several decades; however, disparities persist among subsets of the population. Notably, blacks have not experienced the same improvements on the whole as whites. Furthermore, frequent reports of relatively poorer health statistics among the black population have led to a broad assumption that black race reliably predicts relatively poorer health outcomes. However, substantial intraethnic and intraracial heterogeneity exists; moreover, individuals with similar risk factors and environmental exposures are often known to experience vastly different cardiovascular health outcomes. Thus, some individuals have good outcomes even in the presence of cardiovascular risk factors, a concept known as resilience. Methods and Results The MECA (Morehouse‐Emory Center for Health Equity) Study was designed to investigate the multilevel exposures that contribute to “resilience” in the face of risk for poor cardiovascular health among blacks in the greater Atlanta, GA, metropolitan area. We used census tract data to determine “at‐risk” and “resilient” neighborhoods with high or low prevalence of cardiovascular morbidity and mortality, based on cardiovascular death, hospitalization, and emergency department visits for blacks. More than 1400 individuals from these census tracts assented to demographic, health, and psychosocial questionnaires administered through telephone surveys. Afterwards, ≈500 individuals were recruited to enroll in a clinical study, where risk biomarkers, such as oxidative stress, and inflammatory markers, endothelial progenitor cells, metabolomic and micro RNA profiles, and subclinical vascular dysfunction were measured. In addition, comprehensive behavioral questionnaires were collected and ideal cardiovascular health metrics were assessed using the American Heart Association's Life Simple 7 measure. Last, 150 individuals with low Life Simple 7 were recruited and randomized to a behavioral mobile health (eHealth) plus health coach or eHealth only intervention and followed up for improvement. Conclusions The MECA Study is investigating socioenvironmental and individual behavioral measures that promote resilience to cardiovascular disease in blacks by assessing biological, functional, and molecular mechanisms. REGISTRATION URL : https://www.clini​caltr​ials.gov . Unique identifier: NCT 03308812.

Background Multiple biomarkers have been independently and additively associated with major adverse cardiovascular events in patients with coronary artery disease. We investigated the prognostic value of suPAR (soluble urokinase‐type plasminogen activator receptor) and hsTnI (high‐sensitivity troponin I) levels in symptomatic patients with no obstructive coronary artery disease. We hypothesized that high levels of these biomarkers will be associated with the risk of future adverse outcomes. Methods and Results Plasma levels of suPAR and hsTnI were measured in 556 symptomatic patients with no obstructive coronary artery disease. A biomarker risk score was calculated by counting the number of biomarkers above the median in this cohort (suPAR>2523 pg/mL and hsTnI>2.7 pg/mL). Survival analyses were performed with models adjusted for traditional risk factors. All‐cause death and major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, and heart failure) served as clinical outcomes over a median follow‐up of 6.2 years. Mean age was 57±10 years, 49% of the cohort patients were female, and 68% had a positive stress test. High suPAR and hsTnI levels were independent predictors of all‐cause death (hazard ratio=3.2 [95% CI, 1.8–5.7] and 1.3 [95% CI, 1.0–1.7], respectively; both P P Conclusions Among symptomatic patients with no obstructive coronary artery disease, higher levels of suPAR and hsTnI were independently and additively associated with an increased risk of adverse events. Whether modification of these biomarkers will improve risk in these patients needs further investigation.

Background Lower extremity peripheral arterial disease (PAD) is a public health problem and many patients with PAD experience claudication despite adequate medical and/or surgical management. Mobilization of endogenous progenitor cells using Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is a novel therapeutic option that has shown promising results in experimental models and phase I/IIA clinical trials. The GPAD-3 trial will study the effect of two successive administrations of GM-CSF at 3-month interval for improving claudication among patients with lower extremity PAD. Methods We plan to recruit 176 patients in this ongoing randomized, double-blind, placebo-controlled Phase IIB trial. After screening for inclusion and exclusion criteria, eligible subjects undergo a 4-week screening phase where they perform subcutaneous placebo injections thrice weekly and walk at least three times a day until they develop claudication. After the screening phase, eligible subjects undergo baseline testing and are randomized 2:1 to receive 500 μg/day of GM-CSF subcutaneously thrice weekly for three weeks or placebo injections. After 3 months, follow-up endpoint testing is performed and subjects in the GM-CSF group receive the second administration of the drug for three weeks while subjects in placebo group receive matching placebo injections. All participants undergo endpoint testing at six-month and nine-month follow-up. The primary endpoint is change in 6-min walk distance between baseline and 6-month follow-up. Conclusion GPAD-3 explores a novel approach to address the need for alternative therapies that can alleviate symptoms among patients with lower extremity PAD. If successful, this study will pave the way for a pivotal Phase III trial.