Aakash Garg

Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses.

Ruane et al. demonstrate a role for the microbiota in modulating protective immunity to intranasal vaccination via the ability of lung dendritic cells to induce B cell IgA class switching.

Phenotype and function of nasal dendritic cells

Intranasal (i.n.) vaccination generates immunity across local, regional, and distant sites. However, nasal dendritic cells (DCs), pivotal for the induction of i.n. vaccine-induced immune responses, have not been studied in detail. Here, by using a variety of parameters, we define nasal DCs in mice and humans. Distinct subsets of “classical” DCs, dependent on the transcription factor zbtb46 were identified in the murine nose. The murine nasal DCs were Fms-related tyrosine 3 kinase ligand responsive and displayed unique phenotypic and functional characteristics, including the ability to present antigen, induce an allogeneic T-cell response, and migrate in response to lipopolysaccharide or live bacterial pathogens. Importantly, in a cohort of human volunteers, BDCA-1+ DCs were observed to be the dominant nasal DC population at steady state. During chronic inflammation, the frequency of both BDCA-1+ and BDCA-3hi DCs was reduced in the nasal tissue, associating the loss of these immune sentinels with chronic nasal inflammation. The present study is the first detailed description of the phenotypic, ontogenetic, and functional properties of nasal DCs, and will inform the design of preventative immunization strategies as well as therapeutic modalities against chronic rhinosinusitis.

Chemotherapy induced Takotsubo cardiomyopathy

Chemotherapy has been linked with Takotsubo cardiomyopathy. Most of the literature on chemotherapy associated Takotsubo cardiomyopathy is on the drug 5-fluorouracil. In this report, we describe the case of a 55-year-old Asian male who developed Takotsubo cardiomyopathy while receiving dual chemotherapy with cytarabine and daunorubicin for acute myeloid leukemia. To our knowledge, it is the first case of Takotsubo cardiomyopathy associated with daunorubicin and/or cytarabine.

Thirty-Day Readmissions After Left Ventricular Assist Device Implantation in the United States: Insights From the Nationwide Readmissions Database

Background: Early readmissions contribute significantly to heart failure–related morbidity and negatively affect quality of life. Data on left ventricular assist device (LVAD)–related 30-day readmissions are scarce and limited to small studies. Methods and Results: Patients undergoing LVAD implantation between January 2013 and November 2014 who survived the index hospitalization were identified in the Nationwide Readmissions Database. We analyzed the incidence, predictors, causes, and costs of 30-day readmissions. Of 2510 LVAD recipients, 788 (31%) were readmitted within 30 days. Length of index hospitalization ≥31 days (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.07–1.50) and female sex (HR, 1.19; 95% CI, 1.01–1.42) were associated with a higher risk of 30-day readmission, whereas private insurance (HR, 0.83; 95% CI, 0.70–0.99), pre-LVAD use of short-term mechanical circulatory support (HR, 0.53; 95% CI, 0.29–0.98), and discharge to a short-term hospital facility (HR, 0.41; CI, 0.21–0.78) were associated with a lower risk. Cardiac causes accounted for 23.8% of readmissions: heart failure (13.4%) and arrhythmias (8.1%). Noncardiovascular causes accounted for 76.2% of readmissions: infection (30.2%), bleeding (17.6%), and device-related causes (8.2%). Mean length of stay for readmission was 10.7 days (median, 6 days), and average hospital cost per readmission was

Role of Vasodilator Testing in Pulmonary Hypertension.

34 948±2457. Conclusions: Early readmissions are frequent after LVAD implantation even in contemporary times. Preimplant identification of high-risk patients, and a protocol-driven follow-up using a multidisciplinary approach will be needed to reduce readmissions and improve outcomes.

A dendritic cell targeted vaccine induces long-term HIV-specific immunity within the gastrointestinal tract

Pulmonary hypertension is clinically defined by a mean pulmonary artery (PA) pressure of 25mm Hg or more at rest, as measured by right heart catheterization. To identify patients who are likely to have a beneficial response to calcium channel blockers (CCBs) and therefore a better prognosis, acute vasodilator testing should be performed in patients in certain subsets of pulmonary arterial hypertension (PAH). A near normalization of pulmonary hemodynamics is needed before patients can be considered for therapy with CCBs. Intravenous adenosine, intravenous epoprostenol, inhaled nitric oxide, or inhaled iloprost are the standard agents used for vasoreactivity testing in patients with idiopathic PAH. In this review we describe the various aspects of vasodilator testing including the rationale, pathophysiology and agents used in the procedure.

Behavioural, Mucosal and Systemic Immune Parameters in HIV-infected and Uninfected Injection Drug Users

Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events, including the observation that there is a profound loss of gastrointestinal (GI) CD4+ T cells during acute HIV-1 infection, highlight the importance of inducing HIV-specific immunity within the gut. Here we report on the generation of cellular and humoral immune responses in the intestines by a mucosally administered, dendritic cell (DC) targeted vaccine. Our results show that nasally delivered α-CD205-p24 vaccine in combination with polyICLC, induced polyfunctional immune responses within naso-pulmonary lymphoid sites that disseminated widely to systemic and mucosal (GI tract and the vaginal epithelium) sites. Qualitatively, while α-CD205-p24 prime-boost immunization generated CD4+ T-cell responses, heterologous prime-boost immunization with α-CD205-p24 and NYVAC gag-p24 generated high levels of HIV-specific CD4+ and CD8+ T cells within the GI tract. Finally, DC-targeting enhanced the amplitude and longevity of vaccine-induced immune responses in the GI tract. This is the first report of a nasally delivered, DC-targeted vaccine to generate HIV-specific immune responses in the GI tract and will potentially inform the design of preventative approaches against HIV-1 and other mucosal infections.

Clinical Application of Biomarkers in Heart Failure with a Preserved Ejection Fraction: A Review

Objective Injection drug use (IDU) remains a major risk factor for HIV-1 acquisition. The complex interplay between drug use, non-sterile injection, and Hepatitis C remains poorly understood. We conducted a pilot study to determine the effect of IDU on immune parameters among HIV-uninfected and -infected individuals. We hypothesized that IDU could further augment immunological changes associated with HIV-1 infection, which could in turn affect HIV pathogenesis Methods HIV-uninfected and -infected subjects with IDU, and non-IDU controls were recruited to obtain socio-demographic and drug-related behaviours. Blood (PBMC) and mucosal (MMC) mononuclear cells were analysed for cellular markers of immune activation (CD38 and Ki67). Serum ELISA was performed to determine levels of soluble CD14, a marker of immune activation. Results No significant quantitative differences in CD4+ and CD8+ T cell levels were observed between IDU and non-IDU subjects when accounting for the presence of HIV-1 infection. However, increased levels of cellular and soluble markers of immune activation were documented in cells and plasma of HIV-uninfected IDU subjects compared to non-injectors. Additionally, sharing of injection paraphernalia was related to immune activation among HIV-uninfected IDU subjects. Conclusion IDU, with or without HIV-1 infection, results in a significant increase in immune activation in both the peripheral blood and the GI tract. This may have significant impact on HIV transmission, pathogenesis, and immunologic responses to combination antiviral therapy. This study provides compelling preliminary results which in turn support larger studies to better define the relationship between IDU, infection with HIV-1, co-infection with Hepatitis C and immunity.

National Trends in the Incidence, Management, and Outcomes of Heart Failure Complications in Patients Hospitalized for ST-Segment Elevation Myocardial Infarction

Heart failure with a preserved ejection fraction (HFpEF) is increasingly prevalent and a leading cause of morbidity and mortality worldwide. HFpEF has a complex pathophysiology, with recent evidence suggesting that an interaction of cardiovascular and noncardiovascular comorbidities (e.g. obesity, hypertension, diabetes, coronary artery disease, and chronic kidney disease) induces an inflammatory state that eventually leads to myocardial structural and functional alterations. Current ACCF/AHA guidelines suggest incorporation of biomarkers along with clinical and imaging tools to establish the diagnosis and disease severity in heart failure (HF). However, the majority of data on biomarkers relating to their levels, or their role in accurate diagnosis, prognostication, and disease activity, has been derived from studies in undifferentiated HF or HF with a reduced EF (HFrEF). As the understanding of the mechanisms underlying HFpEF continues to evolve, biomarkers reflecting different pathways including neurohormonal activation, myocardial injury, inflammation, and fibrosis have a clinical utility beyond the diagnostic scope. Accordingly, in this review article we describe the various established and novel plasma biomarkers and their emerging value in diagnosis, prognosis, response, and guiding of targeted therapy in patients with HFpEF.

Safety and efficacy of vorapaxar in secondary prevention of atherosclerotic disease: A meta-analysis of randomized control trials

Objective To analyze contemporary trends in the incidence, management, and clinical outcomes of heart failure (HF) complications in patients hospitalized for ST-segment elevation myocardial infarction (STEMI) in the United States. Patients and Methods Using the 2003 through 2010 Nationwide Inpatient Sample databases, all patients with STEMI who were 18 years and older with acute HF were identified. Overall trends in the incidence of HF, coronary intervention, and in-hospital mortality were analyzed. Results Of 1,990,002 hospitalizations with a primary diagnosis of STEMI, 471,525 (23.7%) had HF complication (decreasing from 25.4% [95% CI, 25.3%-25.6%] in 2003 to 20.7% [95% CI, 20.5%-20.8%]) in 2010 (P trend<.001). The incidence of cardiogenic shock in patients with HF-complicated STEMI increased from 13.9% (95% CI, 13.6%-14.1%) to 22.6% (95% CI, 22.2%-23.0%) during this period (P trend<.001). From 2003 through 2010, the use of diagnostic coronary angiography and percutaneous coronary intervention increased in patients with HF-complicated STEMI from 44.3% to 62.1% and from 25.0% to 48.1%, respectively. In-hospital mortality decreased significantly in patients with HF-complicated STEMI (from 18.1% to 15.1%) and in subgroups of those with (from 42.4% to 29.9%) and without (from 14.1% to 10.8%) cardiogenic shock (all P trend<.001). The adjusted odds ratio (AOR) (per year) of death was 0.992 (95% CI, 0.988-0.997; P<.001), which changed significantly after additional adjustment for coronary intervention (AOR [per year], 1.012; 95% CI, 1.008-1.017; P<.001). Conclusion The incidence and in-hospital mortality of HF-complicated STEMI has decreased significantly during recent times along with increased use of percutaneous coronary intervention and diagnostic coronary angiography.