Immunologic changes are detectable in the peripheral blood transcriptome of clinically asymptomatic Chagas cardiomyopathy patients.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a neglected parasitic disease that affects approximately 6 million individuals worldwide. Of those infected, 20-30% will go on to develop chronic Chagas cardiomyopathy (CCC), and ultimately many of these individuals will progress to advanced heart failure. The mechanism by which this progression occurs is poorly understood, as few studies have focused on early CCC. In this study, we sought to understand the physiologic changes associated with T. cruzi infection and the development of CCC. We analyzed gene expression in the peripheral blood of asymptomatic Chagas patients with early structural heart disease, Chagas patients without any signs or symptoms of disease, and Chagas-negative patients with and without early structural heart disease. Our analysis shows that early CCC was associated with a downregulation of various peripheral immune response genes, with gene expression changes suggestive of reduced antigen presentation and T cell activation. Notably, these genes and processes were distinct from those of early cardiomyopathy in Chagas-negative patients, suggesting that the processes mediating CCC may be unique from those mediating progression to other cardiomyopathies. This work highlights the importance of the immune response in early CCC, providing insight into the early pathogenesis of this disease. The changes we have identified may serve as biomarkers of progression and could inform strategies for the treatment of CCC in its early stages, before significant cardiac damage has occurred.

NYX-2925 induces metabotropic N-methyl-d-aspartate receptor (NMDAR) signaling that enhances synaptic NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.

N-methyl-d-aspartate receptors (NMDARs) mediate both physiological and pathophysiological processes, although selective ligands lack broad clinical utility. NMDARs are composed of multiple subunits, but N-methyl-d-aspartate receptor subunit 2 (GluN2) is predominately responsible for functional heterogeneity. Specifically, the GluN2A- and GluN2B-containing subtypes are enriched in adult hippocampus and cortex and impact neuronal communication via dynamic trafficking into and out of the synapse. We sought to understand if ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3,4]octan-2-yl) butanamide (NYX-2925), a novel NMDAR modulator, alters synaptic levels of GluN2A- or GluN2B-containing NMDARs. Low-picomolar NYX-2925 increased GluN2B colocalization with the excitatory post-synaptic marker post-synaptic density protein 95 (PSD-95) in rat primary hippocampal neurons within 30 min. Twenty-four hours following oral administration, 1 mg/kg NYX-2925 increased GluN2B in PSD-95-associated complexes ex vivo, and low-picomolar NYX-2925 regulated numerous trafficking pathways in vitro. Because the NYX-2925 concentration that increases synaptic GluN2B was markedly below that which enhances long-term potentiation (mid-nanomolar), we sought to elucidate the basis of this effect. Although NMDAR-dependent, NYX-2925-mediated colocalization of GluN2B with PSD-95 occurred independent of ion flux, as colocalization increased in the presence of either the NMDAR channel blocker (5R,10S)-(-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate or glycine site antagonist 7-chlorokynurenic acid. Moreover, while mid-nanomolar NYX-2925 concentrations, which do not increase synaptic GluN2B, enhanced calcium transients, functional plasticity was only enhanced by picomolar NYX-2925. Thus, NYX-2925 concentrations that increase synaptic GluN2B facilitated the chemical long-term potentiation induced insertion of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunit levels. Basal (unstimulated by chemical long-term potentiation) levels of synaptic GluA1 were only increased by mid-nanomolar NYX-2925. These data suggest that NYX-2925 facilitates homeostatic plasticity by initially increasing synaptic GluN2B via metabotropic-like NMDAR signaling. Cover Image for this issue: doi: 10.1111/jnc.14735.

The epidemiologic characteristics, temporal trends, predictors of death, and discharge disposition in patients with a diagnosis of sepsis: A cross-sectional retrospective cohort study.

PURPOSE: To assess recent epidemiologic characteristics, temporal trends, and predictors of death and discharge disposition in patients with sepsis. MATERIAL AND METHODS: This is a cross-sectional retrospective cohort study using the US National Inpatient Sample (NIS) data from 2009 to 2012. The study population included adults (18years and older) with sepsis-related International Classification of Diseases, Ninth Revision, Clinical Modification codes at the time of discharge. Factors associated with in-hospital mortality and patient discharge disposition were derived from multivariate analyses using multinomial logistic models by SAS PROC LOGISTIC with GLOGIT link. RESULTS: Of 1 303 640 patients admitted, 15% died, 30% were discharged to home without home care, 34% were transferred to a skilled outpatient facility, and 4% were transferred to another short-term hospital. In-hospital mortality decreased from 16.5% to 13.8% (P<.001) across time. Length of stay also decreased from 6.7 to 5.9days (P<.001). Reductions in mortality and length of stay were seen despite an increase in the number of comorbidities (P<.001). Multivariate analysis revealed that the strongest predictors of in-hospital mortality were respiratory, cardiovascular, and hepatic failures, and neurologic events. The predictors of transfer to an outpatient facility were a major operative procedure, neurologic event, respiratory failure, and weight loss. Weight loss was also an independent predictor of in-hospital mortality. CONCLUSION: Certain comorbidities and organ failures were associated with death and discharge to a skilled outpatient facility.

The value of an infectious diseases specialist.

Infectious diseases (ID) specialists have played a major role in patient care, infection control, and antibiotic management for many years. With the rapidly changing nature of health care, it has become necessary for ID specialists to articulate their value to multiple audiences. This article summarizes the versatile attributes possessed by ID specialists and delineates their value to patients, hospitals, and other integral groups in the health care continuum.