Orexinergic Input to Dopaminergic Neurons of the Human Ventral Tegmental Area

The mesolimbic reward pathway arising from dopaminergic (DA) neurons of the ventral tegmental area (VTA) has been strongly implicated in reward processing and drug abuse. In rodents, behaviors associated with this projection are profoundly influenced by an orexinergic input from the lateral hypothalamus to the VTA. Because the existence and significance of an analogous orexigenic regulatory mechanism acting in the human VTA have been elusive, here we addressed the possibility that orexinergic neurons provide direct input to DA neurons of the human VTA. Dual-label immunohistochemistry was used and orexinergic projections to the VTA and to DA neurons of the neighboring substantia nigra (SN) were analyzed comparatively in adult male humans and rats. Orexin B-immunoreactive (IR) axons apposed to tyrosine hydroxylase (TH)-IR DA and to non-DA neurons were scarce in the VTA and SN of both species. In the VTA, 15.062.8% of TH-IR perikarya in humans and 3.260.3% in rats received orexin B-IR afferent contacts. On average, 0.2460.05 and 0.0560.005 orexinergic appositions per TH-IR perikaryon were detected in humans and rats, respectively. The majority(86–88%) of randomly encountered orexinergic contacts targeted the dendritic compartment of DA neurons. Finally, DA neurons of the SN also received orexinergic innervation in both species. Based on the observation of five times heavierorexinergic input to TH-IR neurons of the human, compared with the rat, VTA, we propose that orexinergic mechanism acting in the VTA may play just as important roles in reward processing and drug abuse in humans, as already established well in rodents

Association between COVID-19 mandatory lockdown and decreased incidence of preterm births and neonatal mortality

Previous studies suggest a decrease in preterm births (PTB) during de coronavirus disease 2019 (COVID-19), possibly due to the effect of the mandatory lockdown. Nevertheless, other reports have been unable to confirm this finding. Most of these studies originated in high-income countries and evaluated a limited number of potential confounders, and all of them assessed a short lockdown period. In addition, an important question remains unanswered: How can we be sure that the observed changes are due to lockdown, when most of the pregnancies delivered in the lockdown period were conceived prior to it?To date there is insufficient evidence to support the notion that public health interventions during the lockdown prevent PTB . The aim of this study was to compare the incidence of PTB, neonatal mortality (NM) and stillbirths adjusted by potential confounders during the lockdown period assessing a time window of nine and a half months during which all the pregnancies analyzed in the exposed group were conceived after the lockdown, with the corresponding incidence in the previous year where all the unexposed pregnancies analyzed were conceived before the lockdown.publishedVersionFil: Cuestas, Eduardo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas; Argentina.Fil: Cuestas, Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ciencias de la Salud; Argentina.Fil: Gómez Flores, Martha E. Gobierno de la Provincia de Buenos Aires. Hospital Doctor Ramon Carrillo; Argentina.Fil: Charras, María D. Gobierno de la Provincia de Buenos Aires. Hospital Doctor Ramon Carrillo; Argentina.Fil: Peyrano, Alberto J. Hospital Materno Provincial Dr. Raúl Felipe Lucini; Argentina.Fil: Montenegro, Clara. Hospital Materno Provincial Dr. Raúl Felipe Lucini; Argentina.Fil: Sosa-Boye, Ignacio. Clínica Universitaria Reina Fabiola; Argentina.Fil: Burgos, Verónica. Clínica Universitaria Reina Fabiola; Argentina.Fil: Giusti, Graciela. Clínica y Maternidad del Sol; Argentina.Fil: Espósito, Mario. Clínica y Maternidad del Sol; Argentina.Fil: Blanco Pool, Silvyana S. Hospital Misericordia Nuevo Siglo; Argentina.Fil: Blanco Pool, Silvyana S. Sanatorio Allende; Argentina.Fil: Gurevich, Debora P. Sanatorio Allende; Argentina.Fil: Gurevich, Debora P. Hospital Misericordia Nuevo Siglo; Argentina.Fil: Ahumada, Luis A. Sanatorio Allende; Argentina.Fil: Ahumada, Luis A. Hospital Misericordia Nuevo Siglo; Argentina.Fil: Pontoriero, Ricardo D. Hospital Misericordia Nuevo Siglo; Argentina.Fil: Rizzotti, Alina. Hospital Privado Universitario de Córdoba; Argentina.Fil: Bas, José I. Hospital Privado Universitario de Córdoba; Argentina.Fil: Vaca, María B. Hospital Universitario de Maternidad y Neonatología; Argentina.Fil: Miranda, María J. Hospital Universitario de Maternidad y Neonatología; Argentina.Fil: Ferreyra, Mirta E. Sanatorio del Salvador; Argentina.Fil: Ferreyra, Mirta E. Hospital Misericordia Nuevo Siglo; Argentina.Fil: Moreno, Gabriela C. Sanatorio del Salvador; Argentina.Fil: Pedicino, Héctor. Instituto Universidad Escuela de Medicina del Hospital Italiano; Argentina.Fil: Rojas-Rios, Melvy. Instituto Universidad Escuela de Medicina del Hospital Italiano; Argentina

Socioeconomic inequalities in low birth weight risk before and during the COVID-19 pandemic in Argentina: A cross-sectional study

Background: The coronavirus disease 2019 (COVID-19) pandemic may have exacerbated existing socioe- conomic inequalities in health. In Argentina, public hospitals serve the poorest uninsured segment of the population, while private hospitals serve patients with health insurance. This study aimed to assess whether socioeconomic inequalities in low birth weight (LBW) risk changed during the first wave of the COVID-19 pandemic. Methods: This multicenter cross-sectional study included 15929 infants. A difference-in-difference (DID) analysis of socioeconomic inequalities between public and private hospitals in LBW risk in a pandemic cohort (March 20 to July 19, 2020) was compared with a prepandemic cohort (March 20 to July 19, 2019) by using medical records obtained from ten hospitals. Infants were categorized by weight as LBW < 2500 g, very low birth weight (VLBW) < 1500 g and extremely low birth weight (ELBW) < 1000 g. Log binomial regression was performed to estimate risk differences with an interaction term representing the DID estimator. Covariate-adjusted models included potential perinatal confounders. Findings: Of the 8437 infants in the prepandemic cohort, 4887 (57 ? 9%) were born in public hospitals. The pandemic cohort comprised 7492 infants, 4402 (58 ? 7%) of whom were born in public hospitals. The DID estimators indicated no differences between public versus private hospitals for LBW risk ( −1 ? 8% [95% CI −3 ? 6, 0 ? 0]) and for ELBW risk ( −0 ? 1% [95% CI −0 ? 6, 0 ? 3]). Significant differences were found between public versus private hospitals in the DID estimators ( −1 ? 2% [95% CI, −2 ? 1, −0 ? 3]) for VLBW risk. The results were comparable in covariate-adjusted models. Interpretation: In this study, we found evidence of decreased disparities between public and private hos- pitals in VLBW risk. Our findings suggest that measures that prioritize social spending to protect the most vulnerable pregnant women during the pandemic contributed to better birth outcomes. Funding: No funding was secured for this study.Fil: Cuestas, Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Gómez Flores, Martha E.. Gobierno de la Provincia de Buenos Aires. Hospital Doctor Ramón Carrillo; ArgentinaFil: Charras, María D.. Gobierno de la Provincia de Buenos Aires. Hospital Doctor Ramón Carrillo; ArgentinaFil: Peyrano, Alberto J.. Hospital Materno Provincial Dr. Raúl Felipe Lucini; ArgentinaFil: Montenegro, Clara. Hospital Materno Provincial Dr. Raúl Felipe Lucini; ArgentinaFil: Sosa Boye, Ignacio. No especifíca;Fil: Burgos, Verónica. Universidad Católica de Córdoba. Facultad de Medicina. Clínica Universitaria Reina Fabiola; ArgentinaFil: Giusti, Graciela. Clínica y Maternidad del Sol; ArgentinaFil: Espósito, Mario. Clínica y Maternidad del Sol; ArgentinaFil: Blanco Pool, Silvyana S.. Hospital Misericordia Nuevo Siglo ; Gobierno de la Provincia de Cordoba; ArgentinaFil: Gurevich, Debora P.. Hospital Misericordia Nuevo Siglo ; Gobierno de la Provincia de Cordoba; ArgentinaFil: Ahumada, Luis A.. Hospital Misericordia Nuevo Siglo ; Gobierno de la Provincia de Cordoba; ArgentinaFil: Pontoriero, Ricardo D.. Hospital Misericordia Nuevo Siglo ; Gobierno de la Provincia de Cordoba; ArgentinaFil: Rizzotti, Alina. Hospital Privado Universitario de Córdoba; ArgentinaFil: Bas, José I.. Hospital Privado Universitario de Córdoba; ArgentinaFil: Vaca, María B.. Hospital Universitario de Maternidad y Neonatología; ArgentinaFil: Miranda, María J.. Hospital Universitario de Maternidad y Neonatología; ArgentinaFil: Ferreyra, Mirta E.. Hospital Misericordia Nuevo Siglo ; Gobierno de la Provincia de Cordoba; ArgentinaFil: Moreno, Gabriela C.. Gobierno de la Provincia de Buenos Aires. Hospital Doctor Ramón Carrillo; ArgentinaFil: Pedicino, Héctor. Hospital Italiano; ArgentinaFil: Rojas Rios, Melvy. Hospital Italiano; Argentin

Restricted T-Cell Repertoire in the Epicardial Adipose Tissue of Non-ST Segment Elevation Myocardial Infarction Patients

Aims: Human epicardial adipose tissue, a dynamic source of multiple bioactive factors, holds a close functional and anatomic relationship with the epicardial coronary arteries and communicates with the coronary artery wall through paracrine and vasocrine secretions. We explored the hypothesis that T-cell recruitment into epicardial adipose tissue (EAT) in patients with non-ST segment elevation myocardial infarction (NSTEMI) could be part of a specific antigen-driven response implicated in acute coronary syndrome onset and progression. Methods and Results: We enrolled 32 NSTEMI patients and 34 chronic coronary syndrome (CCS) patients undergoing coronary artery bypass grafting (CABG) and 12 mitral valve disease (MVD) patients undergoing surgery. We performed EAT proteome profiling on pooled specimens from three NSTEMI and three CCS patients. We performed T-cell receptor (TCR) spectratyping and CDR3 sequencing in EAT and peripheral blood mononuclear cells of 29 NSTEMI, 31 CCS, and 12 MVD patients. We then used computational modeling studies to predict interactions of the TCR beta chain variable region (TRBV) and explore sequence alignments. The EAT proteome profiling displayed a higher content of pro-inflammatory molecules (CD31, CHI3L1, CRP, EMPRINN, ENG, IL-17, IL-33, MMP-9, MPO, NGAL, RBP-4, RETN, VDB) in NSTEMI as compared to CCS (P &lt; 0.0001). CDR3-beta spectratyping showed a TRBV21 enrichment in EAT of NSTEMI (12/29 patients; 41%) as compared with CCS (1/31 patients; 3%) and MVD (none) (ANOVA for trend P &lt; 0.001). Of note, 11/12 (92%) NSTEMI patients with TRBV21 perturbation were at their first manifestation of ACS. Four patients with the first event shared a distinctive TRBV21-CDR3 sequence of 178 bp length and 2/4 were carriers of the human leukocyte antigen (HLA)-A*03:01 allele. A 3D analysis predicted the most likely epitope able to bind HLA-A3*01 and interact with the TRBV21-CDR3 sequence of 178 bp length, while the alignment results were consistent with microbial DNA sequences. Conclusions: Our study revealed a unique immune signature of the epicardial adipose tissue, which led to a 3D modeling of the TCRBV/peptide/HLA-A3 complex, in acute coronary syndrome patients at their first event, paving the way for epitope-driven therapeutic strategies

Weekly Journal Scan: is transcatheter replacement therapy for tricuspid regurgitation ready for prime time?

The TRISCEND II trial (EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy Using a Novel Device) was an international, multicentre, industry-funded, randomized controlled trial (RCT) aiming to compare safety and effectiveness of transcatheter tricuspid valve replacement (TTVR) using the EVOQUE system (Edwards Lifesciences) along with medical therapy to medical therapy alone in the treatment of patients with symptomatic, severe tricuspid regurgitation (TR).1 ̇ Patients with functional and/or degenerative TR graded as at least severe on transthoracic echocardiogram (assessed by the echo core lab using a 5-grade classification)2 who had signs or symptoms of TR or had been hospitalized for associated heart failure (HF) despite medical therapy were included. Exclusion criteria included severe right ventricular (RV) systolic dysfunction, prior heart transplantation, anatomy that precluded proper device delivery, deployment and/or function, estimated glomerular filtration rate = 25 mL/min/1.73 m2 or long-term renalreplacement therapy, and life expectancy &lt; 12 months. ̇ The primary endpoint, assessed at 12 months, was a hierarchical composite of all-cause death, durable implantation of a RV assist device or heart transplantation, tricuspid valve surgery or percutaneous intervention, annualized rate of HF hospitalization, an improvement of =10 points in the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score, an improvement of at least one New York Heart Association (NYHA) functional class, and an increase in the 6-min walk distance (6MWD) of =30 m. A win ratio analysis was performed for the primary endpoint. Secondary endpoints were a composite of death and HF hospitalization; all-cause hospitalizations; all-cause death; reduction in TR of =1 grade; reduction in NYHA functional class by =1 grade; change in KCCQ-OS from baseline; and change in 6MWD from baseline. ̇ From May 2021 through April 2023, a total of 400 patients (mean age, 79 years; 76% female) were enrolled at 45 centres in the USA and Germany and randomized in a 2:1 ratio to undergo either TTVR plus medical therapy (n = 267) or medical therapy alone (n = 133); 73% of patients had functional TR, with 57% showing parameters for massive or torrential TR; 94% of patients had atrial fibrillation. The mean pulmonary artery systolic pressure was 38 mmHg, and the mean tricuspid annular plane systolic excursion was 16 mm. Medical therapy was determined by the heart team and included stable oral diuretic medications. In the TTVR group, warfarin or another anticoagulant plus aspirin was recommended for at least 6 months after the procedure. ̇ At 12 months, the win ratio favouring TTVR was 2.0 (95% confidence interval, 1.6-2.6; P &lt; .001). In comparisons of patient pairs, those in the TTVR group showed more wins than the medical therapy group with respect to all-cause death (14.8% vs. 12.5%), tricuspid valve intervention (3.2% vs. 0.6%), and improvement in KCCQ-OS score (23.1% vs. 6.0%), NYHA class (10.2% vs. 0.8%), and 6MWD (1.1% vs. 0.9%). As compared with the medical therapy group, the TTVR group showed fewer wins with respect to the annualized rate of HF hospitalization (9.7% vs. 10.0%). ̇ As compared with patients in the medical therapy group, those in the TTVR group more frequently showed an increase of =10 points in the KCCQ-OS score (66% vs. 37%), a decrease of =1 NYHA class (79% vs. 24%), and an increase of =30 m in 6MWD (48% vs. 32%). At 12 months, 73% of the patients in the TTVR group had no residual TR, and 23% had mild TR. In the medical therapy group, most patients had severe (41%), massive (20%), or torrential TR (23%) at 12 months. The incidence of severe bleeding was higher in the TTVR group than in the medical therapy group (15.4% vs. 5.3%, P = .003), as well as the rate of permanent pacemaker implantation (17.4% vs. 2.3%, P &lt; .001)