Point-of-care assessment of platelet reactivity in the emergency department may facilitate rapid rule-out of acute coronary syndromes: a prospective cohort pilot feasibility study

Objective: Accurate, efficient and cost-effective disposition of patients presenting to emergency departments (EDs) with symptoms suggestive of acute coronary syndromes (ACS) is a growing priority. Platelet activation is an early feature in the pathogenesis of ACS; thus, we sought to obtain an insight into whether point-of-care testing of platelet function: (1) may assist in the rule-out of ACS; (2) may provide additional predictive value in identifying patients with non-cardiac symptoms versus ACS-positive patients and (3) is logistically feasible in the ED. Design: Prospective cohort feasibility study. Setting: Two urban tertiary care sites, one located in the USA and the second in Argentina. Participants: 509 adult patients presenting with symptoms of ACS. Main outcome measures Platelet reactivity was quantified using the Platelet Function Analyzer-100, with closure time (seconds required for blood, aspirated under high shear, to occlude a 150 µm aperture) serving as the primary endpoint. Closure times were categorised as ‘normal’ or ‘prolonged’, defined objectively as the 90th centile of the distribution for all participants enrolled in the study. Diagnosis of ACS was made using the standard criteria. The use of antiplatelet agents was not an exclusion criterion. Results: Closure times for the study population ranged from 47 to 300 s, with a 90th centile value of 138 s. The proportion of patients with closure times ≥138 s was significantly higher in patients with non-cardiac symptoms (41/330; 12.4%) versus the ACS-positive cohort (2/105 (1.9%); p=0.0006). The specificity of ‘prolonged’ closure times (≥138 s) for a diagnosis of non-cardiac symptoms was 98.1%, with a positive predictive value of 95.4%. Multivariate analysis revealed that the closure time provided incremental, independent predictive value in the rule-out of ACS. Conclusions: Point-of-care assessment of platelet reactivity is feasible in the ED and may facilitate the rapid rule-out of ACS in patients with prolonged closure times

Reversal of SARS-CoV2-Induced Hypoxia by Nebulized Sodium Ibuprofenate in a Compassionate Use Program

Introduction: Sodium ibuprofenate in hypertonic saline (NaIHS) administered directly to the lungs by nebulization and inhalation has antibacterial and anti-inflammatory effects, with the potential to deliver these benefits to hypoxic patients. We describe a compassionate use program that offered this therapy to hospitalized COVID-19 patients. Methods: NaIHS (50 mg ibuprofen, tid) was provided in addition to standard of care (SOC) to hospitalized COVID-19 patients until oxygen saturation levels of > 94% were achieved on ambient air. Patients wore a containment hood to diminish aerosolization. Outcome data from participating patients treated at multiple hospitals in Argentina between April 4 and October 31, 2020, are summarized. Results were compared with a retrospective contemporaneous control (CC) group of hospitalized COVID-19 patients with SOC alone during the same time frame from a subset of participating hospitals from Córdoba and Buenos Aires. Results: The evolution of 383 patients treated with SOC + NaIHS [56 on mechanical ventilation (MV) at baseline] and 195 CC (21 on MV at baseline) are summarized. At baseline, NaIHS-treated patients had basal oxygen saturation of 90.7 ± 0.2% (74.3% were on supplemental oxygen at baseline) and a basal respiratory rate of 22.7 ± 0.3 breath/min. In the CC group, basal oxygen saturation was 92.6 ± 0.4% (52.1% were on oxygen supplementation at baseline) and respiratory rate was 19.3 ± 0.3 breath/min. Despite greater pulmonary compromise at baseline in the NaIHS-treated group, the length of treatment (LOT) was 9.1 ± 0.2 gs with an average length of stay (ALOS) of 11.5 ± 0.3 days, in comparison with an ALOS of 13.3 ± 0.9 days in the CC group. In patients on MV who received NaIHS, the ALOS was lower than in the CC group. In both NaIHS-treated groups, a rapid reversal of deterioration in oxygenation and NEWS2 scores was observed acutely after initiation of NaIHS therapy. No serious adverse events were considered related to ibuprofen therapy. Mortality was lower in both NaIHS groups compared with CC groups. Conclusions: Treatment of COVID-19 pneumonitis with inhalational nebulized NaIHS was associated with rapid improvement in hypoxia and vital signs, with no serious adverse events attributed to therapy. Nebulized NaIHS s worthy of further study in randomized, placebo-controlled trials (ClinicalTrials.gov: NCT04382768).Fil: Salva, Oscar. Clínica Independencia; ArgentinaFil: Doreski, Pablo A.. Fundación Respirar; ArgentinaFil: Giler, Celia S.. Clínica Independencia; ArgentinaFil: Quinodoz, Dario C.. Sanatorio de la Cañada; ArgentinaFil: Guzmán, Lucia G.. Sanatorio de la Cañada; ArgentinaFil: Muñoz, Sonia Edith. 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: Carrillo, Mariana Norma del Valle. 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: Porta, Daniela Josefina. 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: Ambasch, Germán. Sanatorio Privado Mayo; ArgentinaFil: Coscia, Esteban. Sanatorio Privado Mayo; ArgentinaFil: Tambini Diaz, Jorge L.. Sanatorio Privado Mayo; ArgentinaFil: Bueno, Germán D.. Sanatorio Privado Mayo; ArgentinaFil: Fandi, Jorge O.. Clínica Independencia; ArgentinaFil: Maldonado, Miriam A.. Sanatorio San Roque; ArgentinaFil: Peña Chiappero, Leandro E.. Sanatori San Roque; ArgentinaFil: Fournier, Fernando. Clínica Francesa; ArgentinaFil: Pérez, Hernán A.. Sanatorio Alive; Argentina. University of Maryland; Estados UnidosFil: Quiroga, Mauro A.. Instituto Modelo de Cardiología; ArgentinaFil: Sala Mercado, Javier Agustin. Instituto Modelo de Cardiología; ArgentinaFil: Martínez Picco, Carlos. Clínica del Sol; ArgentinaFil: Beltrán, Marcelo Alejandro. Hospital Dr. Alberto Duhau; ArgentinaFil: Castillo Argañarás, Luis Fernando. Hospital Dr. Alberto Duhau; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ríos, Nicolás Martínez. Quimica Luar Srl; ArgentinaFil: Kalayan, Galia I.. Provincia de Córdoba. Ministerio de Ciencia y Técnica. Centro de Excelencia en Productos y Procesos de Córdoba; ArgentinaFil: Beltramo, Dante Miguel. Provincia de Córdoba. Ministerio de Ciencia y Técnica. Centro de Excelencia en Productos y Procesos de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Garcia, Nestor Horacio. 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; Argentina. Provincia de Córdoba. Ministerio de Ciencia y Técnica. Centro de Excelencia en Productos y Procesos de Córdoba; Argentin

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury

Background-: Emerging evidence suggests that adaptive induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction. Methods and results-: Anesthetized pigs underwent 45 minutes of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS) (an agent that purportedly upregulates autophagy; 20 mg/kg) or saline at 10 minutes before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 minutes following CAPS treatment and assayed (by immunoblotting) for 2 proteins involved in autophagosome formation: Beclin-1 and microtubule-associated protein light chain 3-II. To investigate whether the efficacy of CAPS was maintained with delayed treatment, additional pigs received CAPS (20 mg/kg) at 30 minutes after occlusion. Expression of Beclin-1 and microtubule-associated protein light chain 3-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5 and 41±4%, respectively, in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline controls (P\u3c0.01 and P\u3c0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins. Conclusion-: Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection. © 2010 American Heart Association, Inc

Modulation of cardiac output alters the mechanisms of the muscle metaboreflex pressor response

Muscle metaboreflex activation during submaximal dynamic exercise in normal subjects elicits a pressor response primarily due to increased cardiac output (CO). However, when the ability to increase CO is limited, such as in heart failure or during maximal exercise, the muscle metaboreflex-induced increases in arterial pressure occur via peripheral vasoconstriction. How the mechanisms of this pressor response are altered is unknown. We tested the hypothesis that this change in metaboreflex function is dependent on the level of CO. The muscle metaboreflex was activated in dogs during mild dynamic exercise (3.2 km/h) via a partial reduction of hindlimb blood flow. Muscle metaboreflex activation increased CO and arterial pressure, whereas vascular conductance of all areas other than the hindlimbs did not change. CO was then reduced to the same level observed during exercise before the muscle metaboreflex activation via partial occlusion of the inferior and superior vena cavae. Arterial pressure dropped rapidly with the reduction in CO but, subsequently, nearly completely recovered. With the removal of the muscle metaboreflex-induced rise in CO, substantial peripheral vasoconstriction occurred that maintained arterial pressure at the same levels as before CO reduction. Therefore, the muscle metaboreflex function is nearly instantaneously shifted from increased CO to increased vasoconstriction when the muscle metaboreflex-induced rise in CO is removed. We conclude that whether vasoconstriction occurs with muscle metaboreflex depends on whether CO rises