Potential impact of cardiology phone-consultation for patients risk-stratified by the HEART pathway

Objective Bedside consultation by cardiologists may facilitate safe discharge of selected patients from the emergency department (ED) even when admission is recommended by the History, Electrocardiogram, Age, Risk factors, Troponin (HEART) pathway. If bedside evaluation is unavailable, phone consultation between emergency physicians and cardiologists would be most impactful if the resultant disposition is discordant with the HEART pathway. We therefore evaluate discordance between actual disposition and that suggested by the HEART pathway in patients presenting to the ED with chest pain for whom cardiology consultation occurred exclusively by phone and to assess the impact of phone-consultation on disposition. Methods We performed a single-center, retrospective study of adults presenting to the ED with chest pain whose emergency physician had a phone consultation with a cardiologist. Actual disposition was abstracted from the medical record. HEART pathway category (low-risk, discharge; high-risk, admit) was derived from ED documentation. For discharged patients, major adverse cardiac events were assessed at 30 days by chart review and phone follow-up. Results For the 170 patients that had cardiologist phone consultation, discordance between actual disposition and the HEART pathway was 17%. The HEART pathway recommended admission for nearly 80% of discharged patients. Following cardiologist phone-consultation, 10% of high-risk patients were discharged, with the majority having undergone a functional study recommended by the cardiologist. At 30 days, discharged patients had experienced no episodes of major adverse cardiac events or rehospitalization for cardiac reasons. Conclusion For patients presenting to the ED with chest pain, cardiology phone-consultation has the potential to safely impact disposition, primarily by facilitating functional testing in high-risk individuals

Dysfunctional BMPR2 signaling drives an abnormal endothelial requirement for glutamine in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is increasingly recognized as a systemic disease driven by alteration in the normal functioning of multiple metabolic pathways affecting all of the major carbon substrates, including amino acids. We found that human pulmonary hypertension patients (WHO Group I, PAH) exhibit systemic and pulmonary-specific alterations in glutamine metabolism, with the diseased pulmonary vasculature taking up significantly more glutamine than that of controls. Using cell culture models and transgenic mice expressing PAH-causing BMPR2 mutations, we found that the pulmonary endothelium in PAH shunts significantly more glutamine carbon into the tricarboxylic acid (TCA) cycle than wild-type endothelium. Increased glutamine metabolism through the TCA cycle is required by the endothelium in PAH to survive, to sustain normal energetics, and to manifest the hyperproliferative phenotype characteristic of disease. The strict requirement for glutamine is driven by loss of sirtuin-3 (SIRT3) activity through covalent modification by reactive products of lipid peroxidation. Using 2-hydroxybenzylamine, a scavenger of reactive lipid peroxidation products, we were able to preserve SIRT3 function, to normalize glutamine metabolism, and to prevent the development of PAH in BMPR2 mutant mice. In PAH, targeting glutamine metabolism and the mechanisms that underlie glutamine-driven metabolic reprogramming represent a viable novel avenue for the development of potentially disease-modifying therapeutics that could be rapidly translated to human studies

The Heat Shock Response of Mycobacterium Tuberculosis: Linking Gene Expression, Immunology and Pathogenesis

The regulation of heat shock protein (HSP) expression is critically important to pathogens such as Mycobacterium tuberculosis and dysregulation of the heat shock response results in increased immune recognition of the bacterium and reduced survival during chronic infection. In this study we use a whole genome spotted microarray to characterize the heat shock response of M. tuberculosis. We also begin a dissection of this important stress response by generating deletion mutants that lack specific transcriptional regulators and examining their transcriptional profiles under different stresses. Understanding the stimuli and mechanisms that govern heat shock in mycobacteria will allow us to relate observed in vivo expression patterns of HSPs to particular stresses and physiological conditions. The mechanisms controlling HSP expression also make attractive drug targets as part of a strategy designed to enhance immune recognition of the bacterium

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Triggering of Nocturnal Arrhythmias by Sleep-Disordered Breathing Events

This study sought to evaluate respiratory disturbances as potential triggers for arrhythmia in patients with sleep-disordered breathing (SDB). SDB is associated with an increased risk of atrial fibrillation and nonsustained ventricular tachycardia (NSVT) as well as a predilection for sudden cardiac death during nocturnal sleeping hours. However, prior research has not established whether respiratory disturbances operate as triggers for nocturnal arrhythmias. Overnight polysomnograms from the Sleep Heart Health Study (n = 2,816) were screened for paroxysmal atrial fibrillation and NSVT. We used the case-crossover design to determine whether apneas and/or hypopneas are temporally associated with episodes of paroxysmal atrial fibrillation or NSVT. For each arrhythmia, 3 periods of sinus rhythm were identified as control intervals. Polysomnograms were examined for the presence of respiratory disturbances, oxygen desaturations, and cortical arousals within a 90-s hazard period preceding each arrhythmia or control period. Fifty-seven participants with a wide range of SDB contributed 62 arrhythmias (76% NSVT). The odds of an arrhythmia after a respiratory disturbance were nearly 18 times (odds ratio: 17.5; 95% confidence interval: 5.3 to 58.4) the odds of an arrhythmia occurring after normal breathing. The absolute rate of arrhythmia associated with respiratory disturbances was low (1 excess arrhythmia per 40,000 respiratory disturbances). Neither hypoxia nor electroencephalogram-defined arousals alone increased arrhythmia risk. Although the absolute arrhythmia rate is low, the relative risk of paroxysmal atrial fibrillation and NSVT during sleep is markedly increased shortly after a respiratory disturbance. These results support a direct temporal link between SDB events and the development of these arrhythmias