Molecular mapping of the rabbit atrioventricular node

The atrioventricular node (AVN) of the heart is responsible for the important conduction delay between atrial systole and ventricular systole. The anatomical architecture and functional properties of the AVN are complex. Ionic currents have been characterised in the AVN at both the whole tissue level and single cell level. However, little is known about the molecular basis of these ionic currents. There were two aims of this research: 1) to generate an accurate three-dimensional reconstruction of the rabbit AVN conduction axis and 2) to use real time PCR and in situ hybridisation to measure levels of mRNA for specific ion channels and membrane proteins in the rabbit AVN and surrounding atrial and ventricular tissue. Neurofilament-M (NF-M) immunolabelling revealed a tract of cells extending from the posterior nodal extension through the compact node to the common bundle. The PNE appeared to correspond to the slow pathway. Loosely packed atrial muscle comprised the anterior region of the AVN conduction axis closest to the enclosed part of the AVN and most likely represents the fast pathway. Lower nodal cells extended from the common bundle to the lower extremities of the compact node and PNE. Significant differences in the mRNA levels between the PNE and atrial muscle for the pacemaker channel HCN4, INa channels Navl. 1 and Na, 1.5, the Ica,L channel Cav 1.3, the I to channel ß-subunit KChIP2 and Cx43 were found HCNI, Nav 1.1, Cav 1.3 and NF-M mRNA were significantly higher in the PNE, compact node and common bundle compared to the atrium and ventricle. Kir 2.1 mRNA was significantly higher in the ventricular muscle compared to the PNE and atrial muscle. Atrial natriuretic peptide (ANP) mRNA, was significantly higher in the atrial muscle compared to other tissues. For mRNAs for the Ito channels, Kv 4.2 and Kv 4.3, the delayed rectifier K+ channels, Kv 1.5, ERG, K, LQTI and minK, the inward rectifier K+ channels, Kir 2.2, Kir6.2 and ß-subunit SUR2A, and the Ca2+ handling proteins, RYR2, RYR3, NCXI and SERCA2a, there were no significant differences between tissues. In situ hybridisation staining revealed further complexity of the AVN conduction axis tissue. A region of loosely packed atrial tissue immediately adjacent to the nodal tissue was KChIP2 negative and Nav1.5 negative, and the lower nodal cells were both Cav 1.2 and Cav 1.3 positive. This study has described a complex architecture of the AVN and added further complexity by providing a detailed account of ion channel expression throughout this tissue

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Reforming Healthcare: What's the Evidence?

NHS reform continues to be a topical yet contentious issue in the UK. 'Reforming Healthcare: What's the evidence?' is the first major critical overview of the research published on healthcare reform in England from 1990 onwards by a team of leading UK health policy academics. It explores work considering the Conservative internal market of the 1990s and New Labour's healthcare reorganisations, including its attempts at performance management and the reintroduction of market-based reform from 2004 to 2010. It then considers the implications of this research for current debates about healthcare reorganisation in England, and internationally. As the most up-to-date summary of what research says works in English healthcare reform, this essential review is aimed at anyone interested in the wide-ranging debates about health reorganisation, but especially students and academics interested in social policy, public management and health policy