Discovery, Characterization, and Optimization of a Novel Positive Allosteric Modulator-Antagonist of the D Dopamine Receptor.

To identify novel D3 dopamine receptor (D3R)-selective antagonist scaffolds, we conducted a high-throughput screen of a small-molecule library using a β-arrestin recruitment assay. The lead hit compound, , displayed unprecedented D3R selectivity as well as unusual positive allosteric modulator (PAM)-antagonist activity, which may confer unique therapeutic advantages to this scaffold. Iterative medicinal chemistry was used to synthesize and characterize 137 analogues, with several demonstrating both high D3R selectivity and improved D3R potency in β-arrestin recruitment and G protein activation assays.

Genomics of chronic dry cough unravels neurological pathways.

Background: Chronic dry cough is a symptom of common lung conditions, occurs as a side effect of ACE inhibitors (ACEis), or may be unexplained. Despite chronic dry cough representing a substantial health burden, its biological mechanisms remain unclear. We hypothesised shared genetic architecture between chronic dry cough and ACEi-induced cough and aimed to identify causal genes underlying both phenotypes.

Hospitalization for COVID-19 and Risk Factors for Severe Disease Among Children: 2022-2024.

Objectives: We assessed characteristics associated with pediatric COVID-19 hospitalizations and risk factors for severe disease among hospitalized children aged 6 months and older.

Methods: Using data from COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) during October 1, 2022, to April 30, 2024, we described demographic characteristics, underlying medical conditions, COVID-19 vaccination status, and clinical outcomes, including severe disease (intensive care unit admission, mechanical ventilation, extracorporeal membrane oxygenation, in-hospital death), of hospitalized children aged 6 months to 17 years residing in the COVID-NET catchment area with laboratory-confirmed SARS-CoV-2 infection. Multivariable log-linked Poisson generalized estimating equations were conducted to assess risk factors for severe disease among children aged 6 to 23 months and 2 to 17 years.

Oscillometry to assess ventilation heterogeneity during hospital admission for acute cardiorespiratory illness.

Rationale: Hospitalisation due to exacerbations of cardiorespiratory disease results in reduced lung function and increased airways obstruction. However, traditional measures of lung function require maximal effort which is difficult when patients are unwell ( FEV) and may focus on larger airways away from the major part of airways disease ( peak flow). We aimed to measure whole airways function using oscillometry in patients during hospitalisation with cardiorespiratory illness compared with healthy controls.

The role of human factors in the decision to administer general anaesthesia for emergency caesarean deliveries: a qualitative interview study of anaesthesia trainees in Ireland.

Background: Neuraxial anaesthesia is generally preferred over general anaesthesia (GA) for emergency caesarean deliveries (CD) due to its benefits for both mother and baby. While GA is sometimes required and unavoidable, it may also be performed unnecessarily in some cases. This study aimed to explore how trainee anaesthetists make the decision to administer GA for emergency caesarean delivery and more specifically how human factors may influence this decision-making process.