Arterial properties as determinants of left ventricular mass and fibrosis in severe aortic Stenosis : findings from ACRIN PA 4008

Background-The role of arterial load in severe aortic stenosis is increasingly recognized. However, patterns of pulsatile load and their implications in this population are unknown. We aimed to assess the relationship between the arterial properties and both (1) left ventricular remodeling and fibrosis and (2) the clinical course of patients with severe aortic stenosis undergoing aortic valve replacement (AVR). Methods and Results-We enrolled 38 participants with symptomatic severe aortic stenosis scheduled to undergo surgical AVR. Aortic root characteristic impedance, wave reflections parameters (reflection magnitude, reflected wave transit time), and myocardial extracellular mass were measured with cardiac magnetic resonance imaging and arterial tonometry Cardiac magnetic resonance imaging was repeated at 6 months in 30 participants. A reduction in cellular mass (133.6 versus 113.9 g; P=0.002) but not extracellular mass (42.3 versus 40.6 g; P=0.67) was seen after AVR. Participants with higher extracellular mass exhibited greater reflection magnitude (0.68 versus 0.54; P=0.006) and lower aortic root characteristic impedance (56.3 versus 96.9 dynes/s per cm(5); P=0.006). Reflection magnitude was a significant predictor of smaller improvement in the quality of life (Kansas City Cardiomyopathy Questionnaire score) after AVR (R=-0.51; P=0.0026). The 6-minute walk distance at 6 months after AVR was positively correlated with the reflected wave transit time (R=0.52; P=0.01). Conclusions-Consistent with animal studies, arterial wave reflections are associated with interstitial volume expansion in severe aortic stenosis and predict a smaller improvement in quality of life following AVR. Future trials should assess whether wave reflections represent a potential therapeutic target to mitigate myocardial interstitial remodeling and to improve the clinical status of this patient population

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

A Nationwide Study of Clinical Outcomes After Robot-Assisted Coronary Artery Bypass Surgery and Hybrid Revascularization in the Netherlands

Objective: Robot-assisted minimally invasive direct coronary artery bypass (RA-MIDCAB) surgery and hybrid coronary revascularization (HCR) are minimally invasive alternative strategies to conventional coronary artery bypass surgery in patients with isolated left anterior descending (LAD) stenosis or multivessel coronary disease. We analyzed a large, multicenter data-set based on the Netherlands Heart Registration including all patients undergoing RA-MIDCAB. Methods: We included 440 consecutive patients who underwent RA-MIDCAB with the left internal thoracic artery to LAD between January 2016 and December 2020. A proportion of patients underwent percutaneous coronary intervention (PCI) of non-LAD vessels (i.e., HCR). The primary outcome was all-cause mortality at median follow-up of 1 year, which was subdivided into cardiac and noncardiac. Secondary outcomes included target vessel revascularization (TVR) at median follow-up as well as 30-day mortality, perioperative myocardial infarction, reoperation for bleeding or anastomosis-related problems, and in-hospital ischemic cerebrovascular accident (iCVA). Results: Among all patients, 91 (21%) underwent HCR. At median (IQR) follow-up of 19 (8 to 28) months, 11 patients (2.5%) had died. In 7 patients, the cause of death was defined as cardiac. TVR occurred in 25 patients (5.7%), of whom 4 underwent CABG and 21 underwent PCI. At 30-day follow-up, 6 patients (1.4%) had a perioperative myocardial infarction, of whom 1 died. One patient (0.2%) developed an iCVA, and 18 patients (4.1%) underwent reoperation for bleeding or anastomosis-related problems. Conclusions: The clinical outcomes of patients undergoing RA-MIDCAB or HCR in the Netherlands are good and promising when compared with the currently available literature

Using performance data and reproductive measurements to predict fertility in replacement beef heifers

Abstract This study investigated the predictive value of reproductive tract evaluation and growth characteristics measured 30–70 d prior to the breeding season on 1) pregnancy outcome and 2) time to conception in replacement beef heifers. A total of 1,992 heifers (BW 329 ± 42 kg; age 347 ± 27 d) were delivered for enrollment in the Georgia Heifer Evaluation and Reproductive Development (HERD) program between 2006 and 2011 at two locations. Physical traits were selected to assess management of heifers prior to entering the program in addition to developmental traits traditionally measured in the HERD program and included: reproductive tract maturity score (RTS), weight 70 d prior to breeding as a percentage of target weight, hip height (HH) 40–50 d prior to breeding, and average daily gain 40–50 d prior to breeding. Cattle entered in the program were of similar age and subjected to comparable nutritional and management programs. Chi-square test of homogeneity (pregnancy status) and the Kaplan–Meier product limit method (number of days from initial breeding to conception) were used to analyze univariate associations with predictor variables. Multivariate analyses of pregnancy status and time to conception were performed using logistic regression and Cox regression, respectively. The odds of pregnancy increased by 15% for every 2.5 cm increase in HH (P = 0.001), and by 20% for every 30-d increase in heifer age at the start of the breeding period (P = 0.019). Although RTS was associated (P = 0.015) with pregnancy status in the univariate analysis, after adjusting for the other variables included in the final multivariable model there was no significant association (P &amp;gt; 0.05). RTS and heifer age were not associated (P &amp;gt; 0.05) with time to conception in the multivariable analysis and were not included in the final model. However, HH was significantly (P = 0.005) associated with the time to conception after adjusting for location and year of enrollment. After 35 d, the hazard rate for conception increased 15% for every 2.5 cm increase in HH [hazard ratio (95% confidence interval) = 1.15 (1.04, 1.26); P = 0.005]. Variables intended to indicate prior management (average daily gain and weight 70 d prior to breeding as a percentage of target weight) were not found to be associated with pregnancy or time to conception. The results suggest that factors relating to maturity can be used to select heifers that are more likely to achieve pregnancy and have reduced times to conception.</jats:p

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

Background: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4&nbsp;mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60&nbsp;days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148&nbsp;serious adverse events&nbsp;in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality.&nbsp;In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11&nbsp;years older, with more comorbidities. Conclusion: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu (2022-500385-99-00)