Reliability of pulse waveform separation analysis: effects of posture and fasting

Objective: Oscillometric pulse wave analysis devices enable, with relative simplicity and objectivity, the measurement of central hemodynamic parameters. The important parameters are central blood pressures and indices of arterial wave reflection, including wave separation analysis (backward pressure component P b and reflection magnitude). This study sought to determine whether the measurement precision (between-day reliability) of P b and reflection magnitude: exceeds the criterion for acceptable reliability; and is affected by posture (supine, seated) and fasting state. Methods: Twenty healthy adults (50% female, 27.9 years, 24.2 kg/m2) were tested on six different mornings: 3 days fasted, 3 days nonfasted condition. On each occasion, participants were tested in supine and seated postures. Oscillometric pressure waveforms were recorded on the left upper arm. Results: The criterion intra-class correlation coefficient value of 0.75 was exceeded for P b (0.76) and reflection magnitude (0.77) when participants were assessed under the combined supine-fasted condition. The intra-class correlation coefficient was lowest for P b in seated-nonfasted condition (0.57), and lowest for reflection magnitude in the seated-fasted condition (0.56). For P b, the smallest detectible change that must be exceeded in order for a significant change to occur in an individual was 2.5 mmHg, and for reflection magnitude, the smallest detectable change was 8.5%. Conclusion: Assessments of P b and reflection magnitude are as follows: exceed the criterion for acceptable reliability; and are most reliable when participants are fasted in a supine position. The demonstrated reliability suggests sufficient precision to detect clinically meaningful changes in reflection magnitude and Pb

Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers.

BACKGROUND: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. METHODS: Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). RESULTS: The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. LIMITATIONS: The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. CONCLUSIONS: Biological motion preference elicits small-to-medium-sized case-control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear

Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

Abstract: Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry

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

Cardiovascular Paediatric Medicines Development: Have Paediatric Investigation Plans Lost Heart?

This work aimed to establish whether paediatric needs in cardiovascular diseases have been met by paediatric investigation plans (PIPs) produced since the development of the European Union Paediatric Regulation in 2007. The European Medicines Agency repository was searched for patterns in the development of paediatric medicines in general. Next, positive PIPs related to cardiovascular diseases were scrutinized for outcomes and compared to specific paediatric cardiovascular needs. In total, 1866 PIPs were identified with 12% corresponding to decisions taken for cardiovascular medicines. However, despite this therapeutic area having the greatest number of overall PIPs, only 14% of established needs in paediatric cardiovascular diseases were addressed by PIPs with positive decisions. Further, 71.9% of PIPs with decisions in cardiovascular disease corresponded to full waivers, so the product would not be studied in paediatrics. Despite the progress found in overall numbers of PIPs published, cardiovascular products are still commonly used off-label in paediatrics. Particularly, there is a need to develop products to treat heart failure and hypertension, two areas with clear unmet clinical needs in paediatrics. A case study on valsartan showed that industry, regulators, health technology assessment bodies, and prescribers should work together to reduce off-label use of paediatric cardiovascular diseases (CVD)

Fitness and Fatness Are Both Associated with Cardiometabolic Risk in Preadolescents

Objective: To determine the associations between cardiorespiratory fitness (CRF) and fatness (overweight-obesity) with cardiometabolic disease risk among preadolescent children. Study design: This cross-sectional study recruited 392 children (50% female, 8-10 years of age). Overweight-obesity was classified according to 2007 World Health Organization criteria for body mass index. High CRF was categorized as a maximum oxygen uptake, determined using a shuttle run test, exceeding 35 mL·kg−1·minute−1 in girls and 42 mL·kg−1·minute−1 in boys. Eleven traditional and novel cardiometabolic risk factors were measured including lipids, glucose, glycated hemoglobin, peripheral and central blood pressure, and arterial wave reflection. Factor analysis identified underlying cardiometabolic disease risk factors and a cardiometabolic disease risk summary score. Two-way analysis of covariance determined the associations between CRF and fatness with cardiometabolic disease risk factors. Results: Factor analysis revealed four underlying factors: blood pressure, cholesterol, vascular health, and carbohydrate-metabolism. Only CRF was significantly (P = .001) associated with the blood pressure factor. Only fatness associated with vascular health (P = .010) and carbohydrate metabolism (P = .005) factors. For the cardiometabolic disease risk summary score, there was an interaction effect. High CRF was associated with decreased cardiometabolic disease risk in overweight-obese but not normal weight children (P = .006). Conversely, high fatness was associated with increased cardiometabolic disease risk in low fit but not high fit children (P \u3c .001). Conclusions: In preadolescent children, CRF and fatness explain different components of cardiometabolic disease risk. However, high CRF may moderate the relationship between fatness and cardiometabolic disease risk