The effects of emotional states and traits on time perception

Background: Models of time perception share an element of scalar expectancy theory known as the internal clock, containing specific mechanisms by which the brain is able to experience time passing and function effectively. A debate exists about whether to treat factors that influence these internal clock mechanisms (e.g., emotion, personal- ity, executive functions, and related neurophysiological components) as arousal- or attentional-based factors. Purpose: This study investigated behavioral and neurophysiological responses to an affective time perception Go/ NoGo task, taking into account the behavioral inhibition (BIS) and behavioral activation systems (BASs), which are components of reinforcement sensitivity theory. Methods: After completion of self-report inventories assessing personality traits, electroencephalogram (EEG/ERP) and behavioral recordings of 32 women and 13 men recruited from introductory psychology classes were completed during an affective time perception Go/NoGo task. This task required participants to respond (Go) and inhibit (NoGo) to positive and negative affective visual stimuli of various durations in comparison to a standard duration. Results: Higher BAS scores (especially BAS Drive) were associated with overestimation bias scores for positive stimuli, while BIS scores were not correlated with overestimation bias scores. Furthermore, higher BIS Total scores were associ- ated with higher N2d amplitudes during positive stimulus presentation for 280 ms, while higher BAS Total scores were associated with higher N2d amplitudes during negative stimuli presentation for 910 ms. Discussion: Findings are discussed in terms of arousal-based models of time perception, and suggestions for future research are considered

Identification of Antifungal Compounds Active against Candida albicans Using an Improved High-Throughput Caenorhabditis elegans Assay

Candida albicans, the most common human pathogenic fungus, can establish a persistent lethal infection in the intestine of the microscopic nematode Caenorhabditis elegans. The C. elegans–C. albicans infection model was previously adapted to screen for antifungal compounds. Modifications to this screen have been made to facilitate a high-throughput assay including co-inoculation of nematodes with C. albicans and instrumentation allowing precise dispensing of worms into assay wells, eliminating two labor-intensive steps. This high-throughput method was utilized to screen a library of 3,228 compounds represented by 1,948 bioactive compounds and 1,280 small molecules derived via diversity-oriented synthesis. Nineteen compounds were identified that conferred an increase in C. elegans survival, including most known antifungal compounds within the chemical library. In addition to seven clinically used antifungal compounds, twelve compounds were identified which are not primarily used as antifungal agents, including three immunosuppressive drugs. This assay also allowed the assessment of the relative minimal inhibitory concentration, the effective concentration in vivo, and the toxicity of the compound in a single assay

Generational distribution of a Candida glabrata population: Resilient old cells prevail, while younger cells dominate in the vulnerable host.

Similar to other yeasts, the human pathogen Candida glabrata ages when it undergoes asymmetric, finite cell divisions, which determines its replicative lifespan. We sought to investigate if and how aging changes resilience of C. glabrata populations in the host environment. Our data demonstrate that old C. glabrata are more resistant to hydrogen peroxide and neutrophil killing, whereas young cells adhere better to epithelial cell layers. Consequently, virulence of old compared to younger C. glabrata cells is enhanced in the Galleria mellonella infection model. Electron microscopy images of old C. glabrata cells indicate a marked increase in cell wall thickness. Comparison of transcriptomes of old and young C. glabrata cells reveals differential regulation of ergosterol and Hog pathway associated genes as well as adhesion proteins, and suggests that aging is accompanied by remodeling of the fungal cell wall. Biochemical analysis supports this conclusion as older cells exhibit a qualitatively different lipid composition, leading to the observed increased emergence of fluconazole resistance when grown in the presence of fluconazole selection pressure. Older C. glabrata cells accumulate during murine and human infection, which is statistically unlikely without very strong selection. Therefore, we tested the hypothesis that neutrophils constitute the predominant selection pressure in vivo. When we altered experimentally the selection pressure by antibody-mediated removal of neutrophils, we observed a significantly younger pathogen population in mice. Mathematical modeling confirmed that differential selection of older cells is sufficient to cause the observed demographic shift in the fungal population. Hence our data support the concept that pathogenesis is affected by the generational age distribution of the infecting C. glabrata population in a host. We conclude that replicative aging constitutes an emerging trait, which is selected by the host and may even play an unanticipated role in the transition from a commensal to a pathogen state.post-print10768 K

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Effect of abciximab on the pattern of reperfusion in patients with acute myocardial infarction treated with primary angioplasty

Timely reperfusion therapy in acute myocardial infarction limits infarct size and improves survival.(1) Compared with fibrinolytic therapy, primary angioplasty achieves Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in a higher proportion of patients and is associated with improved early outcome.(2) Despite superior ability to relieve epicardial artery stenosis, mechanical revascularization is frequently associated with embolization of plaque and platelet thrombus to the distal capillary bed, which may result in a no-reflow phenomenon similar to that observed with fibrinolysis.(3) Because platelet IIb/IIIa receptor blockade with abciximab has been shown to reduce the incidence of acute ischemic events after coronary angioplasty, the combination of primary angioplasty and platelet integrin inhibition has been tested in the ReoPro And Primary PTCA Organization and Randomized Trial (RAPPORT).(4) In patients undergoing angioplasty and receiving abciximab, the 7-day incidence of reinfarction and urgent reintervention was reduced by 76% (p = 0.06) and 79% (p = 0.008), respectively, when compared with placebo. It is not known whether abciximab affected infarct size or the speed of reperfusion WP investigated whether the platelet inhibition afforded by abciximab altered the pattern of reperfusion in patients undergoing primary angioplasty with respect to peak creatine kinase (CK) release, infarct size expressed as area-under-the-curve (AUC), and time-to-peak CK