Search

A regulated stress response is essential for healthy child growth and development trajectories. We conducted a cluster-randomized trial in rural Bangladesh (funded by the Bill & Melinda Gates Foundation, ClinicalTrials.gov NCT01590095) to assess the effects of an integrated nutritional, water, sanitation, and handwashing intervention on child health. We previously reported on the primary outcomes of the trial, linear growth and caregiver-reported diarrhea. Here, we assessed additional prespecified outcomes: physiological stress response, oxidative stress, and DNA methylation (N = 759, ages 1–2 years). Eight neighboring pregnant women were grouped into a study cluster. Eight geographically adjacent clusters were block-randomized into the control or the combined nutrition, water, sanitation, and handwashing (N + WSH) intervention group (receiving nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap). Participants and data collectors were not masked, but analyses were masked. There were 358 children (68 clusters) in the control group and 401 children (63 clusters) in the intervention group. We measured four F2-isoprostanes isomers (iPF(2α)-III; 2,3-dinor-iPF(2α)-III; iPF(2α)-VI; 8,12-iso-iPF(2α)-VI), salivary alpha-amylase and cortisol, and methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including the NGFI-A binding site. Compared with control, the N + WSH group had lower concentrations of F2-isoprostanes isomers (differences ranging from −0.16 to −0.19 log ng/mg of creatinine, P < 0.01), elevated post-stressor cortisol (0.24 log µg/dl; P < 0.01), higher cortisol residualized gain scores (0.06 µg/dl; P = 0.023), and decreased methylation of the NGFI-A binding site (−0.04; P = 0.037). The N + WSH intervention enhanced adaptive responses of the physiological stress system in early childhood. A regulated stress response is essential for healthy child growth and development. Here, the authors show that a nutrition, water, sanitation, and hygiene intervention enhanced adaptive responses of the physiological stress system in early childhood. [ABSTRACT FROM AUTHOR]

There is a public health need to understand how different frequencies of COVID-19 booster vaccines may mitigate the risk of severe COVID-19, while accounting for waning of protection and differential risk by age and immune status. By analyzing United States COVID-19 surveillance and seroprevalence data in a microsimulation model, here we show that more frequent COVID-19 booster vaccination (every 6–12 months) in older age groups and the immunocompromised population would effectively reduce the burden of severe COVID-19, while frequent boosters in the younger population may only provide modest benefit against severe disease. In persons 75+ years, the model estimated that annual boosters would reduce absolute annual risk of severe COVID-19 by 199 (uncertainty interval: 183–232) cases per 100,000 persons, compared to a one-time booster vaccination. In contrast, for persons 18–49 years, the model estimated that annual boosters would reduce this risk by 14 (10–19) cases per 100,000 persons. Those with prior infection had lower benefit of more frequent boosting, and immunocompromised persons had larger benefit. Scenarios with emerging variants with immune evasion increased the benefit of more frequent variant-targeted boosters. This study underscores the benefit of considering key risk factors to inform frequency of COVID-19 booster vaccines in public health guidance and ensuring at least annual boosters in high-risk populations. [ABSTRACT FROM AUTHOR]

Background Uptake of coronavirus disease 2019 (COVID-19) bivalent vaccines and the oral medication nirmatrelvir-ritonavir (Paxlovid) has remained low across the United States. Assessing the public health impact of increasing uptake of these interventions in key risk groups can guide further public health resources and policy and determine what proportion of severe COVID-19 is avertable with these interventions. Methods This modeling study used person-level data from the California Department of Public Health on COVID-19 cases, hospitalizations, deaths, and vaccine administration from 23 July 2022 to 23 January 2023. We used a quasi-Poisson regression model calibrated to recent historical data to predict future COVID-19 outcomes and modeled the impact of increasing uptake (up to 70% coverage) of bivalent COVID-19 vaccines and nirmatrelvir-ritonavir during acute illness in different risk groups. Risk groups were defined by age (≥50, ≥65, ≥75 years) and vaccination status (everyone, primary series only, previously vaccinated). We predicted the number of averted COVID-19 cases, hospitalizations, and deaths and number needed to treat (NNT). Results The model predicted that increased uptake of bivalent COVID-19 boosters and nirmatrelvir-ritonavir (up to 70% coverage) in all eligible persons could avert an estimated 15.7% (95% uncertainty interval [UI], 11.2%–20.7%; NNT: 17 310) and 23.5% (95% UI, 13.1%–30.0%; NNT: 67) of total COVID-19–related deaths, respectively. In the high-risk group of persons ≥65 years old alone, increased uptake of bivalent boosters and nirmatrelvir-ritonavir could avert an estimated 11.9% (95% UI, 8.4%–15.1%; NNT: 2757) and 22.8% (95% UI, 12.7%–29.2%; NNT: 50) of total COVID-19–related deaths, respectively. Conclusions These findings suggest that prioritizing uptake of bivalent boosters and nirmatrelvir-ritonavir among older age groups (≥65 years) would be most effective (based on NNT) but would not address the entire burden of severe COVID-19. [ABSTRACT FROM AUTHOR]

Background: Different types of assessments influence learning and learning behaviour. Multiple‐choice questions (MCQs) reward partial knowledge and encourage surface learning, while open‐ended questions (OEQs) promote deeper learning. Currently, MCQs is part of team‐based learning (TBL) curriculum, and it is challenging to implement OEQs as immediate feedback is necessary. Objectives: We asked if MCQ and OEQs affect student achievement, student learning and student engagement differently in a TBL classroom. Methods: MCQs and OEQs test scores of N = 66 students were automatically captured in Learning Activity Management System (LAMS) and were compared using a switching replications quasi‐experimental design with pre‐ and post‐tests to answer the research questions. Student learning approaches and engagement in the team activities were assessed using the study process questionnaire and the structure of observed learning outcomes taxonomy respectively. Results and Conclusions: Students get significantly higher MCQ scores than OEQs for the same set of questions, but the reverse is true for application exercises (AEs), which focus on higher‐level application. Most students significantly deepened their learning approaches before OEQs, while poorly prepared students were less engaged during OEQ discussions. Interestingly students subjected to OEQs took less time and scored higher in AE discussions, suggesting better focus on higher‐level thinking. Implications: This project is significant as it bridges our understanding of the value of OEQs and TBL. Our approach is transferable to other courses, and thus it can improve the quality of teaching and learning in tertiary education. Lay Description: What is already known about this topic?: Multiple‐choice questions (MCQs) do not promote deep learning as much as open‐ended questions (OEQ) do.Team‐based learning (TBL) requires MCQs because of the need for immediate feedback.Automated marking can make it more efficient to provide immediate feedback on OEQs as required by the TBL approach. What this paper adds?: OEQs changed student‐learning approaches in the TBL context.OEQs changed the quality of team discussions during the team‐readiness assessment.Test (tRAT) and application exercise phases.Students were concerned about the validity of automated grading. Implications for practitioners: Consider using OEQs in TBL context for deepening student learning.Consider how to defuse students' scepticism of new technology.Consider forming teams with a mix of deep and surface learners. [ABSTRACT FROM AUTHOR]

Multicomponent immune receptors are essential complexes in which distinct ligand-recognition and signaling subunits are held together by interactions between acidic and basic residues of their transmembrane helices. A 2:1 acidic-to-basic motif in the transmembrane domains of the subunits is necessary and sufficient to assemble these receptor complexes. Here, we study a prototype for these receptors, a DAP12-NKG2C 2:1 heterotrimeric complex, in which the two DAP12 subunits each contribute a single transmembrane Asp residue, and the NKG2C subunit contributes a Lys to form the complex. DAP12 can also associate with 20 other subunits using a similar motif. Here, we use molecular-dynamics simulations to understand the basis for the high affinity and diversity of interactions in this group of receptors. Simulations of the transmembrane helices with differing protonation states of the Asp-Asp-Lys triad identified a structurally stable interaction in which a singly-protonated Asp-Asp pair forms a hydrogen-bonded carboxyl-carboxylate clamp that clasps onto a charged Lys side chain. This polar motif was also supported by density functional theory and a Protein Data Bank-wide search. In contrast, the helices are dynamic at sites distal to the stable carboxyl-carboxylate clamp motif. Such a locally stable but globally dynamic structure is well suited to accommodate the sequence and structural variations in the transmembrane helices of multicomponent receptors, which mix and match subunits to create combinatorial functional diversity from a limited number of subunits. It also supports a signaling mechanism based on multisubunit clustering rather than propagation of rigid conformational changes through the membrane. [ABSTRACT FROM AUTHOR]

The unprecedented global health threat of SARS-CoV-2 has sparked a continued interest in discovering novel anti-COVID-19 agents. To this end, we present here a computer-based protocol for identifying potential compounds targeting RNA-dependent RNA polymerase (RdRp). Starting from our previous study wherein, using a virtual screening campaign, we identified a fumiquinazolinone alkaloid quinadoline B (Q3), an antiviral fungal metabolite with significant activity against SARS-CoV-2 RdRp, we applied in silico combinatorial methodologies for generating and screening a library of anti-SARS-CoV-2 candidates with strong in silico affinity for RdRp. For this study, the quinadoline pharmacophore was subjected to structural iteration, obtaining a Q3-focused library of over 900,000 unique structures. This chemical library was explored to identify binders of RdRp with greater affinity with respect to the starting compound Q3. Coupling this approach with the evaluation of physchem profile, we found 26 compounds with significant affinities for the RdRp binding site. Moreover, top-ranked compounds were submitted to molecular dynamics to evaluate the stability of the systems during a selected time, and to deeply investigate the binding mode of the most promising derivatives. Among the generated structures, five compounds, obtained by inserting nucleotide-like scaffolds (1, 2, and 5), heterocyclic thiazolyl benzamide moiety (compound 3), and a peptide residue (compound 4), exhibited enhanced binding affinity for SARS-CoV-2 RdRp, deserving further investigation as possible antiviral agents. Remarkably, the presented in silico procedure provides a useful computational procedure for hit-to-lead optimization, having implications in anti-SARS-CoV-2 drug discovery and in general in the drug optimization process. [ABSTRACT FROM AUTHOR]

Shingled magnetic recording (SMR) is a new technology based on partially overlapping, or shingling, adjacent tracks, which is capable of increasing the density of a disk drive up to 10 \Tbit/in^2. To write data on overlapping tracks may erase data being written previously. Therefore, without any data translation layer to redirect updates to different locations to avoid unintended data erasures, the SMR disk cannot be used as a conventional disk to perform unrestricted reads/writes directly. Various data translation/mapping strategies have been proposed to allow the disk to perform unrestricted reads/writes. However, these strategies have tradeoffs in terms of system performance and cost, such as disk space utilization. Nevertheless, system performance varies for different applications and under different workload conditions. [ABSTRACT FROM PUBLISHER]

Discusses the different approaches that teachers and students apply when using the computer. Cautious attitude of teachers when letting students use the computer; Disadvantages of making the computer a machine for the teacher; Goal of educational technology; Description of the Kids Learning In Computer Klubhouses after-school program for the middle school students.