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Studies have repeatedly demonstrated the real-world effectiveness of oral antivirals (OAVs) in preventing hospitalisation and death in patients with mild-to-moderate COVID-19 at high risk for progression to severe COVID-19 when initiated within 5 days of symptom onset, even during waves of Omicron transmission.1 However, there is a need to determine if OAVs are reaching recommended groups, particularly among older adults and socioeconomically disadvantaged groups at higher risk of severe COVID-19. Disparities in access to OAVs based on area-level socioeconomic status (SES) have been documented in the US, UK and Australia,2-4 with substantially lower dispensing rates reported from more deprived areas. However, to the best of our knowledge, no studies have evaluated disparities in OAV access among urbanised Asian populations, including Singapore.

Summary: Background: During pandemics, avoiding time delay in diagnosing infection is crucial. We evaluated factors associated with delayed diagnosis of symptomatic SARS-CoV-2 infection in a national cohort of adult Singaporeans, during which emergence of the more transmissible Omicron variant shifted pandemic management towards endemicity. Methods: Retrospective cross-sectional study amongst all adult Singaporeans diagnosed with symptomatic SARS-CoV-2 infection during the transition from Delta to Omicron BA.1 (September 2021–February 2022). SARS-CoV-2 testing was fully subsidised and compulsory for all symptomatic individuals presenting at primary care. Results and demographic information were extracted from national databases. Time to diagnosis was defined as days from symptom-onset to diagnosis (date of first positive SARS-CoV-2 test); dichotomising into no delay (≤24 h from symptom-onset) and delay >24 h. Multivariable logistic regression was utilised to assess factors associated with delay >24 h, and association of delay >24 h with progression to severe COVID-19. Findings: Of 149,063 Singaporean adults presenting with symptomatic SARS-CoV-2 infection, 75.9% (113,195/149,063) were diagnosed within 24 h of symptom-onset. On multivariable analysis, female gender, older age (>60 years), Chinese (vs. Malay) ethnicity, socioeconomic status (housing type), primary care characteristics, presentation during Omicron BA.1 (vs. Delta), symptom-onset on Friday/Saturday (vs. Monday), and not having completed a primary vaccination series were independently associated with higher odds of delay >24 h. Delay >24 h was independently associated with severe COVID-19 (adjusted odds-ratio, aOR = 1.45, 95% CI = 1.27–1.65, p 60 years) had higher odds of delay in diagnosis. Delay >24 h in diagnosis was independently associated with severe COVID-19. Funding: This study was not grant-funded.

Background Early in the pandemic, transmission risk from asymptomatic infection was unclear, making it imperative to monitor infection in workplace settings. Further, data on SARS-CoV-2 seroprevalence within university populations has been limited. Methods We performed a longitudinal study of University research employees on campus July-December 2020. We conducted questionnaires on COVID-19 risk factors, RT-PCR testing, and SARS-CoV-2 serology using an in-house spike RBD assay, laboratory-based Spike NTD assay, and standard nucleocapsid platform assay. We estimated prevalence and cumulative incidence of seroconversion with 95% confidence intervals using the inverse of the Kaplan-Meier estimator. Results 910 individuals were included in this analysis. At baseline, 6.2% (95% CI 4.29–8.19) were seropositive using the spike RBD assay; four (0.4%) were seropositive using the nucleocapsid assay, and 44 (4.8%) using the Spike NTD assay. Cumulative incidence was 3.61% (95% CI: 2.04–5.16). Six asymptomatic individuals had positive RT-PCR results. Conclusions Prevalence and incidence of SARS-CoV-2 infections were low; however, differences in target antigens of serological tests provided different estimates. Future research on appropriate methods of serological testing in unvaccinated and vaccinated populations is needed. Frequent RT-PCR testing of asymptomatic individuals is required to detect acute infections, and repeated serosurveys are beneficial for monitoring subclinical infection.

This study used the Rasch model to assess the unidimensionality and item-person fit of an Academic Self-Concept Questionnaire (ASCQ) that is based on the Confucian Heritage Culture (CHC) perspective. Knowledge of the relationship between academic achievement and academic self-concept is particularly useful because academic achievement is overemphasized in the CHC. ASCQ largely satisfies the Rasch model for unidimensionality. However, four items had poor Infit statistics, suggesting that they do not contribute significantly to the scale hierarchy. Rasch model also confirmed the unidimensionality of the two subscales--Academic Confidence and Academic Effort. The academic self-concept scale, academic effort and academic confidence subscales were also been found to be valid with students with learning disabilities. Results from this study will extend the predominantly Western based literature regarding Academic Self-Concept by reaffirming the construct of a CHC measure of academic self-concept that incorporates the values of academic effort and academic confidence. (Contains 2 tables and 5 figures.)

A 67-year-old woman had delayed initial diagnosis of her right low flow carotid cavernous fistula (CCF) during the coronavirus disease (COVID-19) pandemic due to difficulty detecting ocular signs via online virtual examinations. Her right eye conjunctival erythema and proptosis with medial rectus enlargement on computed tomography scan was initially misdiagnosed as euthyroid thyroid-associated orbitopathy without lid retraction. She developed vision loss, and increasing episcleral venous congestion and CCF was suspected. Computed tomographic angiography did not show an obvious fistula. Digital subtraction angiography revealed the right-sided low flow CCF, which was fed from vessels from the contralateral side.

Abstract We performed a comprehensive analysis of the transcriptional changes occurring during human induced pluripotent stem cell (hiPSC) differentiation to cardiomyocytes. Using single cell RNA-seq, we sequenced > 20,000 single cells from 55 independent samples representing two differentiation protocols and multiple hiPSC lines. Samples included experimental replicates ranging from undifferentiated hiPSCs to mixed populations of cells at D90 post-differentiation. Differentiated cell populations clustered by time point, with differential expression analysis revealing markers of cardiomyocyte differentiation and maturation changing from D12 to D90. We next performed a complementary cluster-independent sparse regression analysis to identify and rank genes that best assigned cells to differentiation time points. The two highest ranked genes between D12 and D24 (MYH7 and MYH6) resulted in an accuracy of 0.84, and the three highest ranked genes between D24 and D90 (A2M, H19, IGF2) resulted in an accuracy of 0.94, revealing that low dimensional gene features can identify differentiation or maturation stages in differentiating cardiomyocytes. Expression levels of select genes were validated using RNA FISH. Finally, we interrogated differences in cardiac gene expression resulting from two differentiation protocols, experimental replicates, and three hiPSC lines in the WTC-11 background to identify sources of variation across these experimental variables.

Introduction: Despite the accumulating Canadian evidence regarding the relations between urban form and health behaviours, less is known about the associations between urban form and health conditions. Our study aim was to undertake a scoping review to synthesize evidence from quantitative studies that have investigated the relationship between built environment and chronic health conditions, self-reported health and qual¬ity of life, and injuries in the Canadian adult population. Methods: From January to March 2017, we searched 13 databases to identify peer-reviewed quantitative studies from all years that estimated associations between the objectively-measured built environment and health conditions in Canadian adults. Studies under¬taken within urban settings only were included. Relevant studies were catalogued and synthesized in relation to their reported study and sample design, and health outcome and built environment features. Results: Fifty-five articles met the inclusion criteria, 52 of which were published after 2008. Most single province studies were undertaken in Ontario (n = 22), Quebec (n = 12), and Alberta (n = 7). Associations between the built environment features and 11 broad health outcomes emerged from the review, including injury (n = 19), weight status (n = 19), cardiovascular disease (n = 5), depression/anxiety (n = 5), diabetes (n = 5), mortality (n = 4), self-rated health (n = 2), chronic conditions (n = 2), metabolic condi¬tions (n = 2), quality of life (n = 1), and cancer (n = 1). Consistent evidence for asso-ciations between aggregate built environment indicators (e.g., walkability) and diabetes and weight and between connectivity and route features (e.g., transportation route, trails, pathways, sidewalks, street pattern, intersections, route characteristics) and injury were found. Evidence for greenspace, parks and recreation features impacting multiple health outcomes was also found. Conclusion: Within the Canadian context, the built environment is associated with a range of chronic health conditions and injury in adults, but the evidence to date has limi¬tations. More research on the built environment and health incorporating rigorous study designs are needed to provide stronger causal evidence to inform policy and practice.

Introduction. En dépit de données canadiennes abondantes sur les associations entre amé¬nagement urbain et comportements liés à la santé, nous savons peu de chose sur les associa¬tions entre aménagement urbain et problèmes de santé. Cet examen de la portée est destiné à offrir une synthèse des données tirées d’études quantitatives ayant examiné la relation entre l’environnement bâti et les problèmes de santé chroniques, l’état de santé et la qualité de vie autodéclarés ainsi que les blessures au sein de la population canadienne adulte. Méthodologie. De janvier à mars 2017, nous avons effectué des recherches dans 13 bases de données afin de sélectionner, sans égard à la date de publication, les études quantitatives ayant fait l’objet d’une évaluation par les pairs et portant sur les associations entre des mesures objectives de l’environnement bâti et divers problèmes de santé affectant les adultes cana¬diens. Seules les études menées en milieu urbain ont été incluses. Nous avons catalogué et synthétisé les études pertinentes en fonction de leur sujet et de leur plan d’étude ainsi que de leurs résultats sur le plan de la santé et des caractéristiques de l’environnement bâti. Résultats. Cinquante-cinq articles ont répondu aux critères d’inclusion, dont 52 publiés après 2008. La plupart des études menées dans une seule province ont porté sur Ontario (n = 22), le Québec (n = 12) ou l’Alberta (n = 7). L’examen a permis de dégager des associations entre les caractéristiques du milieu bâti et 11 résultats généraux en matière de santé, à savoir les blessures (n = 19), le poids (n = 19), les maladies cardiovasculaires (n = 5), la dépression et l’anxiété (n = 5), le diabète (n = 5), la mortalité (n = 4), l’état de santé autoévalué (n = 2), les problèmes de santé chroniques (n = 2), les troubles du métabolisme (n = 2), la qualité de vie (n = 1) et le cancer (n = 1). Nous avons relevé des données probantes cohérentes mon¬trant des associations entre les indicateurs agrégés de l’environnement bâti (p. ex. le potentiel piétonnier) et le diabète et le poids, ainsi qu’entre la connectivité et les caractéristiques des itinéraires (p. ex. itinéraires de transport, pistes, sentiers, trottoirs, tracés de rue, intersections) et les blessures. Nous avons également extrait des données montrant l’impact qu’ont les espaces verts, les parcs et les installations récréatives sur de multiples résultats de santé. Conclusion. En contexte canadien, l’environnement bâti est associé à un éventail de problèmes de santé chroniques et de blessures chez les adultes, mais les données probantes dis¬ponibles sont limitées. Il faut mener davantage de recherches sur l’environnement bâti et la santé fondées sur des plans d’étude rigoureux afin de produire des données probantes plus solides sur les relations causales aptes à orienter les politiques et les pratiques.

Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P=0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permuted P=0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk. [ABSTRACT FROM AUTHOR]

For simulation-based work, researchers often have limited hardware capacities and budgets, so they create a low-cost parallel computing platform using PCs and commodity hardware, assembled and configured as a Beowulf-class computing cluster. Here, an astute approach (for a molecular dynamics simulation example) greatly improves performance through hardware upgrades and other tricks. [ABSTRACT FROM PUBLISHER]

Currently, there is no three-dimensional structure of D-specific dehalogenase (DehD) in the protein database. We modeled DehD using ab initio technique, performed molecular dynamics (MD) simulation and docking of D-2-chloropropionate (D-2CP), D-2-bromopropionate (D-2BP), monochloroacetate (MCA), monobromoacetate (MBA), 2,2-dichloropropionate (2,2-DCP), D,L-2,3-dichloropropionate (D,L-2,3-DCP), and 3-chloropropionate (3-CP) into the DehD active site. The sequences of DehD and D-2-haloacid dehalogenase (HadD) from Pseudomonas putida AJ1 have 15% sequence similarity. The model had 80% of the amino acid residues in the most favored region when compared to the crystal structure of DehI from Pseudomonas putida PP3. Docking analysis revealed that Arg107, Arg134 and Tyr135 interacted with D-2CP, and Glu20 activated the water molecule for hydrolytic dehalogenation. Single residue substitutions at 25-30 °C showed that polar residues of DehD were stable when substituted with nonpolar residues and showed a decrease in activity within the same temperature range. The molecular dynamics simulation of DehD and its variants showed that in R134A variant, Arg107 interacted with D-2CP, while in Y135A, Gln221 and Arg231 interacted with D-2CP. It is our emphatic belief that the new model will be useful for the rational design of DehDs with enhanced potentials. [ABSTRACT FROM AUTHOR]

Background and aimThe COVID-19 pandemic necessitated the transition to online medical education. This study evaluated the efficacy of online case-based tutorials using a serious game tutorial [PlayMed™ (PM)], as compared to a traditional slideshow tutorial (TT).MethodsWe performed a prospective, mixed-methods, randomised controlled trial on undergraduate medical students during the COVID-19 pandemic, from May 2020 to January 2021. Students were block randomised into the PM or TT groups. Tutors conducted online teaching on bronchiolitis and gastroenteritis cases using PM or TT to facilitate the presentation. Educational experience was assessed using a continuous interval scale (0–100; with pre-defined categories) and free text responses. Immediate and long-term knowledge acquisition was assessed using 6 multiple-choice questions (MCQ) for each case (total of 12 MCQ). A modified intention-to-treat mixed methods and a sensitivity per-protocol analysis were performed to compare outcomes between PM and TT groups.ResultsIn total, 80 PM and 73 TT participants attended at least one tutorial. Sixty-five (81%) PM and 52 (71%) TT participants completed at least one survey and were included for analysis. PlayMed™ students had an increased likelihood of completing the surveys, which included the MCQ [odds ratio (95% CI) of 2.4 (1.6–3.8), p

The aim of this paper is to evaluate the safety performances of unsignalised Seagull T-junction configuration on high speed rural roads in NSW. The findings were that two types of crashes, Right Near and Right Through, were predominant among all the crashes, and those that result in casualties. Driver impairment, speeding behaviour and road environment conditions were a factor in a small percentage of these crashes. Of the deemed to be at-fault male drivers, almost two-thirds were at and above the age of 67. However, for each of the other age groups below this, there was a higher incidence of female drivers than male drivers involved in Right Near crashes. The former is consistent with other studies on older male drivers. Consistent with the New South Wales Roads and Traffic Authority (RTA) Safe System approach, key solutions include substantially reduced speeds for through traffic and removal of critical side impact crash types. This may require further investigation prior to implementation.

Abstract The Hippo pathway is a tumor suppressor pathway that is implicated in the regulation of organ size. The pathway has three components: the upstream regulatory factors, the kinase core, and the downstream transcriptional machinery, which consists of YAP, TAZ (transcription co-activators) and TEAD (transcription factor). Formation of YAP/TAZ-TEAD complexes leads to the transcription of growth-promoting genes. Herein, we report the crystal structure of TAZ-TEAD4 complex, which reveals two binding modes. The first is similar to the published YAP-TEAD structure. The second is a unique binding mode, whereby two molecules of TAZ bind to and bridge two molecules of TEAD4. We validated the latter using cross-linking and multi-angle light scattering. Using siRNA, we showed that TAZ knockdown leads to a decrease in TEAD4 dimerization. Lastly, results from luciferase assays, using YAP/TAZ transfected or knockdown cells, give support to the non-redundancy of YAP/TAZ co-activators in regulating gene expression in the Hippo pathway.

The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site.

Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P=0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permuted P=0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.