Genome architecture and stability in the Saccharomyces cerevisiae knockout collection.

Despite major progress in defining the functional roles of genes, a complete understanding of their influences is far from being realized, even in relatively simple organisms. A major milestone in this direction arose via the completion of the yeast Saccharomyces cerevisiae gene-knockout collection (YKOC), which has enabled high-throughput reverse genetics, phenotypic screenings and analyses of synthetic-genetic interactions1-3. Ensuing experimental work has also highlighted some inconsistencies and mistakes in the YKOC, or genome instability events that rebalance the effects of specific knockouts4-6, but a complete overview of these is lacking. The identification and analysis of genes that are required for maintaining genomic stability have traditionally relied on reporter assays and on the study of deletions of individual genes, but whole-genome-sequencing technologies now enable-in principle-the direct observation of genome instability globally and at scale. To exploit this opportunity, we sequenced the whole genomes of nearly all of the 4,732 strains comprising the homozygous diploid YKOC. Here, by extracting information on copy-number variation of tandem and interspersed repetitive DNA elements, we describe-for almost every single non-essential gene-the genomic alterations that are induced by its loss. Analysis of this dataset reveals genes that affect the maintenance of various genomic elements, highlights cross-talks between nuclear and mitochondrial genome stability, and shows how strains have genetically adapted to life in the absence of individual non-essential genes.

Identification of genetic loci jointly influencing COVID-19 and coronary heart diseases.

BACKGROUND: Comorbidities of coronavirus disease 2019 (COVID-19)/coronary heart disease (CHD) pose great threats to disease outcomes, yet little is known about their shared pathology. The study aimed to examine whether comorbidities of COVID-19/CHD involved shared genetic pathology, as well as to clarify the shared genetic variants predisposing risks common to COVID-19 severity and CHD risks. METHODS: By leveraging publicly available summary statistics, we assessed the genetically determined causality between COVID-19 and CHD with bidirectional Mendelian randomization. To further quantify the causality contributed by shared genetic variants, we interrogated their genetic correlation with the linkage disequilibrium score regression method. Bayesian colocalization analysis coupled with conditional/conjunctional false discovery rate analysis was applied to decipher the shared causal single nucleotide polymorphisms (SNPs). FINDINGS: Briefly, we observed that the incident CHD risks post COVID-19 infection were partially determined by shared genetic variants. The shared genetic variants contributed to the causality at a proportion of 0.18 (95% CI 0.18-0.19) to 0.23 (95% CI 0.23-0.24). The SNP (rs10490770) located near LZTFL1 suggested direct causality (SNPs → COVID-19 → CHD), and SNPs in ABO (rs579459, rs495828), ILRUN(rs2744961), and CACFD1(rs4962153, rs3094379) may simultaneously influence COVID-19 severity and CHD risks. INTERPRETATION: Five SNPs located near LZTFL1 (rs10490770), ABO (rs579459, rs495828), ILRUN (rs2744961), and CACFD1 (rs4962153, rs3094379) may simultaneously influence their risks. The current study suggested that there may be shared mechanisms predisposing to both COVID-19 severity and CHD risks. Genetic predisposition to COVID-19 is a causal risk factor for CHD, supporting that reducing the COVID-19 infection risk or alleviating COVID-19 severity among those with specific genotypes might reduce their subsequent CHD adverse outcomes. Meanwhile, the shared genetic variants identified may be of clinical implications for identifying the target population who are more vulnerable to adverse CHD outcomes post COVID-19 and may also advance treatments of 'Long COVID-19.'

Effect of statin therapy patterns on readmission and mortality in patients with intracerebral hemorrhage.

There is limited and inconsistent evidence for the association of statin therapy and statin treatment patterns with the risk of recurrent intracerebral hemorrhage (ICH) in patients with prior ICH. To assess the association of statin therapy and its intensity, type, initiation time, and discontinuation with the risk of recurrent ICH and mortality in Chinese patients with ICH. Patients with newly diagnosed ICH in the Beijing Employee Medical Claims Data database from 2010 to 2017 were included. Post-ICH statin users (post-diagnosis only) and nonusers (never), statin discontinuers (pre-diagnosis only) and continuers (pre- and post-diagnosis) were matched on a 1:1 propensity score, respectively. Adjusted Cox proportional risk models were used to estimate the risk ratios for ICH readmission and mortality under various statin patterns. A total of 2668 post-ICH statin users and 2668 nonusers without a history of statin use were enrolled. Post-ICH statin users had a lower risk of ICH readmission (HR, 0.57; 95% CI 0.48, 0.69) and all-cause death (0.56: 0.49, 0.63) than nonusers. Low/moderate-intensity treatment was associated with a 63% lower risk of recurrent ICH compared with nonusers (0.37: 0.29, 0.46), whereas high-intensity treatment did not reduce the risk (0.93: 0.74, 1.16). Both low/moderate-intensity (0.42: 0.36, 0.48) and high-intensity statins (0.57: 0.48, 0.69) were associated with a lower risk of all-cause mortality. The risk of ICH readmission was 53% (0.47: 0.30, 0.74) lower with adherence to rosuvastatin than with atorvastatin. Only starting medication within 30 days of the first diagnosis of ICH reduced the risk of ICH readmission (0.49: 0.40, 0.60). Among patients with a history of statin use, 1807 discontinuing and 1,807 continuing users of statins were included. The risk of ICH readmission (4.00: 3.32, 4.80) and the risk of all-cause death (4.01: 3.57, 4.50) were substantially increased in statin discontinuation compared with continued statin use. Statin therapy after ICH was associated with lower risks for ICH readmission and all-cause mortality compared with non-statin therapy, especially at low/moderate intensity and early initiation of statins after ICH. Adherence to rosuvastatin was associated with a lower risk of recurrence of ICH than atorvastatin. Among patients with a statin history prior to ICH, discontinuation of statins after ICH was associated with increased risk of ICH recurrence and death.

Multi-locus genome-wide association studies reveal the dynamic genetic architecture of flowering time in chrysanthemum.

KEY MESSAGE: The dynamic genetic architecture of flowering time in chrysanthemum was elucidated by GWAS. Thirty-six known genes and 14 candidate genes were identified around the stable QTNs and QEIs, among which ERF-1 was highlighted. Flowering time (FT) adaptation is one of the major breeding goals in chrysanthemum, a multipurpose ornamental plant. In order to reveal the dynamic genetic architecture of FT in chrysanthemum, phenotype investigation of ten FT-related traits was conducted on 169 entries in 2 environments. The broad-sense heritability of five non-conditional FT traits, i.e., budding (FBD), visible coloring (VC), early opening (EO), full-bloom (OF) and decay period (DP), ranged from 56.93 to 84.26%, which were higher than that of the five derived conditional FT traits (38.51-75.13%). The phenotypic variation coefficients of OF_EO and DP_OF were relatively large ranging from 30.59 to 36.17%. Based on 375,865 SNPs, the compressed variance component mixed linear model 3VmrMLM was applied for a multi-locus genome-wide association study (GWAS). As a result, 313 quantitative trait nucleotides (QTNs) were identified for the non-conditional FT traits in single-environment analysis, while 119 QTNs and 67 QTN-by-environment interactions (QEIs) were identified in multi-environment analysis. As for the conditional traits, 343 QTNs were detected in single-environment analysis, and 119 QTNs and 83 QEIs were identified in multi- environment analysis. Among the genes around stable QTNs and QEIs, 36 were orthologs of known FT genes in Arabidopsis and other plants; 14 candidates were mined by combining the transcriptomics data and functional annotation, including ERF-1, ACA10, and FOP1. Furthermore, the haplotype analysis of ERF-1 revealed six elite accessions with extreme FBD. Our findings contribute to the understanding of dynamic genetic architecture of FT and provide valuable resources for future chrysanthemum molecular breeding programs.

Detecting Gene-Gene Interaction among DNA Repair Genes in Chinese non-Syndromic Cleft lip with or Without Palate Trios.

OBJECTIVE: The objective of this study is to investigate the gene-gene interactions associated with NSCL/P among DNA repair genes. DESIGN: This study included 806 NSCL/P case-parent trios from China. Quality control process was conducted for genotyped single nucleotide polymorphisms (SNPs) located in six DNA repair genes (ATR, ERCC4, RFC1, TYMS, XRCC1 and XRCC3). We tested gene-gene interactions with Cordell's method using statistical package TRIO in R software. Bonferroni corrected significance level was set as P = 4.24 × 10-4. We also test the robustness of the interactions by permutation tests. SETTING: Not applicable. PATIENTS/PARTICIPANTS: A total of 806 NSCL/P case-parent trios (complete trios: 682, incomplete trios: 124) with Chinese ancestry. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Not applicable. RESULTS: A total of 118 SNPs were extracted for the interaction tests. Fourteen pairs of significant interactions were identified after Bonferroni correction, which were confirmed in permutation tests. Twelve pairs were between ATR and ERCC4 or XRCC3. The most significant interaction occurred between rs2244500 in TYMS and rs3213403 in XRCC1(P = 8.16 × 10-15). CONCLUSIONS: The current study identified gene-gene interactions among DNA repair genes in 806 Chinese NSCL/P trios, providing additional evidence for the complicated genetic structure underlying NSCL/P. ATR, ERCC4, XRCC3, TYMS and RFC1 were suggested to be possible candidate genes for NSCL/P.

[Gene-gene/gene-environment interaction of transforming growth factor-ß signaling pathway and the risk of non-syndromic oral clefts].

OBJECTIVE: To explore the association between polymorphisms of transforming growth factor-ß (TGF-ß) signaling pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Asian populations, while considering gene-gene interaction and gene-environment interaction. METHODS: A total of 1 038 Asian NSCL/P case-parent trios were ascertained from an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate the genes affec-ting risk to NSCL/P. After stringent quality control measures, 343 single nucleotide polymorphism (SNP) spanning across 10 pivotal genes in the TGF-ß signaling pathway were selected from the original genome-wide association study(GWAS) dataset for further analysis. The transmission disequilibrium test (TDT) was used to test for SNP effects. The conditional Logistic regression models were used to test for gene-gene interaction and gene-environment interaction. Environmental factors collected for the study included smoking during pregnancy, passive smoking during pregnancy, alcohol intake during pregnancy, and vitamin use during pregnancy. Due to the low rates of exposure to smoking during pregnancy and alcohol consumption during pregnancy (<3%), only the interaction between maternal smoking during pregnancy and multivitamin supplementation during pregnancy was analyzed. The threshold for statistical significance was rigorously set at P =1.46×10-4, applying Bonferroni correction to account for multiple testing. RESULTS: A total of 23 SNPs in 4 genes yielded nominal association with NSCL/P (P<0.05), but none of these associations was statistically significant after Bonferroni' s multiple test correction. However, there were 6 pairs of SNPs rs4939874 (SMAD2) and rs1864615 (TGFBR2), rs2796813 (TGFB2) and rs2132298 (TGFBR2), rs4147358 (SMAD3) and rs1346907 (TGFBR2), rs4939874 (SMAD2) and rs1019855 (TGFBR2), rs4939874 (SMAD2) and rs12490466 (TGFBR2), rs2009112 (TGFB2) and rs4075748 (TGFBR2) showed statistically significant SNP-SNP interaction (P<1.46×10-4). In contrast, the analysis of gene-environment interactions did not yield any significant results after being corrected by multiple testing. CONCLUSION: The comprehensive evaluation of SNP associations and interactions within the TGF-ß signaling pathway did not yield any direct associations with NSCL/P risk in Asian populations. However, the significant gene-gene interactions identified suggest that the genetic architecture influencing NSCL/P risk may involve interactions between genes within the TGF-ß signaling pathway. These findings underscore the necessity for further investigations to unravel these results and further explore the underlying biological mechanisms.

[A ssociations of short-term ambient particulate matter exposure and MTNR1B gene with triglyceride-glucose index: A family-based study].

OBJECTIVE: To explore the effects of short-term particulate matter (PM) exposure and the melatonin receptor 1B (MTNR1B) gene on triglyceride-glucose (TyG) index utilizing data from Fang-shan Family-based Ischemic Stroke Study in China (FISSIC). METHODS: Probands and their relatives from 9 rural areas in Fangshan District, Beijing, were included in the study. PM data were obtained from fixed monitoring stations of the National Air Pollution Monitoring System. TyG index was calculated by fasting triglyceride and glucose concentrations. The associations of short-term PM exposure and rs10830963 polymorphism of the MTNR1B gene with the TyG index were assessed using mixed linear models, in which covariates such as age, sex, and lifestyles were adjusted for. Gene-environment inter-action analysis was furtherly performed using the maximum likelihood methods to explore the potential effect modifier role of rs10830963 polymorphism in the association of PM with TyG index. RESULTS: A total of 4 395 participants from 2 084 families were included in the study, and the mean age of the study participants was (58.98±8.68) years, with 53. 90% females. The results of association analyses showed that for every 10 µg/m3 increase in PM2.5 concentration, TyG index increased by 0.017 (95%CI: 0.007-0.027), while for per 10 µg/m3 increment in PM10, TyG index increased by 0.010 (95%CI: 0.003-0.017). And the associations all had lagged effects. In addition, there was a positive association between the rs10830963 polymorphism and the TyG index. For per increase in risk allele G, TyG index was elevated by 0.040 (95%CI: 0.004-0.076). The TyG index was 0.079 (95%CI: 0.005-0.152) higher in carriers of the GG genotype compared with carriers of the CC genotype. The interaction of rs10830963 polymorphism with PM exposure had not been found to be statistically significant in the present study. CONCLUSION: Short-term exposure to PM2.5 and PM10 were associated with higher TyG index. The G allele of rs10830963 polymorphism in the MTNR1B gene was associated with the elevated TyG index.

Enhancing Built-in Electric Fields via Molecular Symmetry Modulation in Supramolecular Photocatalysts for Highly Efficient Photocatalytic Hydrogen Evolution.

Nature-inspired supramolecular self-assemblies are attractive photocatalysts, but their quantum yields are limited by poor charge separation and transportation. A promising strategy for efficient charge transfer is to enhance the built-in electric field by symmetry breaking. Herein, an unsymmetric protonation, N-heterocyclic π-conjugated anthrazoline-based supramolecular photocatalyst SA-DADK-H+ was developed. The unsymmetric protonation breaks the initial structural symmetry of DADK, resulting in ca. 50-fold increase in the molecular dipole, and facilitates efficient charge separation and transfer within SA-DADK-H+. The protonation process also creates numerous active sites for H2O adsorption, and serves as crucial proton relays, significantly improving the photocatalytic efficiency. Remarkably, SA-DADK-H+ exhibits an outstanding hydrogen evolution rate of 278.2 mmol g-1 h-1 and a remarkable apparent quantum efficiency of 25.1 % at 450 nm, placing it among the state-of-the-art performances in organic semiconductor photocatalysts. Furthermore, the versatility of the unsymmetric protonation approach has been successfully applied to four other photocatalysts, enhancing their photocatalytic performance by 39 to 533 times. These findings highlight the considerable potential of unsymmetric protonation induced symmetry breaking strategy in tailoring supramolecular photocatalysts for efficient solar-to-fuel production.

Multi-locus genome-wide association study and genomic prediction for flowering time in chrysanthemum.

MAIN CONCLUSION: Multi-locus GWAS detected several known and candidate genes responsible for flowering time in chrysanthemum. The associations could greatly increase the predictive ability of genome selection that accelerates the possible application of GS in chrysanthemum breeding. Timely flowering is critical for successful reproduction and determines the economic value for ornamental plants. To investigate the genetic architecture of flowering time in chrysanthemum, a multi-locus genome-wide association study (GWAS) was performed using a collection of 200 accessions and 330,710 single-nucleotide polymorphisms (SNPs) via 3VmrMLM method. Five flowering time traits including budding (FBD), visible colouring (VC), early opening (EO), full-bloom (OF) and senescing (SF) stages, plus five derived conditional traits were recorded in two environments. Extensive phenotypic variations were observed for these flowering time traits with coefficients of variation ranging from 6.42 to 38.27%, and their broad-sense heritability ranged from 71.47 to 96.78%. GWAS revealed 88 stable quantitative trait nucleotides (QTNs) and 93 QTN-by-environment interactions (QEIs) associated with flowering time traits, accounting for 0.50-8.01% and 0.30-10.42% of the phenotypic variation, respectively. Amongst the genes around these stable QTNs and QEIs, 21 and 10 were homologous to known flowering genes in Arabidopsis; 20 and 11 candidate genes were mined by combining the functional annotation and transcriptomics data, respectively, such as MYB55, FRIGIDA-like, WRKY75 and ANT. Furthermore, genomic selection (GS) was assessed using three models and seven unique marker datasets. We found the prediction accuracy (PA) using significant SNPs identified by GWAS under SVM model exhibited the best performance with PA ranging from 0.90 to 0.95. Our findings provide new insights into the dynamic genetic architecture of flowering time and the identified significant SNPs and candidate genes will accelerate the future molecular improvement of chrysanthemum.

Dose-response relationships of tea and coffee consumption with gout: a prospective cohort study in the UK Biobank.

OBJECTIVES: The association of tea or coffee consumption with gout is inconsistently reported. Few prospective studies have explored their dose-response relationship. Therefore, we aimed to quantitatively investigate the association between tea, coffee and the risk of developing gout. METHODS: The study included 447 658 participants in the UK Biobank who were initially free of gout. Tea and coffee consumption were assessed at baseline. We used Cox proportional hazards models to estimate the associations between tea/coffee consumption and incident gout, with restricted cubic spline added to the Cox models to evaluate the dose-response relationships. RESULTS: During a median follow-up period of 13.42 years, we recorded 3,053 gout cases. The associations between tea, coffee and gout were nonlinear, with a significant reduction in the risk by ∼ six cups/day of tea and three cups/day of coffee. Compared with those who were not tea and coffee drinkers, those who consumed >6 cups/day of tea or coffee were associated with 23% (HR 0.77, 95% CI, 0.66, 0.91) and 40% (HR 0.60, 95% CI, 0.47, 0.77) lower risks of gout, respectively, and both caffeinated and decaffeinated coffee consumption were associated with a decreased risk. Moreover, hyperuricaemia may modify the association between coffee and gout. Compared with non-coffee consumers with hyperuricaemia, those with ≥4 cups/day coffee intake without hyperuricaemia had the lowest risk (HR 0.34, 95% CI, 0.28, 0.41). CONCLUSION: Consumption of tea or coffee had a strong nonlinear association in gout risk reduction. Hyperuricaemia status had a potential effect modification on the association of coffee intake with gout.

Evidence of the folate-mediated one-carbon metabolism pathway genes in controlling the non-syndromic oral clefts risks.

The folate-mediated one-carbon metabolism pathway is thought to play an important role in the etiology of non-syndromic oral clefts (NSOFC), although none of the genes in this pathway has shown significant signals in genome-wide association studies (GWAS). Recent evidence indicated that enhanced understanding could be gained by aggregating multiple SNPs effect simultaneously into polygenic risk score (PRS) to assess its association with disease risks. This study is aimed to assess the association between the genetic effect of folate-mediated one-carbon metabolism pathway and NSOFC risks using PRS based on a case-parent trio design. A total of 297 SNPs mapped from 18 genes in the folate-mediated one-carbon metabolism pathway were aggregated from a GWAS of 2458 case-parent trios recruited from an international consortium. We found a PRS based on the folate-mediated one-carbon metabolism pathway was significant among all NSOFC trios (OR = 1.95, 95% CI: 1.66-2.28, p = 2.39 × 10-16 ), as well as two major subtypes, non-syndromic cleft lip with or without cleft palate (NSCL/P) trios (OR = 1.71, 95% CI: 1.50-1.96, p = 7.66 × 10-15 ) and non-syndromic cleft palate only (NSCPO) trios (OR = 1.51, 95% CI: 1.36-1.68, p = 2.1 × 10-14 ). Similar results were also observed in further subgroup analyses stratified into Asian and European trios. The averaged PRS of the folate-mediated one-carbon metabolism pathway varied between the NSOFC case group and its comparison group (p < 0.05) with higher average PRS in the cases. Moreover, the top 5% pathway PRS group had 2.25 (95% CI: 1.85-2.73) times increased NSOFC risk, also 3.09 (95% CI: 2.50-3.81) and 2.06 (95% CI: 1.39-3.02) times increased risk of NSCL/P and NSCPO compared to the remainder of the distribution. The results of our study confirmed the folate-mediated one-carbon metabolism pathway was important in controlling risk to NSOFC and this study enhanced evidence towards understanding the genetic risks of NSOFC.

Short-term exposure to reduced specific-size ambient particulate matter increase the risk of cause-specific cardiovascular disease: A national-wide evidence from hospital admissions.

Evidence for the health effects of ambient PM1 (particulate matter with an aerodynamic diameter ≤ 1 µm) pollution is limited, and it remains unclear whether a smaller particulate matter has a greater impact on human health. We conducted a time-series study in 184 major cities by extracting daily hospital data on admissions for ischemic heart disease, heart failure, heart rhythm disturbances, and stroke between 2014 and 2017 from a medical insurance claims database of 0.28 billion beneficiaries. City-specific associations were estimated with over-dispersed generalized additive models. A random-effects meta-analysis was used to estimate regional and national average associations. We conducted stratified and meta-regression analyses to explore potential effect modifiers of the association. We recorded 8.83 million cardiovascular admissions during the study period. At the national-average level, a 10-µg/m3 increase in same-day PM1, PM2.5(particulate matter with an aerodynamic diameter ≤ 2.5 µm) and PM10(particulate matter with an aerodynamic diameter ≤ 10 µm) concentrations corresponded to a 1.14% (95% confidence interval 0.88-1.41%), 0.55% (0.40-0.70%), and 0.45% (0.36-0.55%) increase in cardiovascular admissions, respectively. PM1 exposure was also positively associated with all cardiovascular disease subtypes, including ischemic heart disease (1.28% change; 0.99-1.56%), heart failure (1.30% change; 0.70-1.91%), heart rhythm disturbances (1.11% change; 0.65-1.58%), and ischemic stroke (1.29% change; 0.88-1.71%). The associations between PM1 and cardiovascular admissions were stronger in cities with lower PM1 levels, higher air temperatures and relative humidity, as well as in subgroups with elder age (all P < 0.05). This study provides robust evidence of short-term associations between PM1 concentrations and increased hospital admissions for all major cardiovascular diseases in China. Our findings suggest a greater short-term impact on cardiovascular risk from PM1 in comparison to PM2.5 and PM10.

Association between ambient fine particulate matter and adult outpatient visits for rheumatoid arthritis in Beijing, China.

The association between fine particulate matter (PM2.5) and rheumatoid arthritis (RA) is currently unclear, especially in Beijing, a city with severe air pollution. Our study aimed to explore the relationship between short-term outdoor exposure to PM2.5 and RA outpatient visits using a time-series analysis in Beijing. We used the Beijing's Medical Claims for Employees database to identify patients with RA in 2010-2012. A generalized additive model with a Poisson link was used to estimate the percentage change in RA outpatient visits after the PM2.5 concentration increased by 10 µg/m3. From January 1, 2010, to June 30, 2012, a total of 541,061 RA outpatient visits were identified. During the study period, the average daily (standard deviation) concentration of PM2.5 was 99.5 (75.3) µg/m3. A 10 µg/m3 increase in PM2.5 concentration was correlated with a 0.21% (95% CI, 0.18-0.23%) increase in outpatient visits for RA on the same day. A significant association for the cumulative effect of PM2.5 was found, and the largest significant association was observed for a lag of 0-3 days (0.26%; 95% CI, 0.23-0.29%). Stratified analyses revealed that females (0.29%, 95% CI: 0.26-0.33%) and 18-65 years old patients (0.29%, 95% CI: 0.25-0.32%) were most susceptible to the effects of PM2.5 exposure. The current findings showed that short-term exposure to PM2.5 was followed by an increase in the number of outpatient visits for RA in Beijing. Future studies should investigate the mechanisms underlying this association.

Gender disparities in the mediating role of symptom knowledge level in reducing acute coronary syndrome (ACS) decision delay: Findings from a community-based study in China.

BACKGROUND: Implementing training programs to educate patients on the prodromal symptoms of acute coronary syndrome (ACS) may assist patients in accurately recognizing these symptoms, and ultimately decrease their time delay in seeking emergency medical services (EMS). However, the effectiveness of this approach remains uncertain, particularly among the Chinese population. METHODS: A cross-sectional study was conducted within 22 communities in Beijing, China between 2015 and 2018, with a total of 1099 participants recruited. The study utilized a standardized questionnaire to evaluate the presence of intentional decision delay in turning to EMS under a hypothetical chest pain, the participants' knowledge of ACS prodromal symptoms, and whether they had ever received any training programs aimed at increasing their symptom knowledge. Mediation analysis was performed with regression models and bootstrapping methods, and gender difference was further analyzed through moderated mediation analysis. RESULTS: A total of 1099 participants (58.2% female, median [IQR] age 34 [20]) were included in the study. The results of the mediation analysis indicated that training programs were associated with a decrease risk in decision delay, with increased knowledge playing a mediating role (mediation effect/total effect = 36.59%, P < 0.0001). Gender modified this mediation effect, with it being observed only in the male group. Specifically, training programs were not found to significantly decrease decision delay among females (P > 0.05), even though they did improve women's knowledge of ACS prodromal symptoms (ß = 0.57, P = 0.012). CONCLUSION: The results suggested a relationship between prior training programs and reduced decision delay, with increased knowledge of prodromal symptoms of ACS serving as a mediator. However, the effect was only observed in male participants and not in female participants. This highlights the notion that mere transfer of knowledge regarding ACS prodromal symptoms may not be sufficient to mitigate decision delay in the female population. Further research is needed to corroborate these results and to gain deeper insights into the gender-specific barriers encountered in this study.

Wound complications and bleeding with new oral anticoagulants in patients undergoing total joint arthroplasty: A systematic review and meta-analysis of randomized controlled trials.

AIMS: The results of associations between new oral anticoagulants (NOACs) and wound complications after total joint arthroplasty remain inconsistent. We conducted a systematic review and meta-analysis of randomized controlled trials to make comparisons with low molecular weight heparins (LMWH) on the clinical outcomes of total wound complications, together with other efficacy and safety endpoints to further evaluate the safety and efficacy of NOACs. METHODS: This meta-analysis was conducted based on a published protocol (PROSPERO: CRD42019140841). We searched for available articles in PubMed, Embase and Cochrane Library through Jun 62 021. Random-effects meta-analyses, including subgroup analyses, were conducted to estimate the pooled relative risk (RR) and 95% confidence interval (CI) for specific doses of NOACs. RESULTS: We retrieved 1683 studies, of which 20 were eligible for inclusion. We found that apixaban was associated with a lower incidence of total wound complications compared with LMWH (RR = 0.81; 95% CI: 0.65-1.00), while dabigatran and rivaroxaban did not increase the risk of total wound complications. In addition, apixaban was associated with a reduction in the risk of major/clinically relevant nonmajor bleeding events compared to LMWH (RR = 0.80, 95% CI: 0.65-0.99), while rivaroxaban increased the risk for major/clinically relevant nonmajor bleeding events (RR = 1.23, 95% CI: 1.02-1.50). Moreover, all 4 NOACs were associated with lower incidences of major venous thromboembolism compared with LMWH. CONCLUSION: A lower risk of wound complications was detected for apixaban, while dabigatran and rivaroxaban did not increase the risk when compared with LMWH. The efficacy of 4 NOACs was broadly similar.

Trends in Hospital Admissions for Chronic Obstructive Pulmonary Diseases After Comprehensive Tobacco Control Policies in Beijing, China.

INTRODUCTION: Only a few studies have examined the effectiveness of tobacco control policies on respiratory conditions, and the results were less consistent. The 2015 Beijing tobacco control policy package incorporating all six components of MPOWER has been implemented since Jun 2015. The present study aimed to evaluate the impact of a comprehensive tobacco control policy package on hospital admissions for chronic obstructive pulmonary disease (COPD) in Beijing, China. AIMS AND METHODS: An interrupted time-series study was conducted based on the hospital admission information for about 18 million residents, who were covered by the Beijing Medical Claim Data for Employees from January 2013 to June 2017. The average percentage change of COPD hospital admission rates and reductions in hospital admission numbers were estimated by segmented Poisson regression models. RESULTS: There were 54 040 COPD hospital admissions with a crude rate of 67.2 per 100 000 residents during the observational period. After the implementation of the policy package, the hospital admission rates of COPD were reduced by -14.7% (95%CI: -17.8%, -11.5%) immediately. The secular trend was slowed down by -3.0% (95% CI: -5.6%, -0.4%) annually. A total of 5 581 reductions in COPD hospital admissions were estimated during the 25 months post-law period, accounting for 17.5% (95% CI: 12.5%, 22.5%) of overall COPD hospital admissions. More reductions were shown in males and those aged over 65 years old. CONCLUSIONS: The results indicated significant protections against hospitalization of COPD after the 2015 Beijing comprehensive tobacco control policy package. The results provide support for public health benefits for respiratory conditions from WHO-recommended tobacco control measures. IMPLICATIONS: Only a few studies have examined the effectiveness of tobacco control policies on respiratory conditions, and the results were less consistent. Based on medical records for about 18 million residents, this study showed an association between comprehensive tobacco control policies and significant reductions of hospital admissions for chronic obstructive pulmonary disease. The results provide support for public health benefits for respiratory conditions from WHO-recommended tobacco control measures.

Measurement properties of performance-based measures to assess physical function in knee osteoarthritis: A systematic review.

OBJECTIVE: To systematically review the measurement properties of performance-based measures to assess physical function in people with knee osteoarthritis. DATA SOURCES: PubMed, Web of Science, Embase, Scopus, CINAHL, and PsycINFO were searched in May 2022. METHODS: This study was conducted in accordance with the guidelines recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Clinical trials on the psychometric properties of performance-based tools for measuring physical function in people with knee osteoarthritis were included. Two reviewers independently rated measurement properties using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). "Best evidence synthesis" was made using COnsensus-based Standards for the selection of health Measurement INstruments outcomes and the quality of findings. RESULTS: Thirty-six out of 3425 publications were eligible for inclusion. Thirty-two performance-based measures were evaluated including 26 single-activity measures and 6 multi-activity measures. Measurement properties evaluated included internal consistency (2 measures), reliability (23 measures), measurement error (20 measures), hypotheses testing for construct validity (22 measures), and responsiveness (23 measures). On balance of the limited evidence, the walk 40 m fast-paced test and 6-minute walking test were the best rated walking tests. The 30-second chair stand test and timed up and go test were the best rated sit-to-stand tests. The Performance Tests Measures and Physical Activity Restrictions may be the suitable multi-activity measures for knee osteoarthritis. CONCLUSIONS: Further good quality research investigating the measurement properties, and in particular, the measurement error of performance-based measures in patients with knee osteoarthritis is needed.

Exploring gene-gene interaction in family-based data with an unsupervised machine learning method: EPISFA.

Gene-gene interaction (G × G) is thought to fill the gap between the estimated heritability of complex diseases and the limited genetic proportion explained by identified single-nucleotide polymorphisms. The current tools for exploring G × G were often developed for case-control designs with less considerations for their applications in families. Family-based studies are robust against bias led from population stratification in genetic studies and helpful in understanding G × G. We proposed a new algorithm epistasis sparse factor analysis (EPISFA) and epistasis sparse factor analysis for linkage disequilibrium (EPISFA-LD) based on unsupervised machine learning to screen G × G. Extensive simulations were performed to compare EPISFA/EPISFA-LD with a classical family-based algorithm FAM-MDR (family-based multifactor dimensionality reduction). The results showed that EPISFA/EPISFA-LD is a tool of both high power and computational efficiency that could be applied in family designs and is applicable within high-dimensionality datasets. Finally, we applied EPISFA/EPISFA-LD to a real dataset drawn from the Fangshan/family-based Ischemic Stroke Study in China. Five pairs of G × G were discovered by EPISFA/EPISFA-LD, including three pairs verified by other algorithms (FAM-MDR and logistic), and an additional two pairs uniquely identified by EPISFA/EPISFA-LD only. The results from EPISFA might offer new insights for understanding the genetic etiology of complex diseases. EPISFA/EPISFA-LD was implemented in R. All relevant source code as well as simulated data could be freely downloaded from https://github.com/doublexism/episfa.

SAMHD1 Sheds Moonlight on DNA Double-Strand Break Repair.

SAMHD1 (sterile α motif and histidine (H) aspartate (D) domain-containing protein 1) is known for its antiviral activity of hydrolysing deoxynucleotides required for virus replication. Daddacha et al. identify a hydrolase-independent, moonlighting function of SAMHD1 that facilitates homologous recombination of DNA double-strand breaks (DSBs) by promoting recruitment of C-terminal binding protein interacting protein (CTIP), a DNA-end resection factor, to damaged DNA. These findings could benefit anticancer treatment.

Impact of a comprehensive tobacco control policy package on acute myocardial infarction and stroke hospital admissions in Beijing, China: interrupted time series study.

OBJECTIVE: To evaluate a comprehensive tobacco control policy package on hospital admissions for acute myocardial infarction (AMI) and stroke in a global city. DESIGN: Interrupted time series study. SETTING: Beijing, China. POPULATION: 31 707 AMI and 128 116 stroke hospital admissions recorded by the Beijing Medical Claim Data for Employees in 17.7 million residents from January 2013 to June 2017. INTERVENTION: The policy package including all components of MPOWER has been implemented since June 2015. MAIN OUTCOME MEASURES: The immediate change of AMI and stroke hospital admissions and the annual change in the secular trend. RESULTS: There was a secular increase trend for the crude hospital admission rates of AMI and stroke during the observational period. After implementation of the policy, immediate reductions were observed in the hospital admissions for both AMI (-5.4%, 95% CI -10.0% to -0.5%) and stroke (-5.6%, 95% CI -7.8% to -3.3%). In addition, the secular increase trend for stroke was slowed down by -15.3% (95% CI -16.7% to -13.9%) annually. Compared with the hypothetical scenario where the policy had not taken place, an estimated 18 137 (26.7%) stroke hospital admissions had been averted during the 25 months of postpolicy period. CONCLUSIONS: The results indicated significant health benefits on cardiovascular morbidity after the Beijing tobacco control policy package, which highlighted the importance for a comprehensive tobacco control policy at the national level in China. Similar tobacco control policy which consists of all components of MPOWER is urgently needed in other areas, especially in settings with high tobacco consumption, to achieve greater public health gains.