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Purpose: To examine the effects of fresh fruit, dried fruit, raw vegetables, and cooked vegetables on type 2 diabetes (T2D) progression trajectory. Methods: We included 429,886 participants in the UK Biobank who were free of diabetes and diabetes complications at baseline. Food groups were determined using a validated food frequency questionnaire. Outcomes were T2D incidence, complications, and mortality. Multi-state model was used to analyze the effects of food groups on T2D progression. Results: During a follow-up of 12.6 years, 10,333 incident T2D cases were identified, of whom, 3961 (38.3%) developed T2D complications and 1169 (29.5%) died. We found that impacts of four food groups on T2D progression varied depending on disease stage. For example, compared to participants who ate less than one piece of dried fruit per day, the hazard ratios and 95% confidence intervals for those who ate ≥ 2 pieces of dried fruit per day were 0.82 (0.77, 0.87), 0.88 (0.85, 0.92), and 0.86 (0.78, 0.95) for transitions from diabetes-free state to incident T2D, from diabetes-free state to total death, and from incident T2D to T2D complications, respectively. Higher intake of fresh fruit was significantly associated with lower risk of disease progression from diabetes-free state to all-cause death. Higher intake of raw and cooked vegetables was significantly associated with lower risks of disease progression from diabetes-free state to incident T2D and to total death. Conclusions: These findings indicate that higher intake of fresh fruit, dried fruit, raw vegetables, and cooked vegetables could be beneficial for primary and secondary prevention of T2D. [ABSTRACT FROM AUTHOR]

Background There is a close association between diet and abdominal pain; however, relationship between inflammatory diet and characteristics of abdominal pain has not been characterized yet. Methods This study analyzed baseline data from the UK Biobank, 3-item DHQ-Abdominal Pain Questionnaire (DHQ-3Q), which including abdominal pain in the past 3 months, severity of abdominal pain, and frequency of abdominal pain, and data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. Energy-adjusted Dietary Inflammatory Index (E-DII), constructed based on 26 or 27 nutrients, was analyzed using continuous or categorical methods. Logistic regression and restricted cubic spline analyses examined the association between E-DII and abdominal pain. Results In UK Biobank, compared to participants in the lowest quintile of E-DII, the adjusted ORs for the highest quintile were 1.12 (95% CI 1.02–1.24; P  = .022), 1.05 (95% CI 1.00–1.09; P  = .030), 1.26 (95% CI 1.17–1.36; P  < .001), and 1.10 (95% CI 1.00–1.20; P  = .044) for chronic abdominal pain, abdominal pain in the past three months, severity of abdominal pain, and frequency of abdominal pain, respectively. In NHANES, compared to participants in the lowest quintile of E-DII, the adjusted ORs for the highest quintile were 1.46 (95% CI 1.20–1.77; P  < .001), 1.75 (95% CI 1.20–2.60; P  = .005), 1.45 (95% CI 1.14–1.87; P  = .003), and 1.18 (95% CI 0.82–1.72; P  = .380) for abdominal pain in the past year, upper left abdominal pain, upper middle abdominal pain, and upper right abdominal pain. Additionally, there was a nonlinear correlation between E-DII score and DHQ-3Q (P nonlinear <.001). Conclusion Following a pro-inflammatory diet is linked to a higher likelihood of experiencing abdominal pain, as well as increased severity and frequency of such pain. Therefore, further longitudinal studies are necessary to investigate this relationship. [ABSTRACT FROM AUTHOR]

There is no reliable causal evidence for the effect of statins on diabetic nephropathy (DN) and diabetic retinopathy (DR), and the results of previous observational studies are contradictory. Genetic variants linked to low-density lipoprotein cholesterol (LDL-C) from a UK biobank genome-wide association study and located within a 100kb window around HMGCR were used to proxy statins, comparing with PCSK9 inhibitors (control). DN and DR genome-wide association study summary statistics were obtained from the FinnGen study. Secondary MR analyses and NHANES cross-sectional data were used for validation. Drug-target Mendelian randomization (MR) was applied to investigate the association between the genetically proxied inhibition of HMGCR and PCSK9 with DN and DR, p < 0.0125 was considered significant after Bonferroni Correction. To triangulate the findings, genetic variants of whole blood-derived targets gene expression (cis-eQTL) and plasma-derived protein (cis-pQTL) levels were used to perform secondary MR analyses and data from the National Health and Nutrition Examination Survey were used for cross-sectional analysis. Genetically proxied inhibition of HMGCR was associated with higher risks of DN and DR (DN: OR = 1.79, p = 0.01; DR: OR = 1.41, p = 0.004), while no such association was found for PCSK9. Secondary MR analyses confirmed these associations. Cross-sectional analysis revealed a positive link between statin use and DR incidence (OR = 1.26, p = 0.03) and a significant negative association with glomerular filtration rate (Beta = − 1.9, p = 0.03). This study provides genetic evidence that genetically proxied inhibition of HMGCR is associated with increased risks of DN/DR, and this effect may not be attributed to their LDL-C-lowering properties. For patients with diabetic dyslipidemia, PCSK9 inhibitors may be a preferable alternative. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that exposure to air pollutants may be associated with specific blood indicators or anemia in certain populations. However, there is insufficient epidemiological data and prospective evidence to evaluate the relationship between environmental air pollution and specific types of anemia. We conducted a large-scale prospective cohort study based on the UK Biobank. Annual average concentrations of NO2, PM2.5, PM2.5-10, and PM10 were obtained from the ESCAPE study using the Land Use Regression (LUR) model. The association between atmospheric pollutants and different types of anemia was investigated using the Cox proportional hazards model. Furthermore, restricted cubic splines were used to explore exposure-response relationships for positive associations, followed by stratification and effect modification analyses by gender and age. After adjusting for demographic characteristics, 3-4 of the four types of air pollution were significantly associated with an increased risk of iron deficiency, vitamin B12 deficiency and folate deficiency anemia, while there was no significant association with other defined types of anemia. After full adjustment, we estimated that the hazard ratios (HRs) of iron deficiency anemia associated with each 10 μg/m3 increase in NO2, PM2.5, and PM10 were 1.04 (95%CI: 1.02, 1.07), 2.00 (95%CI: 1.71, 2.33), and 1.10 (95%CI: 1.02, 1.20) respectively. The HRs of folate deficiency anemia with each 10 μg/m3 increase in NO2, PM2.5, PM2.5-10, and PM10 were 1.25 (95%CI: 1.12, 1.40), 4.61 (95%CI: 2.03, 10.47), 2.81 (95%CI: 1.11, 7.08), and 1.99 (95%CI: 1.25, 3.15) respectively. For vitamin B12 deficiency anemia, no significant association with atmospheric pollution was found. Additionally, we estimated almost linear exposure-response curves between air pollution and anemia, and interaction analyses suggested that gender and age did not modify the association between air pollution and anemia. Our research provided reliable evidence for the association between long-term exposure to PM10, PM2.5, PM2.5-10, NO2, and several types of anemia. NO2, PM2.5, and PM10 significantly increased the risk of iron deficiency anemia and folate deficiency anemia. Additionally, we found that the smaller the PM diameter, the higher the risk, and folate deficiency anemia was more susceptible to air pollution than iron deficiency anemia. No association was observed between the four types of air pollution and hemolytic anemia, aplastic anemia, and other types of anemia. Although the mechanisms are not well understood, we emphasize the need to limit the levels of PM and NO2 in the environment to reduce the potential impact of air pollution on folate and iron deficiency anemia. [ABSTRACT FROM AUTHOR]

Aims: The causal relationship between sarcopenia‐related traits and ischemic stroke (IS) remains poorly understood. This study aimed to explore the causal impact of sarcopenia‐related traits on IS and to identify key mediators of this association. Methods: We conducted univariable, multivariable two‐sample, and two‐step Mendelian randomization (MR) analyses using genome‐wide association study (GWAS) data. This included data for appendicular lean mass (ALM), hand grip strength (HGS), and usual walking pace (UWP) from the UK Biobank, and IS data from the MEGASTROKE consortium. Additionally, 21 candidate mediators were analyzed based on their respective GWAS data sets. Results: Each 1‐SD increase in genetically proxied ALM was associated with a 7.5% reduction in the risk of IS (95% CI: 0.879–0.974), and this correlation remained after controlling for levels of physical activity and adiposity‐related indices. Two‐step MR identified that six mediators partially mediated the protective effect of higher ALM on IS, with the most significant being coronary heart disease (CHD, mediating proportion: 39.94%), followed by systolic blood pressure (36.51%), hypertension (23.87%), diastolic blood pressure (15.39%), type‐2 diabetes mellitus (T2DM, 12.71%), and low‐density lipoprotein cholesterol (7.97%). Conclusion: Our study revealed a causal protective effect of higher ALM on IS, independent of physical activity and adiposity‐related indices. Moreover, we found that higher ALM could reduce susceptibility to IS partially by lowering the risk of vascular risk factors, including CHD, hypertension, T2DM, and hyperlipidemia. In brief, we elucidated another modifiable factor for IS and implied that maintaining sufficient muscle mass may reduce the risk of such disease. [ABSTRACT FROM AUTHOR]

Background: While a few case-control studies indicated a possible correlation of IgG N-glycosylation patterns with pancreatitis, their restricted sample sizes and methodologies prevented conclusive insights into causality or distinguishing traits across pancreatitis types. Method: We conducted a two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 77 IgG N-glycosylation traits and various types of pancreatitis, including acute pancreatitis (AP), chronic pancreatitis (CP), alcohol acute pancreatitis (AAP), and alcohol chronic pancreatitis (ACP). This analysis utilized summary-level data from genomewide association studies (GWAS), employing methods such as IVW, MR-Egger, and weighted median. To ensure the robustness of our findings, several sensitivity analyses, including Cochran's Q statistic, leave-one-out, MR-Egger intercept, and MR-PRESSO global test were conducted. Result: Our study uncovered the causal relationship between specific IgG Nglycosylation traits and various types of pancreatitis. Notably, an increase in genetically predicted IGP7 levels was associated with a decreased risk of developing AP. For CP, our data suggested a protective effect associated with higher levels of both IGP7 and IGP31, contrasting with increased levels of IGP27 and IGP65, which were linked to a heightened risk. Moreover, in the case of AAP, elevated IGP31 levels were causatively associated with a lower incidence, while higher IGP26 levels correlated with an increased risk for ACP. Conclusion: This study establishes causal relationship between specific IgG N-glycosylation patterns and varying risks of different pancreatitis forms, underscoring their potential as predictive biomarkers. These findings necessitate further exploration into the underlying mechanisms, promising to inform more personalized diagnostic and therapeutic strategies in pancreatitis management. [ABSTRACT FROM AUTHOR]

Deciding when to depart on long‐distance, sometimes global, movements can be especially important for flying species. Adverse weather conditions can affect energetic flight costs and navigational ability. While departure timings and conditions have been well‐studied for migratory flights to and from the breeding range, few studies have focussed on flights within the non‐breeding season. Yet in some cases, overwintering ranges can be large enough that ecological barriers, and a lack of resting sites en route, may resist movement, especially in unfavorable environmental conditions. Understanding the conditions that will enable or prohibit flights within an overwintering range is particularly relevant in light of climate change, whereby increases in extreme weather events may reduce the connectivity of sites. We tracked 495 (n = 251 in 2019; n = 244 in 2020) overwintering red knots (Calidris canutus islandica) in the Dutch Wadden Sea and investigated how many departed towards the UK (on westward relocation flights), which requires flying over the North Sea. For those that departed, we used a resource selection model to determine the effect of environmental conditions on the timing of relocation flights. Specifically, we investigated the effects of wind, rain, atmospheric pressure, cloud cover, and migratory timing relative to sunset and tidal cycle, which have all been shown to be crucial to migratory departure conditions. Approximately 37% (2019) and 36% (2020) of tagged red knots departed on westward relocation flights, indicating differences between individuals' space use within the overwintering range. Red knots selected for departures between 1 and 2.5 h after sunset, approximately 4 h before high tide, with tailwinds and little cloud cover. However, rainfall and changes in atmospheric pressure appear unimportant. Our study reveals environmental conditions that are important for relocation flights across an ecological barrier, indicating potential consequences of climate change on connectivity. [ABSTRACT FROM AUTHOR]

Motivation Polygenic risk scores (PRSs) predict individuals' genetic risk of developing complex diseases. They summarize the effect of many variants discovered in genome-wide association studies (GWASs). However, to date, large GWASs exist primarily for the European population and the quality of PRS prediction declines when applied to other ethnicities. Genetic profiling of individuals in the discovery set (on which the GWAS was performed) and target set (on which the PRS is applied) is typically done by SNP arrays that genotype a fraction of common SNPs. Therefore, a key step in GWAS analysis and PRS calculation is imputing untyped SNPs using a panel of fully sequenced individuals. The imputation results depend on the ethnic composition of the imputation panel. Imputing genotypes with a panel of individuals of the same ethnicity as the genotyped individuals typically improves imputation accuracy. However, there has been no systematic investigation into the influence of the ethnic composition of imputation panels on the accuracy of PRS predictions when applied to ethnic groups that differ from the population used in the GWAS. Results We estimated the effect of imputation of the target set on prediction accuracy of PRS when the discovery and the target sets come from different ethnic groups. We analyzed binary phenotypes on ethnically distinct sets from the UK Biobank and other resources. We generated ethnically homogenous panels, imputed the target sets, and generated PRSs. Then, we assessed the prediction accuracy obtained from each imputation panel. Our analysis indicates that using an imputation panel matched to the ethnicity of the target population yields only a marginal improvement and only under specific conditions. Availability and implementation The source code used for executing the analyses is this paper is available at https://github.com/Shamir-Lab/PRS-imputation-panels. [ABSTRACT FROM AUTHOR]

Aims: To investigate the association between glycated haemoglobin (HbA1c) levels and chronic obstructive pulmonary disease (COPD) incidents in the general population, and the association between HbA1c levels and mortality in patients with COPD. Materials and Methods: We investigated the association of HbA1c levels with COPD risk in the general population in the UK Biobank, using data from 420 065 participants. Survival analysis was conducted for 18 854 patients with COPD. We used restricted cubic spline analysis to assess the dose‐response relationship between HbA1c levels and COPD risk and survival. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results: During a median follow‐up of 12.3 years, 11 556 COPD cases were recorded. HbA1c had a non‐linear relationship with COPD risk (p for non‐linearity <.05). Compared with the quintile 2 (32.2‐<34.3 mmol/mol), those with HbA1c levels above 38.7 mmol/mol (quintile 5) had a 22% (HR, 1.22, 95% CI: 1.15‐1.30) higher risk of COPD. Compared with the HbA1c decile 2 (30.5‐<32.2 mmol/mol), the HRs (95% CI) of COPD risk were 1.16 (1.03‐1.30) and 1.36 (1.24‐1.50) in the lowest HbA1c decile (<30.5 mmol/mol) and highest decile (≥41.0 mmol/mol), respectively. The increased COPD risk associated with HbA1c was more pronounced in younger, current smokers, passive smokers, and participants with a higher Townsend deprivation index (all p for interaction <.05). Among patients with COPD, 4569 COPD cases died (488 because of COPD) during a median follow‐up of 5.4 years. Regarding COPD survival, HbA1c had a non‐linear relationship with all‐cause death (p for non‐linearity <.05). Those with HbA1c quintile 5 (≥38.7 mmol/mol) had a 23% (HR, 1.23, 95% CI: 1.10‐1.37) higher risk of all‐cause death compared with the quintile 2 (32.2‐<34.3 mmol/mol). Compared with the HbA1c decile 4 (33.3‐<34.3 mmol/mol), those in the lowest HbA1c decile (<30.5 mmol/mol) and highest HbA1c decile (≥41.0 mmol/mol) had 22% (HR, 1.22; 95% CI: 1.01‐1.47) and 28% (HR, 1.28; 95% CI: 1.11‐1.48) higher risk for overall death. However, no significant association was observed between HbA1c levels and the risk of COPD‐specific death. Conclusions: Our findings indicated that lower and higher HbA1c levels were associated with a higher risk of COPD. In COPD cases, lower and higher HbA1c levels were associated with a higher COPD all‐cause death risk. [ABSTRACT FROM AUTHOR]

Background: Common and rare variants contribute to the etiology of complex traits. However, the extent to which the phenotypic effects of common and rare variants involve shared molecular mediators remains poorly understood. The question is essential to the basic and translational goals of the science of genomics, with critical basic-science, methodological, and clinical consequences. Methods: Leveraging the latest release of whole-exome sequencing (WES, for rare variants) and genome-wide association study (GWAS, for common variants) data from the UK Biobank, we developed a metric, the COmmon variant and RAre variant Convergence (CORAC) signature, to quantify the convergence for a broad range of complex traits. We characterized the relationship between CORAC and effective sample size across phenome-wide association studies. Results: We found that the signature is positively correlated with effective sample size (Spearman ρ = 0.594, P < 2.2e − 16), indicating increased functional convergence of trait-associated genetic variation, across the allele frequency spectrum, with increased power. Sensitivity analyses, including accounting for heteroskedasticity and varying the number of detected association signals, further strengthened the validity of the finding. In addition, consistent with empirical data, extensive simulations showed that negative selection, in line with enhancing polygenicity, has a dampening effect on the convergence signature. Methodologically, leveraging the convergence leads to enhanced association analysis. Conclusions: The presented framework for the convergence signature has important implications for fine-mapping strategies and drug discovery efforts. In addition, our study provides a blueprint for the expectation from future large-scale whole-genome sequencing (WGS)/WES and sheds methodological light on post-GWAS studies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous evidence has identified exposure to fine ambient particulate matter (PM2.5) as a leading risk factor for adverse health outcomes. However, to date, only a few studies have examined the potential association between long-term exposure to PM2.5 and bone homeostasis. OBJECTIVE: We sought to examine the relationship between long-term PM2.5 exposure and bone health and explore its potential mechanism. METHODS: This research included both observational and experimental studies. First, based on human data from UK Biobank, linear regression was used to explore the associations between long-term exposure to PM2.5 (i.e., annual average PM2.5 concentration for 2010) and bone mineral density [BMD; i.e., heel BMD (푛= 37,440) and femur neck and lumbar spine BMD (푛= 29,766)], which were measured during 2014-2020. For the experimental animal study, C57BL/6 male mice were assigned to ambient PM2.5 or filtered air for 6 months via a whole-body exposure system. Micro-computed tomography analyses were applied to measure BMD and bone microstructures. Biomarkers for bone turnover and inflammation were examined with histological staining, immunohistochemistry staining, and enzyme-linked immunosorbent assay. We also performed tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay to determine the effect of PM2.5 exposure on osteoclast activity in vitro. In addition, the potential downstream regulators were assessed by real-time polymerase chain reaction and western blot. RESULTS: We observed that long-term exposure to PM2.5 was significantly associated with lower BMD at different anatomical sites, according to the analysis of UK Biobank data. In experimental study, mice exposed long-term to PM2.5 exhibited excessive osteoclastogenesis, dysregulated osteogenesis, higher tumor necrosis factor-alpha (TNF-α) expression, and shorter femur length than control mice, but they demonstrated no significant differences in femur structure or BMD. In vitro, cells stimulated with conditional medium of PM2.5-stimulated macrophages had aberrant osteoclastogenesis and differences in the protein/mRNA expression of members of the TNF-α/Traf6/c-Fos pathway, which could be partially rescued by TNF-α inhibition. DISCUSSION: Our prospective observational evidence suggested that long-term exposure to PM2.5 is associated with lower BMD and further experimental results demonstrated exposure to PM2.5 could disrupt bone homeostasis, which may be mediated by inflammation-induced osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Aim: To investigate the associations of diabetes, prediabetes and diabetes duration with chronic obstructive pulmonary disease (COPD) risk and survival in the UK Biobank. Materials and Methods: We conducted a prospective analysis among 452 680 participants without COPD at baseline using UK Biobank data. Multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox regression models. The dose–response relationship was explored using restricted cubic splines. A separate survival analysis was conducted for 12 595 patients with incident COPD. Results: Over a median follow‐up of 12.3 years, 12 595 cases of COPD were documented. Compared with the reference group, those with prediabetes and diabetes were associated with an 18% (HR 1.18 [95% CI: 1.13‐1.24]) and 35% (HR 1.35 [95% CI: 1.24‐1.47]) higher risk of COPD, respectively. Diabetes duration was associated with COPD risk, with multivariable HRs (95% CIs) of 1.23 (1.05‐1.44), 1.20 (1.04‐1.39) and 1.18 (1.01‐1.37) for diabetes duration of 7 years or longer, 3 to less than 7 years, and 1 to less than 3 years versus less than 1 year, respectively. Dose–response analysis revealed a non‐linear relationship between diabetes duration and COPD risk. Regarding COPD survival, COPD patients with prediabetes and diabetes had a 9% (HR 1.09 [95% CI: 1.00‐1.19]) and 21% (HR 1.21 [95% CI: 1.05‐1.41]) higher risk of overall death, respectively. Compared with the cases with a diabetes duration of less than 1 year, those with a diabetes duration of 7 years or longer were associated with a 46% higher risk of overall death (HR 1.46 [95% CI: 1.11‐1.92]). Conclusions: Our findings indicate that diabetes, prediabetes and a longer diabetes duration are associated with a higher risk of and worse survival for COPD. Future studies are warranted to determine the optimal way of diabetes control that might reduce COPD risk. [ABSTRACT FROM AUTHOR]

Nighttime Light Emission (NLE) is associated with diminished mental and physical health. The present study examines how NLE and associated urban features (e.g., air pollution, low green space) impact mental and physical wellbeing. We included 200,393 UK Biobank Cohort participants with complete data. The study was carried out in two steps. In Step1, we assessed the relationship between NLE, deprivation, pollution, green space, household poverty and mental and physical symptoms. In Step2, we examined the role of NLE on environment-symptom networks. We stratified participants into high and low NLE and used gaussian graphical model to identify nodes which bridged urban features and mental and physical health problems. We then compared the global strength of these networks in high vs low NLE. We found that higher NLE associated with higher air pollution, less green space, higher economic and neighborhood deprivation, higher household poverty and higher depressed mood, higher tiredness/lethargy and obesity (Rtraining_mean = 0.2624, Ptraining_mean <.001; Rtest_mean = 0.2619, Ptest_mean <.001). We also found that the interaction between environmental risk factors and mental, physical problems (overall network connectivity) was higher in the high NLE network than in the low NLE network (t = 0.7896, P <.001). In areas with high NLE, economic deprivation, household poverty and waist circumference acted as bridge factors between the key urban features and mental health symptoms. In conclusion, NLE, urban features, household poverty and mental and physical symptoms are all interrelated. In areas with high NLE, urban features associate with mental and physical health problems at a greater magnitude than in areas with low NLE. [ABSTRACT FROM AUTHOR]

Aims This study aims to evaluate the short- and long-term associations between COVID-19 and development of cardiovascular disease (CVD) outcomes and mortality in the general population. Methods and Results A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021. Based on age (within 5 years) and sex, each case was randomly matched with up to 10 participants without COVID-19 infection from two cohorts—a contemporary cohort between 16 March 2020 and 30 November 2020 and a historical cohort between 16 March 2018 and 30 November 2018. The characteristics between groups were further adjusted with propensity score-based marginal mean weighting through stratification. To determine the association of COVID-19 with CVD and mortality within 21 days of diagnosis (acute phase) and after this period (post-acute phase), Cox regression was employed. In the acute phase, patients with COVID-19 (n = 7584) were associated with a significantly higher short-term risk of CVD {hazard ratio (HR): 4.3 [95% confidence interval (CI): 2.6– 6.9]; HR: 5.0 (95% CI: 3.0–8.1)} and all-cause mortality [HR: 81.1 (95% CI: 58.5–112.4); HR: 67.5 (95% CI: 49.9–91.1)] than the contemporary (n = 75 790) and historical controls (n = 75 774), respectively. Regarding the post-acute phase, patients with COVID-19 (n = 7139) persisted with a significantly higher risk of CVD in the long-term [HR: 1.4 (95% CI: 1.2–1.8); HR: 1.3 (95% CI: 1.1– 1.6)] and all-cause mortality [HR: 5.0 (95% CI: 4.3–5.8); HR: 4.5 (95% CI: 3.9–5.2) compared to the contemporary (n = 71 296) and historical controls (n = 71 314), respectively. Conclusions COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality. Ongoing monitoring of signs and symptoms of developing these cardiovascular complications post diagnosis and up till at least a year post recovery may benefit infected patients, especially those with severe disease. [ABSTRACT FROM AUTHOR]

Background: Periprosthetic fractures after prosthetic joint replacement have received increasing attention over the past decades. The purpose of this study was to estimate the trends and state of research in periprosthetic fractures. Methods: Articles on periprosthetic fractures were retrieved from the Web of Science database. Information about each article, including country/region, author, institution, issue, journal, and keywords, was recorded for bibliometric analysis. The analysis included only English-language articles from 2000 to 2021, from 58 countries and regions. Results: A total of 1668 original articles meeting the research requirements were obtained. The number of manuscripts on periprosthetic fractures has experienced rapid growth, especially since 2009. Productivity was dominated by the USA, followed by the UK and Germany. The most prolific institution was Mayo Clinic. The most cited article was published by Sharkey, P.F. in 2002. The five most frequent keywords were "periprosthetic fractures", "total hip arthroplasty", " revision", "arthroplasty", "total knee arthroplasty". Conclusions: Based on the current trends of globalization, there is a rising trend in publications on periprosthetic fractures, with the largest annual contributions made by the United States. The most influential contributors are researchers from the United States and England. In addition, Journal of Arthroplasty is the journal with the most research in this field. Geriatric trauma and dual mobility are the new hot topics in this field. Together these studies have played a key role in periprosthetic fractures decision-making and management. [ABSTRACT FROM AUTHOR]

This paper explores student and teacher perspectives of challenges relating to the levels of competence in English of Chinese students studying overseas from the perspective of critical pedagogy. It draws on two complementary studies undertaken by colleagues at the University of Reading. The first--a research seminar attended by representatives from a wide range of UK universities--presents the views of teachers and administrators; the second draws on four case studies of the language learning of Chinese postgraduate students during their first year of study in the UK, and offers the student voice. Interview and focus group data highlight the limitations of current tests of English used as part of the requirements for university admission. In particular, university teachers expressed uncertainty about whether the acceptance of levels of written English which fall far short of native-speaker competence is an ill-advised lowering of standards or a necessary and pragmatic response to the realities of an otherwise uneven playing field. In spite of this ambivalence, there is evidence of a growing willingness on the part of university teachers and support staff to find solutions to the language issues facing Chinese students, some of which require a more strategic institutional approach, while others rely on greater flexibility on the part of individuals. Although the studies reported in this paper were based on British universities, the findings will also be of interest to those involved in tertiary education in other English-speaking countries which are currently attracting large numbers of Chinese students. (Contains 1 note.)

Objective: To investigate the associations of circulating liver function marker levels with the risk of chronic obstructive pulmonary disease (COPD). Methods: We leveraged the data of 372,056 participants from the UK Biobank between 2006 and 2010. The assessed circulating liver function markers included alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), albumin (ALB), and total protein (TP). Incident COPD was identified through linkage to the National Health Service registries. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up period of 12.3 (interquartile range:11.4-13.2) years, we documented 10,001 newly diagnosed COPD cases. Lower levels of ALT, TBIL, ALB, and TP and higher levels of GGT and ALP were nonlinearly associated with elevated COPD risk. The HR (95% CI) for decile 10 vs. 1 was 0.92 (0.84-1.01) for ALT, 0.82 (0.75-0.89) for TBIL, 0.74 (0.67-0.81) for ALB, 0.96 (0.88-1.04) for TP, 1.45 (1.31-1.62) for GGT, and 1.31 (1.19-1.45) for ALP. Restricted cubic spline analyses suggested a U-shaped relationship between AST levels and COPD risk (P for nonlinearity <0.05). Conclusion: We observed that all seven circulating liver function markers were nonlinearly associated with the risk of COPD, indicating the importance of liver function in COPD. [ABSTRACT FROM AUTHOR]

Introduction: The effect of tixagevimab/cilgavimab (Evusheld™; AstraZeneca, UK) should be evaluated in the context of concurrent outbreak situations. Methods: For serologic investigation of tixagevimab/cilgavimab during the BA.5 outbreak period, sera of immunocompromised (IC) hosts sampled before and one month after tixagevimab/cilgavimab administration and those of healthcare workers (HCWs) sampled one month after a 3rd shot of COVID-19 vaccines, five months after BA.1/BA.2 breakthrough infection (BI), and one month after BA.5 BI were investigated. Semi-quantitative anti-spike protein antibody (Sab) test and plaque reduction neutralizing test (PRNT) against BA.5 were performed. Results: A total of 19 IC hosts (five received tixagevimab/cilgavimab 300 mg and 14 received 600 mg) and 41 HCWs (21 experienced BA.1/BA.2 BI and 20 experienced BA.5 BI) were evaluated. Baseline characteristics did not differ significantly between IC hosts and HCWs except for age and hypertension. Sab significantly increased after tixagevimab/cilgavimab administration (median 130.2 BAU/mL before tixagevimab/cilgavimab, 5,665.8 BAU/mL after 300 mg, and 10,217 BAU/mL after 600 mg; both P < 0.001). Sab of one month after the 3rd shot (12,144.2 BAU/mL) or five months after BA.1/BA.2 BI (10,455.8 BAU/mL) were comparable with that of tixagevimab/cilgavimab 600 mg, while Sab of one month after BA.5 BI were significantly higher (22,216.0 BAU/mL; P < 0.001). BA.5 PRNT ND50 significantly increased after tixagevimab/cilgavimab administration (median ND50 29.6 before tixagevimab/cilgavimab, 170.8 after 300 mg, and 298.5 after 600 mg; both P < 0.001). The ND50 after tixagevimab/cilgavimab 600 mg was comparable to those of five months after BA.1 BI (ND50 200.9) while ND50 of one month after the 3rd shot was significantly lower (ND50 107.6; P = 0.019). The ND50 of one month after BA.5 BI (ND50 1,272.5) was highest among tested groups, but statistical difference was not noticed with tixagevimab/cilgavimab 600 mg. Conclusion: Tixagevimab/cilgavimab provided a comparable neutralizing activity against the BA.5 with a healthy adult population who were vaccinated with a 3rd shot and experienced BA.1/BA.2 BI. [ABSTRACT FROM AUTHOR]

Transcriptome-wide association studies (TWASs) aim to detect associations between genetically predicted gene expression and complex diseases or traits through integrating genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) mapping studies. Most current TWAS methods analyze one gene at a time, ignoring the correlations between multiple genes. Few of the existing TWAS methods focus on survival outcomes. Here, we propose a novel method, namely a COx proportional hazards model for NEtwork regression in TWAS (CoNet), that is applicable for identifying the association between one given network and the survival time. CoNet considers the general relationship among the predicted gene expression as edges of the network and quantifies it through pointwise mutual information (PMI), which is under a two-stage TWAS. Extensive simulation studies illustrate that CoNet can not only achieve type I error calibration control in testing both the node effect and edge effect, but it can also gain more power compared with currently available methods. In addition, it demonstrates superior performance in real data application, namely utilizing the breast cancer survival data of UK Biobank. CoNet effectively accounts for network structure and can simultaneously identify the potential effecting nodes and edges that are related to survival outcomes in TWAS. [ABSTRACT FROM AUTHOR]

Background Although smoking is a known potential contributor to back pain, there is still a lack of quantitative studies on the effects of different doses on back pain (BP) occurrence, including a lack of a longitudinal cohorts. To address this gap, we aimed to investigate the association between various smoking-related exposures and back pain incidence to advance global efforts toward smoking cessation and guide primary prevention of BP. Methods In this prospective cohort study, we retrieved data on 438510 patients from the UK Biobank who were free of back pain and who were recruited in 2006-2010, and followed them up from baseline through 1 April 2022. We extracted data on smoking-related exposures, including smoking status (SS), number of cigarettes smoked daily (CPD), and pack-years of own smoking (PY) and examined back pain incidence as an outcome. We used a Cox proportional hazard model adjusted for several covariates, multiple imputation methods, and population attribution fraction. Results During the median follow-up of 12.98 years, 31467 participants developed BP, with incidence rates in former and current smokers of 1.13 (95% confidence interval (CI)=1.10-1.16, P<0.000) and 1.50 (95% CI=1.45-1.56, P<0.000), respectively. The hazard ratios (HRs) of participants who smoked more than 30 CPD and those with more than 30 PY were 1.45 (95% CI=1.36-1.55, P<0.000) and 1.45 (95% CI=1.40-1.50, P<0.000), respectively. Relative to male, female smokers were at more risk of developing BP. Not smoking, quitting smoking, and reducing CPD and PY could lower the BP risk by 7.8%, 5.4%, 9.8%, and 18.0%, respectively. Conclusions Ever smoking, higher cigarette consumption daily, and increased smoking intensity were associated with an increased BP risk. This association was stronger in female smokers. Not smoking, smoking cessation, and reducing smoking volume and intensity were effective measures to prevent BP occurrence. [ABSTRACT FROM AUTHOR]

Background: Both genetic and cardiovascular factors contribute to the risk of developing heart failure (HF), but whether idea cardiovascular health metrics (ICVHMs) offset the genetic association with incident HF remains unclear.Objectives: To investigate the genetic association with incident HF as well as the modification effect of ICVHMs on such genetic association in Chinese and British populations.Methods: An ICVHMs based on smoking, drinking, physical activity, diets, body mass index, waist circumference, blood pressure, blood glucose, and blood lipids, and a polygenic risk score (PRS) for HF were constructed in the China Kadoorie Biobank (CKB) of 96,014 participants and UK Biobank (UKB) of 335,782 participants which were free from HF and severe chronic diseases at baseline.Results: During the median follow-up of 11.38 and 8.73 years, 1451 and 3169 incident HF events were documented in CKB and UKB, respectively. HF risk increased monotonically with the increase of PRS per standard deviation (CKB: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07, 1.32; UKB: 1.07; 1.03, 1.11; P for trend < 0.001). Each point increase in ICVHMs was associated with 15% and 20% lower risk of incident HF in CKB (0.85; 0.81, 0.90) and UKB (0.80; 0.77, 0.82), respectively. Compared with unfavorable ICVHMs, favorable ICVHMs was associated with a lower HF risk, with 0.71 (0.44, 1.15), 0.41 (0.22, 0.77), and 0.48 (0.30, 0.77) in the low, intermediate, and high genetic risk in CKB and 0.34 (0.26, 0.44), 0.32 (0.25, 0.41), and 0.37 (0.28, 0.47) in UKB (P for multiplicative interaction > 0.05). Participants with low genetic risk and favorable ICVHMs, as compared with high genetic risk and unfavorable ICVHMs, had 56~72% lower risk of HF (CKB 0.44; 0.28, 0.70; UKB 0.28; 0.22, 0.37). No additive interaction between PRS and ICVHMs was observed (relative excess risk due to interaction was 0.05 [-0.22, 0.33] in CKB and 0.04 [-0.14, 0.22] in UKB).Conclusions: In CKB and UKB, genetic risk and ICVHMs were independently associated with the risk of incident HF, which suggested that adherence to favorable cardiovascular health status was associated with a lower HF risk among participants with all gradients of genetic risk. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways.Methods: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed.Results: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache.Interpretation: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between body composition and subsequent risk of the major gynecologic malignancies. Methods: This is a prospective analysis of participants from the UK Biobank. We measured baseline body composition and confirmed cancer diagnosis through linkage to cancer and death registries. We evaluated hazard ratios (HRs) and confidence interval (CIs) with COX models adjusting for potential confounders. Results: We document 1430 cases of the top three gynecologic malignancies (uterine corpus cancer 847 cases, ovarian cancer 514 cases, and cervical cancer 69 cases) from 245,084 female participants (75,307 were premenopausal and 169,777 were postmenopausal). For premenopausal women, whole body fat‐free mass (WBFFM) was associated with an increased risk of uterine corpus cancer (Adjusted HR per unit increase 1.04, 95% CI 1.02–1.06). For postmenopausal women, compared with the first quartile, the fourth quartile of WBFFM and whole body fat mass(WBFM) was associated with 2.16 (95% CI 1.49–3.13) times and 1.89 (95% CI 1.31–2.72) times of increased uterine corpus cancer risk, respectively. Regarding the distribution of body fat mass (FM)/fat‐free mass (FFM), FFM distributed in the trunk was associate with increased uterine corpus cancer risk in premenopausal (HR 1.18,95% CI 1.07–1.31) and postmenopausal women (HR 1.13,95% CI 1.09–1.18). Meanwhile, FM/FFM distributed in the limbs present an U‐shaped associations with uterine corpus cancer risk. We did not observe any association between aforementioned body composition indices with ovarian or cervical cancer. Conclusion: FM is associated with an increased risk of uterine corpus cancer in postmenopausal women. Meanwhile, FFM is found to be a risk factor for uterine corpus cancer in both premenopausal and postmenopausal women. No association of body composition with ovarian or cervical cancer was observed. [ABSTRACT FROM AUTHOR]

The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants' effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes. Finding causal variants and genes from GWAS loci results remains a challenge. Here, the authors train a model to predict if a variant affects nearby gene expression, and apply the method to identify new possible causal eQTLs and mechanisms of GWAS loci. [ABSTRACT FROM AUTHOR]

Short-term exposure to air pollutants increases the risk of migraine, but the long-term impacts of exposure to multiple pollutants on migraine have not been established. The aim of this large prospective cohort study was to explore these links. A total of 458,664 participants who were free of migraine at baseline from the UK Biobank were studied. Cox proportional hazards models were used to estimate the risk of new-onset migraine from combined long-term exposure to four pollutants, quantified as an air pollution score using principal component analysis. During a median (IQR) follow-up of 12.5 (11.8, 13.2) years, a total of 5417 new-onset migraine cases were documented. Long-term exposure to multiple air pollutants was associated with an increased risk of new-onset migraine, as indicated by an increased in the SDs of PM 2.5 (hazard ratio (HR): 1.04, 95% CI: 1.01–1.06, P = 0.009), PM 10 (HR: 1.07, 95% CI: 1.04–1.10, P < 0.001), NO 2 (HR: 1.10, 95% CI: 1.07–1.13, P < 0.001) and NOx (HR: 1.04, 95% CI: 1.01–1.07, P = 0.005) in the main model. The air pollution score showed a dose response association with an increased risk of new-onset migraine. Similarly, compared with those of the lowest tertile, the HRs (95% CI) of new-onset migraine were 1.11 (95% CI: 1.04–1.19, P = 0.002) and 1.17 (95% CI: 1.09–1.26, P < 0.001) in tertiles 2 and 3, respectively, according to the main model (P trend < 0.001). Long-term individual and joint exposure to multiple air pollutants is associated with an increased risk of new-onset migraine. [Display omitted] • Air pollution is a risk factor for new-onset migraine. • Long-term exposure to air pollutants increased the risk of new-onset migraine. • The AP score showed a dose-response relation with the risk of new-onset migraine. [ABSTRACT FROM AUTHOR]

The recognition of adiposity as a risk factor for gastric cancer is mainly based on traditional anthropometric indices, such as body mass index, which are unable to discriminate between lean and fat mass. We undertook this study to examine body composition and subsequent risk of gastric cancer. This is a prospective analysis of participants free of cancer from the UK Biobank. We measured baseline body composition with electrical bioimpedance analysis and confirmed cancer diagnosis through linkage to cancer and death registries. We evaluated hazard ratios (HRs) and confidence interval (CIs) with COX models adjusting for potential confounders. We documented 326 cases of cancer from 474,929 participants over a median follow‐up of 6.6 years. Both male (HR 1.70, 95% CI 1.01 to 2.89) and female participants (HR 2.47, 95% CI 1.15 to 5.32) in the highest quartile of whole body fat‐free mass were associated with increased risk of gastric cancer as compared with those in the lowest quartile.Whole body fat mass was associated with a decreased risk of gastric cancer (HR per 5‐unit increase 0.86, 95% CI 0.74 to 0.99) in females, but not in males. We concluded that fat‐free mass and fat mass may have different effects on gastric cancer risk. This study provided evidence for individualized weight management for the prevention of gastric cancer. [ABSTRACT FROM AUTHOR]

Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and replication sample, we identified three genomic loci at the genome-wide significance level (p < 5.0 × 10–8): 2p23.2 (lead SNP rs4477866, discovery p = 3.47 × 10–8, replication p = 1.03 × 10–4), 16q12.2 (rs1421085, discovery p = 2.04 × 10–9, replication p = 6.47 × 10–14) and 18q21.32 (rs11152213, discovery p = 3.47 × 10–8, replication p = 6.69 × 10–6). Our findings not only provide useful insights into lean mass and bone mass development, but also enhance our understanding of the potential genetic correlation between BMD and LBM. [ABSTRACT FROM AUTHOR]

Sarcopenia is a complex polygenic disease, and its molecular mechanism is still unclear. Whole lean body mass (WLBM) is a heritable trait predicting sarcopenia. To identify genomic loci underlying, we performed a whole‐exome sequencing (WES) of WLBM variation with high sequencing depth (more than 40*) in 101 Chinese subjects. We then replicated in the major findings in the large‐scale UK Biobank (UKB) cohort (N = 217,822) for WLBM. The results of four single‐nucleotide polymorphisms (SNPs) were significant both in the discovery stage and replication stage: SNP rs740681 (discovery p = 1.66 × 10–6, replication p =.05), rs2272303 (discovery p = 3.20 × 10–4, replication p = 3.10 × 10–4), rs11170413 (discovery p = 3.99 × 10–4, replication p = 2.90 × 10–4), and rs2272302 (discovery p = 9.13 × 10–4, replication p = 3.10 × 10–4). We combined p values of the significant SNPs. Functional annotations highlighted two candidate genes, including FZR1 and SOAT2, that may exert pleiotropic effects to the development of body mass. Our findings provide useful insights that further enhance our understanding of genetic interplay in sarcopenia. [ABSTRACT FROM AUTHOR]

pH-sensitive polyethylene glycol-conjugated urokinase nanogels (PEG-UK) is a new form of urokinase (UK) nanogels that could release UK at certain pH values. In our former study, we demonstrated that the pH value in the infarcted brain significantly declined to the level that could trigger the delivery of UK from PEG-UK. Thrombolysis is recommended as the first choice for ischemic stroke within the time window. However, it is common for the patients to miss the thrombolysis time window, which is one of the major causes of bad prognosis from ischemic stroke. It remains promising for seeking therapeutic approaches for ischemic stroke by investigating potential protective reagents delivered out of the usually thrombolysis time window. In this study, the protective effect of administration of PEG-UK outside the usual time window and the underlying mechanisms were investigated. PEG-UK was administrated 2 h and a half after ischemic stroke Delayed administration of PEG-UK significantly ameliorated the severity of neurological deficits of permanent middle cerebral occlusion (pMCAO) rats and reduced the infiltration of inflammatory cells and the concentration of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the brain tissues. The content of water and the leakage of Evans Blue (EB) in the PEG-UK group were also decreased. Maintenance of the expression of platelet-derived growth factor-C (PDGF-C) and inhibition of the upregulation of metalloproteinase proteins, low-density lipoprotein receptor-related protein (LRP), nuclear factor κB (NF-κB) p65 and cyclooxygenase-2 (Cox-2) were observed through western blotting and realtime PCR in the PEG-UK group. Besides, delayed administration of PEG-UK attenuated the up regulation of Caspase8 and Caspase9 and the cleavage of Caspase3 and poly (ADP-ribose) polymerase 1 (PARP1) in ischemic lesion sites. Moreover, PEG-UK treatment also inhibited the upregulation and phosphorylation of N-methyl-D-aspartic acid receptors (NMDARs), which has been revealed to play a vital role in mediating excito-neurotoxicity in ischemic stroke. In conclusion, through the inhibition of LRP/NF-κB/Cox-2 pathway, the Caspase cascade and activation of NMDARs, administration of PEG-UK outside the usual time window could still exert protective effects in pMCAO rats through the maintenance of the integrity of BBB and the inhibition of apoptosis and excito-neurotoxicity. • Delayed administration of PEG-UK ameliorated the clinical scores, inflammatory responses and infarct volumes in pMCAO rats. • PEG-UK inhibited ischemia related edema and injuries of blood-brain-barriers (BBB). • PEG-UK attenuated the extent of apoptosis and excito-neurotoxicity in the ischemic brain tissues. • PEG-UK preserved the integrity of BBB by attenuating the activation of MMP-9 via inhibiting the LRP-NF-κB-Cox-2 signaling pathway. [ABSTRACT FROM AUTHOR]

No previous study has examined the impact of air pollution on the cardiovascular disease (CVD) trajectory, especially among asthmatic subjects. Based on the UK Biobank cohort, we retrieved 292,227 adults free of asthma and CVD aged 37–73 years at recruitment (2006–2010). Annual mean concentrations of particulate matter (PM 10 and PM 2.5) and nitrogen oxides (NO 2 and NO x) were assessed at each individual's addresses. We used multi-state models to estimate the associations of air pollution with the trajectory from healthy to incident asthma, subsequent CVD, and death. During a median follow-up of 11.7 years, a total of 6338 (2.2%) participants developed asthma, among which, 638 (10.1%) subsequently proceeded to CVD. We observed significant impacts of various air pollutants on the CVD dynamic transitions, with a more substantial effect of particulate matter pollutants than gaseous air pollutants. For example, the hazard ratios (95% confidence intervals) for per interquartile range increase in PM 2.5 and PM 10 were 1.28 (1.13, 1.44) and 1.27 (1.13, 1.43) for transitions from incident asthma to subsequent CVD. In conclusion, long-term air pollution exposure could affect the CVD trajectory. Distinguishing the effect of air pollutants on CVD transition stages has great significance for CVD health management and clinical prevention, especially among asthma patients. [Display omitted] • Ambient air pollution associated with incident asthma, subsequent cardiovascular disease and death. • Particulate matter pollutants have stronger effects on the dynamic transitions than gaseous air pollutants. • Sex and age might be important effect modifiers in these associations. [ABSTRACT FROM AUTHOR]

Phase imbalance in the U.K. and European low-voltage (415 V, LV) distribution networks causes additional energy losses. A key barrier against understanding the imbalance-induced energy losses is the absence of high-resolution time-series data for LV networks. It remains a challenge to estimate imbalance-induced energy losses in LV networks that only have the yearly average currents of the three phases. To address this insufficient data challenge, this paper proposes a new customized statistical approach, named as the clustering, classification, and range estimation (CCRE) approach. It finds a match between the network with only the yearly average phase currents (the data-scarce network) and a cluster of networks with time series of phase current data (data-rich networks). Then, CCRE performs a range estimation of the imbalance-induced energy loss for the cluster of data-rich networks that resemble the data-scarce network. Chebyshev's inequality is applied to narrow down this range, which represents the confidence interval of the imbalance-induced energy loss for the data-scarce network. Case studies reveal that, given such a few data from the data-scarce networks, more than 80% of these networks are classified to the correct clusters and the confidence of the imbalance-induced energy loss estimation is 89%. [ABSTRACT FROM AUTHOR]

Summary: Background: Current published asthma predictive tools have moderate positive likelihood ratios (+LR) but high negative likelihood ratios (−LR) based on their recommended cut‐offs, which limit their clinical usefulness. Objective: To develop a simple clinically applicable asthma prediction tool within a population‐based birth cohort. Method: Children from the Manchester Asthma and Allergy Study (MAAS) attended follow‐up at ages 3, 8 and 11 years. Data on preschool wheeze were extracted from primary‐care records. Parents completed validated respiratory questionnaires. Children were skin prick tested (SPT). Asthma at 8/11 years (school‐age) was defined as parentally reported (a) physician‐diagnosed asthma and wheeze in the previous 12 months or (b) ≥3 wheeze attacks in the previous 12 months. An asthma prediction tool (MAAS APT) was developed using logistic regression of characteristics at age 3 years to predict school‐age asthma. Results: Of 336 children with physician‐confirmed wheeze by age 3 years, 117(35%) had school‐age asthma. Logistic regression selected 5 significant risk factors which formed the basis of the MAAS APT: wheeze after exercise; wheeze causing breathlessness; cough on exertion; current eczema and SPT sensitisation(maximum score 5). A total of 281(84%) children had complete data at age 3 years and were used to test the MAAS APT. Children scoring ≥3 were at high risk of having asthma at school‐age (PPV > 75%; +LR 6.3, −LR 0.6), whereas children who had a score of 0 had very low risk(PPV 9.3%; LR 0.2). Conclusion: MAAS APT is a simple asthma prediction tool which could easily be applied in clinical and research settings. [ABSTRACT FROM AUTHOR]

Objective(s): The aim of this study is to explore the potential neuroprotective effects of Ginkgolide B (GB), a main terpene lactone and active component in Ginkgo biloba, in hypoxia-induced neuronal damage, and to further investigate its possible mechanisms. Materials and Methods: 54 Sprague-Dawley rats were randomly divided into three groups: the untreated control group (n=18); the hypoxia group (n=18; exposed to 6000 m simulated plateau altitude for six days); and the GB group (n=18; intragastric administration of 12 mg/kg GB three days prior to rapid adaption to 6000 m and on the first two days of hypoxia). After hypoxia exposure for six days, we dissected out the brain hippocampi and performed hematoxylin and eosin staining, Nissl staining, and TUNEL staining. Homogenates of the hippocampi were used to test the oxidative stress indices including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase. Bax and caspase-3 expression in the hippocampal tissue was measured using qRT-PCR. Results: Treatment with GB before exposure to hypoxia could protect neural cells and increase the number of Nissl bodies. TUNEL and qRT-PCR results demonstrated that GB treatment could decrease apoptotic cells in different areas of the hippocampus. Antioxidant defense systems such as SOD, GSH, and catalase were decreased (P<0.05), and the concentration of MDA was reduced significantly in the hippocampi of rats of the GB group (P<0.05). Conclusion: GB could alleviate hypoxia-induced neuronal damage in rat hippocampus by inhibiting oxidative stress and apoptosis. [ABSTRACT FROM AUTHOR]

>bold<>italic/italic<>/bold< Intravenous thrombolysis is known as the only effective reperfusion therapy for acute ischemic stroke (AIS) caused by small branches occlusion. However, it is still unclear whether intra-arterial thrombolysis (IAT) is safe and effective for patients without detectable arterial occlusion. This study evaluated the safety and efficacy of IAT in these patients. >bold<>italic/italic<>/bold< Data were collected on consecutive patients from December 2012 to February 2017 at the Xuanwu Hospital, Capital Medical University. AIS patients without large artery occlusion during digital subtraction angiography (DSA) were divided into 2 groups: (1) Intra-arterial urokinase thrombolysis group (UK group): received intra-arterial urokinase thrombolysis treatment; (2) Control group: cerebral angiography examination only. The primary outcome was 3-month favorable functional outcome (modified Rankin Scale 0–2). >bold<>italic/italic<>/bold< A total of 48 patients received urokinase thrombolysis, and 34 patients underwent DSA examination only. The UK group had more frequent favorable functional outcomes (70.8 vs. 50%, >italic/italic< = 0.032) at 3-month follow-up and higher score of National Institutes of Health Stroke Scale improvement on the second day (>italic/italic< = 0.007). One patient (2%) had symptomatic intracerebral hemorrhage and 3 patients (6.3%) had asymptomatic intracerebral hemorrhage (asICH) in the UK group. One patient (3.3%) had asICH in the control group. There were no significant differences about ICH. >bold<>italic/italic<>/bold< AIS caused by small branches occlusion could benefit from intra-arterial urokinase thrombolysis, and the risk of intracerebral hemorrhage was not significantly higher. [ABSTRACT FROM AUTHOR]

R-loop is a necessary intermediate in specific cellular processes. To profile the landscapes, highlights, and trending topics of R-loop, publications related to R-loop from 1976 to 2022 were downloaded and bibliometric analyses were performed by Bibliometrix in R and VOSviewer. 1428 documents (including 1092 articles and 336 reviews) were included. USA, United Kingdom, and China contributed more than one-third of the publications. The annual publication increased rapidly since 2010. The research trend of R-loop has evolved from the discovery of phenomena to the exploration of molecular mechanisms, from the elucidation of biological functions to the analysis of disease correlations. Ongoing roles of R-loop in DNA repair process was highlighted and further analyzed. This study may accelerate R-loop research by highlighting important researches, understanding the trending topic, and integrating with other areas. • 1598 documents related to R-loop were included from 1976 to 2023. • Current landscape, highlights and trending topics of R-loop. • Trend evolved from elucidation of biological functions to disease correlations. • Ongoing roles of R-loop in DNA repair process was highlighted and further analyzed. • These findings may contribute to accelerating the development of R-loop research. [ABSTRACT FROM AUTHOR]

This paper empirically explores the organizational processes at the onset of disruptions and the factors that determine different configurations of responses. It examines how processes of response, both before and in the aftermath of a disruption, support the building and development of organizational resilience. Using case study data from three U.K. based organizations, this paper makes the following three contributions. First, it identifies the common elements involved in decision making at the onset of a disruption, and explains the iterative stages and processes that led to the development of resilience. It explains the criticality and relationships between the elements of detection, activation, and response. Second, this paper explains why responses vary from one situation to another, by identifying two dimensions that determine the configurations of organizational resilience, namely Preparedness and Adaption. Third, this paper presents the resilience configurations matrix that gives rise to and establishes four distinct types of organizational configurations, which are Process Based, Resourceful, At High Risk, and Resilience Focused. This paper concludes by discussing the implications for theory and practice of resilience. [ABSTRACT FROM AUTHOR]

This paper proposes a novel multi-resolution clustering (MRC) method that for the first time classifies end customers directly from massive, volatile and uncertain smart metering data. It will firstly extract spectral features of load profiles by multi-resolution analysis (MRA), and then cluster and classify these features in the spectral-domain instead of time-domain. The key advantage is that the proposed method will allow a dynamic load profiling to be flexibly re-constructed from each spectral level. MRC addresses three key limitations in time-series based load profiling: i) large sample size: sample size is reduced by a novel two-stage clustering, which firstly clusters each customers' massive daily profiles into several Gaussian mixture models (GMMs) and then clusters all GMMs; ii) volatility: it avoids the interferences between different load features (e.g. magnitude, overall trend, spikes) by decomposing them onto different resolution levels, and then clustering separately; iii) uncertainties: as the GMM can give a probabilistic cluster membership instead of a deterministic one, an additive classification model based on the posterior probability is proposed to reflect the uncertainty between days. The proposed method is implemented on 6369 smart metered customers from Ireland, and compared with the load profiles used by the U.K. industry and traditional K-means clustering. The results show that the developed MRC outperformed the traditional methods in its ability in profiling load for big, volatile and uncertain smart metering data. [ABSTRACT FROM PUBLISHER]

Abstract: Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt–Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea. [Copyright &y& Elsevier]

This study describes the power conversion and control solution used in the electrical power take-off of a 35 kW test rig developed to investigate a linear, direct drive, air-cored, tubular, permanent magnet generator for an offshore wave energy device. The solution proposed is to collect the power extracted directly from individual coils of the generator, which have different induced voltages and cannot easily be connected into a small number of phases. Local energy storage is integrated into the system to smooth the electrical output power and reduce the rating of the downstream inverter for grid interfacing. The solution is demonstrated by analysis, backed up by simulation and test results. This shows the potential and limitations of the proposed conversion technology solution. [ABSTRACT FROM AUTHOR]

This paper explores student and teacher perspectives of challenges relating to the levels of competence in English of Chinese students studying overseas from the perspective of critical pedagogy. It draws on two complementary studies undertaken by colleagues at the University of Reading. The first - a research seminar attended by representatives from a wide range of UK universities - presents the views of teachers and administrators; the second draws on four case studies of the language learning of Chinese postgraduate students during their first year of study in the UK, and offers the student voice. Interview and focus group data highlight the limitations of current tests of English used as part of the requirements for university admission. In particular, university teachers expressed uncertainty about whether the acceptance of levels of written English which fall far short of native-speaker competence is an ill-advised lowering of standards or a necessary and pragmatic response to the realities of an otherwise uneven playing field. In spite of this ambivalence, there is evidence of a growing willingness on the part of university teachers and support staff to find solutions to the language issues facing Chinese students, some of which require a more strategic institutional approach, while others rely on greater flexibility on the part of individuals. Although the studies reported in this paper were based on British universities, the findings will also be of interest to those involved in tertiary education in other English-speaking countries which are currently attracting large numbers of Chinese students. [ABSTRACT FROM AUTHOR]

Abstract: The present study determined the residues of organochlorine pesticides (OCPs) in human milk collected in central Taiwan between December 2000 and November 2001. The OCPs were analyzed by GC/MS for 36 human milk samples from healthy women ranging between 20 and 36 years of age. The predominant OCPs were p,p′-DDE, p,p′-DDT, α-CHL, heptachlor epoxide, heptachlor, β-HCH, and γ-HCH, with median levels of 228, 19, 7.4, 4.0, 2.3, 1.2, and 0.8ng/g lipid, respectively. The residues of OCPs in human milk from central Taiwan were comparable to those described in results from Sweden, the United Kingdom, and Japan, and were significantly lower than those from investigations in Asian countries, including China, Thailand, Indonesia, and Vietnam. Low DDE/DDT ratio (mean=13.6, SD=6.54) indicated that residual OCPs in human milk mainly originate from past exposure. A notable decrease in DDT levels (∑DDT=333ng/g lipid) in human milk was found in this study compared to results from the previous two decades (∑DDT=3595ng/g lipid). Hypothetically, the level of α-CHL was significantly associated with total TEQ levels in Taiwanese human milk because of the sources of food contaminant, i.e. animal fat. Based on low OCP levels in Taiwanese human milk and low estimated median daily intake of total DDTs for a breastfed infant (1358ng/kg/day) with the assumption of an infant weighting 4kg and consuming 699g milk per day in the first month after birth, the Taiwanese policy of breast-feeding promotion was supported. [Copyright &y& Elsevier]

The present study is concerned with the problems in communication which arise between British teachers and Chinese parents in discussions of children's performance in British schools. A discussion of the importance of an understanding of cultural differences for the educational outcomes of ethnic minority children will form the backdrop for an analysis of four parent–teacher meetings and interview data gathered before and after the meetings. It is argued that Chinese parents pay attention to micro aspects of the learning situation, emphasizing accuracy and perfect scores. British teachers, in contrast, consider error as a normal part of the learning process and are more concerned with macro-aspects of learning such as problem-solving. Chinese parents have very high expectations of their children and are prepared to spend a great deal of time and effort in identifying areas where they need support. However, parental efforts to support their children are often perceived as unnecessarily harsh and undermining of children's confidence by British teachers who tend to stress the positive aspects of children's achievements. Considerable importance is attached to the need for dialogue which will increase the awareness of both parents and teachers to differences between Chinese and British expectations of education. [ABSTRACT FROM AUTHOR]

Examines the role of the Gezira Sporting Club of Cairo in Egypt in cultivating elitism and sociocultural imperialism. British's creation of institutions that would cater to their own needs during the colonization of Egypt until the 1950s; Role of the Gezira as the paramount social symbol of British hegemony; Reflection of the insularity of the clubs in the predominance of British members.

• Extends the classic NILM research from household level to substation level. • Deduces the states of different types of loads in a region including PV and EV. • The proposed method improves classic sparse coding, OMP and NMP. • Robust with higher DERs penetration rates and larger forecasting errors. This paper presents a novel extension of the classic nonintrusive load monitoring (NILM) problem from household-appliance level to substation level. A new three-stage regional-NILM method is proposed to deduce the states of different types of loads in a region by disaggregating its substation demand. Three types of loads are considered in this study: (i) traditional loads; (ii) distributed generation such as photovoltaics (PVs); and (iii) flexible loads like electric vehicles (EVs). The proposed method firstly forecasts the traditional load using the long-term historical data and employing spectral analysis to boost the signal-to-noise ratio. Secondly, the PV capacity is deduced by performing peak coincidence analysis between negative residuals and local solar irradiance data. Finally, a novel limited activation matching pursuit method is proposed to estimate the states of the EVs, including the total EV load and number of EVs. The method is assessed on real data collected from 800 substations, 10 PVs and 50 EVs in the UK. Results show the proposed method for estimating the number of EVs outperforms the approaches based on sparse coding, orthogonal matching pursuit and non-negative matching pursuit by 16.5%, 10.2% and 10.0%, respectively. The proposed Regional-NILM solution provides a cost-effective way for distribution network operators to understand the network's state. It can therefore significantly increase the network visibility without requiring expensive monitoring and avoiding data privacy issues. As such, it can improve the efficiency of demand side management, which is required to accommodate the future large number of distributed energy resources connections. [ABSTRACT FROM AUTHOR]

Which life satisfaction components could be a target of positive psychological interventions for longevity is largely unknown. We aimed to investigate association of the composite measure of life satisfaction and its individual components with mortality. This cohort study included UK Biobank participants who responded to questions concerning five components of life satisfaction at baseline. We generated a composite score representing overall life satisfaction, ranging from 0 (lowest) to 5 (highest). The outcomes were all-cause and cause-specific mortality. We used multivariable Cox regression to estimate hazard ratios (HR) for the associations of interest. Among 165,842 eligible participants, 12,261 all-cause deaths were observed over a median of 12.9-year follow-up. Overall life satisfaction was inversely associated with all-cause mortality (adjusted HR 0.94 [95% CI: 0.93–0.95] per 1 score increment). Health satisfaction showed the strongest association with all-cause mortality, with a fully adjusted HR of 0.52 (95% CI: 0.49–0.55) for high/extreme satisfaction and 0.63 (95% CI: 0.59–0.66) for moderate satisfaction, compared with unsatisfaction (P-trend<0.001), independent of other satisfaction components, regardless of physical health and sociodemographics. The association for family, friendship, work and financial satisfaction was attenuated when adjusted for other life satisfaction components. Similar findings were observed for cause-specific mortality. Observational study with single baseline measurement of life satisfaction precludes the ability to establish causal relationship. Higher overall life satisfaction was associated with lower mortality. As the major contributor to lower mortality regardless of physical health and sociodemographics, health satisfaction could be an important target of positive psychological interventions for longevity. • People who felt satisfied with more aspects of life had lower risk of all-cause and cause-specific mortality. • Among the five satisfaction components, health satisfaction was the major contributor to lower risk of mortality. • The inverse association of health satisfaction with mortality did not vary with physical health and sociodemographic status. • Enhancing positive feelings towards health status could serve as a potential strategy for increasing longevity. [ABSTRACT FROM AUTHOR]

Background: Young people (YP; 12–24 years old) with rheumatic diseases face many challenges associated with chronic illness in addition to the physiological and psychosocial changes of adolescence. Timely access to developmentally appropriate multidisciplinary care is key to successfully managing rheumatic diseases, but gaps in the care of this vulnerable age group still exist. This study aimed to develop a benchmarking toolkit to enable comparative evaluation of YP rheumatology services in order to promote best practice and reduce variations in service delivery. Methods: A staged and consultative method was used across a broad group of stakeholders in the UK (YP, parents/other carers, and healthcare professionals, HCPs) to develop this toolkit, with reference to pre-existing standards of YP-friendly healthcare. Eighty-seven YP (median age 19 years, range 12–24 years) and 26 rheumatology HCPs with 1–34 years of experience caring for YP have participated. Results: Thirty quality criteria were identified, which were grouped into four main domains: assessment and treatment, information and involvement, accessibility and environment, and continuity of care. Two toolkit versions, one to be completed by HCPs and one to be completed by patients, were developed. These were further refined by relevant groups and face validity was confirmed. Conclusions: A toolkit has been developed to systematically evaluate and benchmark YP rheumatology services, which is key in setting standards of care, identifying targets for improvement and facilitating research. Engagement from YP, clinical teams, and commissioners with this tool should facilitate investigation of variability in levels of care and drive quality improvement. [ABSTRACT FROM AUTHOR]

To develop effective control strategies to enhance the robustness of multilayer networks against large-scale failures is of significant value. We articulate the idea of ‘remote control’ whereby adaptive perturbations to one network layer are able to enhance the resilience of not only itself but also other interconnected network layers. We analyze the principle of remote control using percolation dynamics by showing analytically and numerically that, with the adaptive generation of a small number of new links in the control layer, not only is this layer but also other layers become dramatically more resistant to cascading failures. We also find that remote control is more effective for scale-free than for random networks. Remote intervention of multilayer network systems through adaptation has real-world applications, which we illustrate using the rail and coach transportation system in the Great Britain. [ABSTRACT FROM AUTHOR]

Abstract The Akko Tower Wreck is the remains of a 25-m-long merchant brig dated to the first half of the 19th century. During the underwater excavations, 105 brass nails were retrieved from the shipwreck. The nails were divided into two groups based on their microstructure: Type A nails were characterized by Widmanstätten plates, while Type B nails by a dendritic microstructure. In each group there were miscellaneous nails, distinguished by their different shapes. Ten miscellaneous nails were characterized by XRF, light microscopy, SEM-EDS analysis, microhardness measurements, anisotropy of magnetic susceptibility examination, and lead isotope analysis. The brass nails were post-cementation products manufactured by casting. The microstructure combined with the AMS analysis, indicated that Type A nails were of better quality than Type B ones. The lead isotope analysis of the nails suggested that their raw material most likely originated in Great Britain. Highlights • Ten miscellaneous brass nails were retrieved from shipwreck and were characterized. • The nails were divided into two groups (A and B) based on their microstructure. • The nails were post-cementation products manufactured in the 19th century by casting. • Type A miscellaneous nails were of better quality than Type B ones. • The nails raw material was most likely originated in Great Britain. [ABSTRACT FROM AUTHOR]