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In this article we offer a conceptual and practical contribution to the field of STEM education by investigating the concepts educators may include in Quantum Technologies (QT) outreach activities. We embed our approach in the discipline-culture (DC) framework, in which we consider the cultural nuances of QT as an important factor which must not be ignored in education efforts. To this end, a survey study by the pilot project Quantum Technologies Education For Everyone (QuTE4E), investigating key concepts for QT outreach, was conducted between December 2021 and June 2022. Here we present the results of the study, analysed through the DC framework, and consider the implications for designing QT outreach activities. The data hints at the perceived value of highlighting core concepts of Quantum Mechanics (QM), while also raising the question of whether QT sits as a discipline of Physics, Computer Science, or elsewhere. This calls for a reordering of the primacy of certain concepts (such as qubit and spin) for outreach purposes, where core concepts in QM might not be core concepts in QT, and vice versa. The results of this study provide valuable insights for those interested in learning more about this rapidly-evolving field.

Loosely attached to other syntactic elements in an utterance, pragmatic markers (PM) are one of the most frequented pragmatic elements that fulfill various functions. Among a great number of PMs encountered in daily conversations, I think is one of the most prevalent PMs in native speaker and non-native speaker discourse. Thus, the purpose of this study was to unravel and compare the overall uses and functions of I think among Turkish learners of English and native speakers of British English. Adopting corpus-driven approach to explore the use of I think in both groups, the uses of the marker were classified depending on their functions that were designated through integrated reading of the data by using Wordsmith Tools 6.0. According to the results, the functions of I think were categorized under the domains of shield, booster, structural, evaluative and interactional. Log likelihood statistics was administrated to figure out whether the difference across the groups was statistical in their use of I think with regard to frequency and functional variety. The results revealed that there was not a statistical difference between the groups regarding the overall uses of the marker. However, differences in the functional distributions of I think across the groups were observed.

Background: Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. Methods: To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. Results: Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose–response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). Conclusions: Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity. [ABSTRACT FROM AUTHOR]

Simple Summary: The standard method for monitoring lameness in U.K. dairy herds is mobility scoring. Data from mobility scoring can be used to estimate the proportion of cows in the herd that are lame (prevalence), the rate at which cows become lame (incidence), and how long cows remain lame (duration). It is unknown how the frequency and accuracy of mobility scoring impact the accuracy of measurement of these parameters. We developed a model to simulate lameness in a range of herd scenarios with different prevalences and durations of lameness. We used this model to understand how the frequency and accuracy of mobility scoring affected the accuracy of lameness parameters calculated from mobility scoring data. Our results showed that reduced accuracy of mobility scoring results in an over-estimation of lameness incidence and an under-estimation of lameness duration. This effect increased with more frequent scoring. Lameness prevalence and the average number of days to first lameness best identified lameness patterns when simulating monthly mobility scoring. We conclude that the frequency and accuracy of mobility scoring should be considered when using mobility scoring data to inform on lameness patterns on farms. Mobility scoring data can be used to estimate the prevalence, incidence, and duration of lameness in dairy herds. Mobility scoring is often performed infrequently with variable sensitivity, but how this impacts the estimation of lameness parameters is largely unknown. We developed a simulation model to investigate the impact of the frequency and accuracy of mobility scoring on the estimation of lameness parameters for different herd scenarios. Herds with a varying prevalence (10, 30, or 50%) and duration (distributed around median days 18, 36, 54, 72, or 108) of lameness were simulated at daily time steps for five years. The lameness parameters investigated were prevalence, duration, new case rate, time to first lameness, and probability of remaining sound in the first year. True parameters were calculated from daily data and compared to those calculated when replicating different frequencies (weekly, two-weekly, monthly, quarterly), sensitivities (60–100%), and specificities (95–100%) of mobility scoring. Our results showed that over-estimation of incidence and under-estimation of duration can occur when the sensitivity and specificity of mobility scoring are <100%. This effect increases with more frequent scoring. Lameness prevalence was the only parameter that could be estimated with reasonable accuracy when simulating quarterly mobility scoring. These findings can help inform mobility scoring practices and the interpretation of mobility scoring data. [ABSTRACT FROM AUTHOR]

OBJECTIVES. We reviewed the use of social media and its influence on rhinoplasty decisions. MATERIAL AND METHODS. The literature survey was performed in PubMed, EBSCO, UpToDate, and ProQuest Central databases of Kırıkkale University and Google and Google Scholar databases. RESULTS. Networking features available through social media sites allow users to discover and share countless photos, videos and links from their desktops and mobile devices. In the United Kingdom, over 55% of facial plastic surgeons reported that their cosmetic patients were inspired to look better in selfies. 53.4% of respondents felt that TV shows promoting plastic surgery impacted the popularity of such procedures, and 65.0% of respondents believed that social media had a similar effect. Males reported being much less satisfied with surgery than females and were less specific about why they were unhappy. One-third of patients regularly looked for information about rhinoplasty on social media. Less than a third were affected by celebrities who had rhinoplasty for cosmetic reasons. However, over three percent believed the social media ads portraying rhinoplasty as a safe surgical procedure. CONCLUSION. We concluded that social media platforms play a significant role for the decision to undergo rhinoplasty and postoperative patient satisfaction. [ABSTRACT FROM AUTHOR]

Background: Adverse childhood experiences (ACEs), including childhood maltreatment, have been linked with increased risk of diabetes and obesity during adulthood. A comprehensive assessment on the associations between childhood maltreatment and all major endocrine diseases, as well as the relative importance of different proposed mechanistic pathways on these associations, is currently lacking. Methods: Based on the UK Biobank, we constructed a cohort including 151,659 participants with self-reported data on childhood maltreatment who were 30 years of age or older on/after January 1, 1985. All participants were followed from the index date (i.e., January 1, 1985, or their 30th birthday, whichever came later) until the first diagnosis of any or specific (12 individual diagnoses and 9 subtypes) endocrine diseases, death, or the end of follow-up (December 31, 2019), whichever occurred first. We used Cox models to examine the association of childhood maltreatment, treated as continuous (i.e., the cumulative number of experienced childhood maltreatment), ordinal (i.e., 0, 1 and ≥ 2), or binary (< 2 and ≥ 2) variable, with any and specific endocrine diseases, adjusted for multiple covariates. We further examined the risk of having multiple endocrine diseases using Linear or Logistic Regression models. Then, sequential mediation analyses were performed to assess the contribution of four possible mechanisms (i.e., suboptimal socioeconomic status (SES), psychological adversities, unfavorable lifestyle, and biological alterations) on the observed associations. Results: During an average follow-up of 30.8 years, 20,885 participants received a diagnosis of endocrine diseases. We observed an association between the cumulative number of experienced childhood maltreatment and increased risk of being diagnosed with any endocrine disease (adjusted hazard ratio (HR) = 1.10, 95% confidence interval 1.09–1.12). The HR was 1.26 (1.22–1.30) when comparing individuals ≥ 2 with those with < 2 experienced childhood maltreatment. We further noted the most pronounced associations for type 2 diabetes (1.40 (1.33–1.48)) and hypothalamic–pituitary–adrenal (HPA)-axis-related endocrine diseases (1.38 (1.17–1.62)), and the association was stronger for having multiple endocrine diseases, compared to having one (odds ratio (95% CI) = 1.24 (1.19–1.30), 1.35 (1.27–1.44), and 1.52 (1.52–1.53) for 1, 2, and ≥ 3, respectively). Sequential mediation analyses showed that the association between childhood maltreatment and endocrine diseases was consistently and most distinctly mediated by psychological adversities (15.38 ~ 44.97%), while unfavorable lifestyle (10.86 ~ 25.32%) was additionally noted for type 2 diabetes whereas suboptimal SES (14.42 ~ 39.33%) for HPA-axis-related endocrine diseases. Conclusions: Our study demonstrates that adverse psychological sequel of childhood maltreatment constitutes the main pathway to multiple endocrine diseases, particularly type 2 diabetes and HPA-axis-related endocrine diseases. Therefore, increased access to evidence-based mental health services may also be pivotal in reducing the risk of endocrine diseases among childhood maltreatment-exposed individuals. [ABSTRACT FROM AUTHOR]

Left ventricular regional wall thickness (LVRWT) is an independent predictor of morbidity and mortality in cardiovascular diseases (CVDs). To identify specific genetic influences on individual LVRWT, we established a novel deep learning algorithm to calculate 12 LVRWTs accurately in 42,194 individuals from the UK Biobank with cardiac magnetic resonance (CMR) imaging. Genome-wide association studies of CMR-derived 12 LVRWTs identified 72 significant genetic loci associated with at least one LVRWT phenotype (P < 5 × 10−8), which were revealed to actively participate in heart development and contraction pathways. Significant causal relationships were observed between the LVRWT traits and hypertrophic cardiomyopathy (HCM) using genetic correlation and Mendelian randomization analyses (P < 0.01). The polygenic risk score of inferoseptal LVRWT at end systole exhibited a notable association with incident HCM, facilitating the identification of high-risk individuals. The findings yield insights into the genetic determinants of LVRWT phenotypes and shed light on the biological basis for HCM etiology. Changes of left ventricular structure are used to predict morbidity and mortality in cardiovascular diseases. Here the authors conducted a study using advanced deep learning technology to analyze left ventricular regional wall thickness (LVRWT) in a large population, identifying 72 significant genetic loci linked to LVRWT traits. [ABSTRACT FROM AUTHOR]

This conceptual research study provides a framework on whether Japanese Omikoshi management principles can be applied in traditional Western management approach or not and aims to foresee its potential effects. The Industrial Revolution began in the 18th century in Great Britain, and it spread rapidly to other countries in Europe and the U.S and then to other parts of the world. Though some Eastern countries, including Japan, began undergoing industrial revolutions and process of economic transformation later than the West, it's obvious that Japanese companies have dramatically brought their competitive challenge to the early-industrialized the Western states within the concept of organizational management and superior manufacturing management systems since 1960s. In sum, this study gives an insight into the main principles in the Western management and Japanese management techniques by comparing their major notions and argues Omikoshi management principles and its prospective outcomes when it is embedded to the today's Western management style. And, in conclusion section, it has been found out that Omikoshi management principles can be applied to the Western management style and so it has been claimed that it will become more encouraging, visionary, democratic, and creative. [ABSTRACT FROM AUTHOR]

• This matched cohort study included 14,620 individuals with audiometry-determined objective hearing loss and 38,479 with subjective hearing loss, together with 29,240 and 38,479 matched unexposed individuals, respectively. • We found both undiagnosed objective and subjective hearing loss were associated with multiple subsequent adverse health consequences, but with discrepancies in comorbidity patterns. • Objective hearing loss had pronounced associations with neurodegenerative disease. • These findings highlight the importance of screening for speech-in-noise hearing impairment in the middle-aged population, for potential early diagnosis and intervention. Hearing impairment is common in the middle-aged population but remains largely undiagnosed and untreated. The knowledge about to what extent and how hearing impairment matters for health is currently lacking. Thus, we aimed to comprehensively examine the adverse health consequences as well as the comorbidity patterns of undiagnosed hearing loss. Based on the prospective cohort of the UK Biobank, we included 14,620 individuals (median age 61 years) with audiometry-determined (i.e., speech-in-noise test) objective hearing loss and 38,479 individuals with subjective hearing loss (i.e., tested negative but with self-reported hearing problems; median age 58 years) at recruitment (2006–2010), together with 29,240 and 38,479 matched unexposed individuals respectively. Cox regression was used to determine the associations of both hearing-loss exposures with the risk of 499 medical conditions and 14 cause-specific deaths, adjusting for ethnicity, annual household income, smoking and alcohol intake, exposure to working noise, and BMI. Comorbidity patterns following both exposures were visualized by comorbidity modules (i.e., sets of connected diseases) identified in the comorbidity network analyses. During a median follow-up of 9 years, 28 medical conditions and mortality related to nervous system disease showed significant associations with prior objective hearing loss. Subsequently, the comorbidity network identified four comorbidity modules (i.e., neurodegenerative, respiratory, psychiatric, and cardiometabolic diseases), with the most pronounced association noted for the module related to neurodegenerative diseases (meta-hazard ratio [HR] = 2.00, 95%confidence interval [CI] 1.67–2.39). For subjective hearing loss, we found 57 associated medical conditions, which were partitioned into four modules (i.e., diseases related to the digestive, psychiatric, inflammatory, and cardiometabolic systems), with meta-HRs varying from 1.17 to 1.25. Undiagnosed hearing loss captured by screening could identify individuals with at greater risk of multiple adverse health consequences, highlighting the importance of screening for speech-in-noise hearing impairment in the middle-aged population, for potential early diagnosis and intervention. [ABSTRACT FROM AUTHOR]

Background. The associations between hip/knee osteoarthritis (OA) and various psychiatry disorders, as well as the underlying genetic determinants, remain unclear. Methods. Based on the community-based prospective data of UK Biobank, we constructed two matched cohorts to assess the bidirectional associations between OA and five common psychiatry disorders. Then, we further examined the existence of overall genetic association for those disease pairs with demonstrated phenotypic association through polygenic risk score (PRS) prediction using individual-level genotyping data of UK Biobank and LD score regression (LDSC) analysis utilizing publicly available GWAS summary statistics. Last, also based on GWAS summary statistics, we performed enrichment analyses to pinpoint specific genetic determinants that might contribute to the observed overall genetic shares. Results. The phenotypic analyses revealed an elevated risk of hip/knee OA among individuals with any psychiatric disorders, compared to their matched unexposed individuals (hazard ratio HR = 1.62 , 95% confidence interval (CI): 1.57-1.68), and vice versa (HR =1.93, 95% CI: 1.83-2.04). We further observed positive associations of knee OA with depression and stress-related disorder in the PRS analyses, which corroborated with the results of LDSC analyses (r for genetic = 0.20 (95% CI: 0.15-0.25) and r for genetic = 0.29 (95% CI: 0.19-0.40), respectively). Using GWAS summary statistics, we identified several shared genes and pathways, particularly the biological process related to HDAC histones, between knee OA and depression/stress-related disorder. Conclusions. Our study demonstrated a bidirectional association between OA and multiple psychiatric disorders, and the findings of shared genetic architectures between knee OA and depression/stress-related disorder provided possible targets for further mechanistic exploration and intervention development. [ABSTRACT FROM AUTHOR]

There is an accelerated demand for non-surgical facial aesthetics (NSFA) encompassing the use of botulinum toxin and dermal fillers. Healthcare professionals may either treat NSFA-related complications in the public sector or practise in the private sector. Currently, there is no standardised undergraduate teaching in the UK to educate healthcare professionals on NSFA. The aim of our study was to compare medical and dental undergraduate students' perceptions and awareness of NSFA, and to understand its role if implemented in each curriculum in the UK. An online questionnaire was devised and distributed via social media platforms to medical and dental students across the UK. Student responses were anonymised and collated as quantitative data, and subsequently analysed. Of the 146 respondents, 89% had no previous teaching on NSFA. Ninety-three per cent of medics and 75% of dentists agreed or strongly agreed that non-surgical aestheticians require dental or medical knowledge to deliver NSFA, and 66% of medics and 75% of dentists agreed or strongly agreed that NSFA should be incorporated into the undergraduate curriculum. Only 7% of medics and 8% of dentists were aware of the steps required to practise NSFA. Incoming doctors and dentists are showing interest in the field yet have no formal teaching in the area. Requiring healthcare professionals to have some baseline understanding of NSFA and its associated complications means that implementing formal education on the subject in the medical and dental curricula is an important consideration. [ABSTRACT FROM AUTHOR]

Although genome-wide association studies (GWASs) have identified over 100 colorectal cancer (CRC) risk loci, an understanding of causal genes or risk variants and their biological functions in these loci remain unclear. Recently, genomic loci 10q26.12 with lead SNP rs1665650 was identified as an essential CRC risk loci of Asian populations. However, the functional mechanism of this region has not been fully clarified. Here, we applied an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk loci 10q26.12. Notably, HSPA12A had the most significant effect among the identified genes and functioned as a crucial oncogene facilitating cell proliferation. Moreover, we conducted an integrative fine-mapping analysis to identify putative casual variants and further explored their association with CRC risk in a large-scale Chinese population consisting of 4054 cases and 4054 controls and also independently validated in 5208 cases and 20,832 controls from the UK biobank cohort. We identified a risk SNP rs7093835 in the intron of HSPA12A that was significantly associated with an increased risk of CRC (OR 1.23, 95% CI 1.08–1.41, P = 1.92 × 10–3). Mechanistically, the risk variant could facilitate an enhancer–promoter interaction mediated by the transcriptional factor (TF) GRHL1 and ultimately upregulate HSPA12A expression, which provides functional evidence to support our population findings. Collectively, our study reveals the important role of HSPA12A in CRC development and illustrates a novel enhancer–promoter interaction module between HSPA12A and its regulatory elements rs7093835, providing new insights into the etiology of CRC. [ABSTRACT FROM AUTHOR]

Background: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. Methods: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3 , and IFN-α/β receptor alpha chain (Ifnar1)–deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. Results: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn−/− , Tlr3−/− , and Ifnar1−/− mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1–BGN–TLR3–interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. Conclusions: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD. [ABSTRACT FROM AUTHOR]

Background: Emerging data suggests the neuroprotective and anti-neuroinflammatory effects of glucosamine. We aimed to examine the association between regular glucosamine use and risk of incident dementia, including dementia subtypes. Methods: We conducted large-scale observational and two-sample Mendelian randomization (MR) analyses. Participants in UK Biobank having accessible data for dementia incidence and who did not have dementia at baseline were included in the prospective cohort. Through the Cox proportional hazard model, we examined the risks of incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia among glucosamine users and non-users. To further test the causal association between glucosamine use and dementia, we conducted a 2-sample MR utilizing summary statistics from genome-wide association studies (GWAS). The GWAS data were obtained from observational cohort participants of mostly European ancestry. Results: During a median follow-up of 8.9 years, there were 2458 cases of all-cause dementia, 924 cases of AD, and 491 cases of vascular dementia. In multivariable analysis, the hazard ratios (HR) of glucosamine users for all-cause dementia, AD, and vascular dementia were 0.84 (95% CI 0.75–0.93), 0.83 (95% CI 0.71–0.98), and 0.74 (95% CI 0.58–0.95), respectively. The inverse associations between glucosamine use and AD appeared to be stronger among participants aged below 60 years than those aged above 60 years (p = 0.04 for interaction). The APOE genotype did not modify this association (p > 0.05 for interaction). Single-variable MR suggested a causal relationship between glucosamine use and lower dementia risk. Multivariable MR showed that taking glucosamine continued to protect against dementia after controlling for vitamin, chondroitin supplement use and osteoarthritis (all-cause dementia HR 0.88, 95% CI 0.81–0.95; AD HR 0.78, 95% CI 0.72–0.85; vascular dementia HR 0.73, 95% CI 0.57–0.94). Single and multivariable inverse variance weighted (MV-IVW) and MR-Egger sensitivity analyses produced similar results for these estimations. Conclusions: The findings of this large-scale cohort and MR analysis provide evidence for potential causal associations between the glucosamine use and lower risk for dementia. These findings require further validation through randomized controlled trials. [ABSTRACT FROM AUTHOR]

The second quantum revolution has been producing groundbreaking scientific and technological outputs since the early 2000s; however, the scientific literature on the impact of this revolution on the industry, specifically on start-ups, is limited. In this paper, we present a landscaping study with a gathered dataset of 441 companies from 42 countries that we identify as quantum start-ups, meaning that they mainly focus on quantum technologies (QT) as their primary priority business. We answer the following questions: (1) What are the temporal and geographical distributions of the quantum start-ups? (2) How can we categorize them, and how are these categories populated? (3) Are there any patterns that we can derive from empirical data on trends? We found that more than 92% of these companies have been founded within the last 10 years, and more than 50% of them are located in the US, the UK, and Canada. We categorized the QT start-ups into six fields: (i) complementary technologies, (ii) quantum computing (hardware), (iii) quantum computing (software/application/simulation), (iv) quantum cryptography/communication, (v) quantum sensing and metrology, and (vi) supporting companies, and analyzed the population of each field both for countries, and temporally. Finally, we argue that low levels of quantum start-up activity in a country might be an indicator of a national initiative to be adopted afterwards, which later sees both an increase in the number of start-ups, and a diversification of activity in different QT fields. [ABSTRACT FROM AUTHOR]

Background: Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach.Methods: A total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset.Results: Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10-8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10-7), Alzheimer's disease (0.80, [0.72, 0.89], P = 3.0 × 10-5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10-14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10-9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite.Conclusions: The present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations. [ABSTRACT FROM AUTHOR]

Background Habitual coffee consumption has been associated with multiple health benefits. A comprehensive analysis of disease trajectory and comorbidity networks in relation to coffee consumption is, however, currently lacking. Objectives We aimed to comprehensively examine the health outcomes associated with habitual coffee consumption, through clarifying its disease trajectory and comorbidity networks. Methods Based on the UK Biobank cohort, we included 395,539 individuals with available information on coffee intake collected at recruitment between 2006 and 2010. These individuals were categorized as having low (<1 cup per day), moderate (1–3 cups), and high (≥4 cups) levels of coffee intake, and were followed through 2020 to ascertain 496 medical conditions. Cox regression was used to assess the associations between high-level coffee intake and the risk of medical conditions with a prevalence ≥0.5% in the study population, after adjusting for multiple confounders, using low-level coffee intake as the reference. Disease-trajectory and comorbidity network analyses were then applied to visualize the temporal and nontemporal relationships between the medical conditions that had an inverse association with high-level coffee intake. Results During a median follow-up of 11.8 years, 31 medical conditions were found to be associated with high-level coffee intake, among which 30 showed an inverse association (HRs ranged from 0.61 to 0.94). The inverse associations were more pronounced for women, compared with men. Disease-trajectory and comorbidity network analyses of these 30 conditions identified 4 major clusters of medical conditions, mainly in the cardiometabolic and gastrointestinal systems, among both men and women; 1 cluster of medical conditions following alcohol-related disorders, primarily among men; as well as a cluster of estrogen-related conditions among women. Conclusions Habitual coffee consumption was associated with lower risks of many medical conditions, especially those in the cardiometabolic and gastrointestinal systems and those related to alcohol use and estrogen regulation. [ABSTRACT FROM AUTHOR]

Medical errors pose high risks to patients. Several organizational factors may impact the high rate of medical errors in complex and dynamic healthcare systems. However, limited research is available regarding probabilistic interdependencies between the organizational factors and patient safety errors. To explore this, we adopt a data‐driven Bayesian Belief Network (BBN) model to represent a class of probabilistic models, using the hospital‐level aggregate survey data from U.K. hospitals. Leveraging the use of probabilistic dependence models and visual features in the BBN model, the results shed new light on relationships existing among eight organizational factors and patient safety errors. With the high prediction capability, the data‐driven approach results suggest that "health and well‐being" and "bullying and harassment in the work environment" are the two leading factors influencing the number of reported errors and near misses affecting patient safety. This study provides significant insights to understand organizational factors' role and their relative importance in supporting decision‐making and safety improvements. [ABSTRACT FROM AUTHOR]

Background: Neonatal diabetes mellitus (NDM) is a rare (1:90,000 newborns) but potentially devastating metabolic disorder characterized by hyperglycemia combined with low levels of insulin. Dominantly-acting insulin (INS) gene mutations cause permanent NDM through single amino acid changes in the protein sequence leading to protein misfolding, which is retained within the endoplasmic reticulum (ER), causing ER stress and β-cell apoptosis. Over 90 dominantly-acting INS gene mutations have been identified in individuals with permanent NDM. Patients and Methods: The study included 70 infants diagnosed with NDM in the first year of life between May 2008 and May 2021 at the Vietnam National Children's Hospital. Sequencing analysis of all the genes known to cause NDM was performed at the Exeter Genomic Laboratory, UK. Clinical characteristics, molecular genetics, and annual data relating to glycemic control (HbA1c) and severe hypoglycemia of those with INS mutations were collected. The main outcomes of interest were HbA1c, daily insulin dose, growth, and cognitive/motor development. Results: Fifty-five of 70 infants (78.5%) with NDM harbored a mutation in a known disease-causing gene and of these, 10 had six different de novo heterozygous INS mutations. Mean gestational age was 38.1 ± 2.5 weeks and mean birth weight was 2.8 ± 0.5 g. They presented with NDM at 20 ± 17 weeks of age; 6/10 had diabetic ketoacidosis with pH 7.13 ± 0.26; plasma glucose level 32.6 ± 14.3 mmol/l and HbA1C 81 ± 15% mmol/mol. After 5.5 ± 4.8 years of insulin treatment, 9/10 have normal development with a developmental quotient of 80-100% and HbA1C 64 ± 7.3 mmol/mol, 9/10 have normal height, weight, and BMI on follow-up. Conclusions: We report a series of Vietnamese NDM cases with dominant INS mutations. INS mutations are the third commonest cause of permanent NDM. We recommend screening of the INS gene in all children diagnosed with diabetes in the first year of life. [ABSTRACT FROM AUTHOR]

Background: To elucidate the influence of childhood asthma on adult height after consideration of genetic heterogeneity in height.Methods: Based on the UK Biobank, we conducted a matched cohort study, including 13,602 European individuals with asthma diagnosed before 18 years old and 136,008 matched unexposed individuals without such an experience. Ascertainment of asthma was based on self-reported data (97.6%) or clinical diagnosis in healthcare registers (2.4%). We studied three height outcomes, including (1) the attained adult height (in centimeters), (2) the height deviation measured as the difference between a person's rank of genetically determined height (based on generated polygenetic risk score) and their rank of attained adult height in the study population (deviation in % of height order after standardization), and (3) the presence of height deficit comparing genetically determined and attained height (yes or no). We applied linear mixed-effect models to assess the associations of asthma diagnosed at different ages with attained adult height and height deviation, and conditional logistic regression models to estimate the associations of asthma with the risk of height deficit.Results: 40.07% (59,944/149,610) of the study participants were born before 1950, and most of them were men (57.65%). After controlling for multiple covariates, childhood asthma was associated with shorter attained adult height, irrespective of age at asthma diagnosis. However, in the analysis of height deviation (deviation in %), we observed the greatest height deviation among individuals with asthma diagnosed before 4 years of age (- 2.57 [95% CI - 4.14 to - 1.00] and - 2.80 [95% CI - 4.06 to - 1.54] for the age of ≤ 2 and 3-4 years, respectively). The magnitude of height deviation in relation to asthma declined thereafter and became null after age 6. Similarly, there was a statistically significant height deficit in relation to an asthma diagnosis at ages ≤ 2 and 3-4 (odds ratios = 1.21, 95% CI 1.04 to 1.40, and 1.15, 95% CI 1.02 to 1.29) but not thereafter. The result pattern was similar when separately analyzing asthma with or without inhaled glucocorticoid (ICS) use, despite that the estimates were consistently stronger among asthma individuals who used ICS.Conclusions: Our results suggest a notable association of childhood asthma, primarily asthma diagnosed at an early age, with adult height, after consideration of genetic heterogeneity in height and use of ICS. This finding highlights the need for surveillance on the growth problems among children with asthma. [ABSTRACT FROM AUTHOR]

Due to the pressure of migration and to solve the question of landless farmers, the Venizelos administration passed a Land Reform in 1917. It also offered the government a chance to secure its rights on the former Ottoman lands in Thessaly. According to the new law, one-fifth of the çiftliks shall be national property. The law further provides that the Greek Government is authorized to expropriate çiftliks at their pre-WWI value. While the lands of the Ottoman subjects absent from Greece were sequestered, British subjects applied British authorities to support their cases. Depending on British documents, this study first claims diverse issues such as the influence of Britain in Greece following WWI, the operations of the British legations in the region, the post-Ottoman statue of old çiftliks, the Levantine presence in the region, and land values in postwar Salonica constituting a single pattern that represents the transition from the empire to nation-states. Second, the study aims to expose how Britain, besides its military presence, tried to protect its economic interests in the region. [ABSTRACT FROM AUTHOR]

Background: With the increasing number of people infected with and recovered from coronavirus disease 2019 (COVID-19), the extent of major health consequences of COVID-19 is unclear, including risks of severe secondary infections.Methods: Based on 445,845 UK Biobank participants registered in England, we conducted a matched cohort study where 5151 individuals with a positive test result or hospitalized with a diagnosis of COVID-19 were included in the exposed group. We then randomly selected up to 10 matched individuals without COVID-19 diagnosis for each exposed individual (n = 51,402). The life-threatening secondary infections were defined as diagnoses of severe secondary infections with high mortality rates (i.e., sepsis, endocarditis, and central nervous system infections) from the UK Biobank inpatient hospital data, or deaths from these infections from mortality data. The follow-up period was limited to 3 months after the initial COVID-19 diagnosis. Using a similar study design, we additionally constructed a matched cohort where exposed individuals were diagnosed with seasonal influenza from either inpatient hospital or primary care data between 2010 and 2019 (6169 exposed and 61,555 unexposed individuals). After controlling for multiple confounders, Cox models were used to estimate hazard ratios (HRs) of life-threatening secondary infections after COVID-19 or seasonal influenza.Results: In the matched cohort for COVID-19, 50.22% of participants were male, and the median age at the index date was 66 years. During a median follow-up of 12.71 weeks, the incidence rate of life-threatening secondary infections was 2.23 (123/55.15) and 0.25 (151/600.55) per 1000 person-weeks for all patients with COVID-19 and their matched individuals, respectively, which corresponded to a fully adjusted HR of 8.19 (95% confidence interval [CI] 6.33-10.59). The corresponding HR of life-threatening secondary infections among all patients with seasonal influenza diagnosis was 4.50, 95% CI 3.34-6.08 (p for difference < 0.01). Also, elevated HRs were observed among hospitalized individuals for life-threatening secondary infections following hospital discharge, both in the COVID-19 (HR = 6.28 [95% CI 4.05-9.75]) and seasonal influenza (6.01 [95% CI 3.53-10.26], p for difference = 0.902) cohorts.Conclusion: COVID-19 patients have increased subsequent risks of life-threatening secondary infections, to an equal extent or beyond risk elevations observed for patients with seasonal influenza. [ABSTRACT FROM AUTHOR]

Nowadays, increase of analyzing stock markets as complex systems lead graph theory to play a key role. For instance, detecting graph communities is an important task in the analysis of stocks, and as planar maximally filtered graphs let us to get important information for the topology of the market. In this study, we first obtain correlation network representation of UK's leading stock market network by using a novel threshold method. Then, we determine vertex clusters by using modularity and analyze clusters in planar maximally filtered graph substructures. Our analyze include a new measure called weighted Gini index for measuring the sparsity. The main goal of this paper is to study the hierarchical evolution of the market communities throughout the Brexit referendum, which is known as the stress period for the stock market. Hence, the overall sample is divided into two sub-periods of pre-referendum, and post-referendum to obtain communities and hierarchical structures. Our results indicate that financial companies are leading elements of the clusters. Moreover, the significant changes within the network topologies are observed for insurance, consumer goods, consumer services, mining, and technology sectors whereas oil and gas and health care sectors have not been affected by Brexit stress. [ABSTRACT FROM AUTHOR]

Background: Neonatal diabetes mellitus (NDM) is defined as insulin-requiring persistent hyperglycemia occurring within the first 6 months of life, which can result from mutations in at least 25 different genes. Activating heterozygous mutations in genes encoding either of the subunits of the ATP-sensitive K+ channel (KATP channel; KCNJ11 or ABCC8) of the pancreatic beta cell are the most common cause of permanent NDM and the second most common cause of transient NDM. Patients with NDM caused by KATP channel mutations are sensitive to sulfonylurea (SU) treatment; therefore, their clinical management can be improved by replacing insulin with oral agents. Patients and Methods: Seventy patients were diagnosed with NDM between May 2008 and May 2021 at Vietnam National Children's Hospital, and molecular genetic testing for all genes known to cause NDM was performed at the Exeter Genomic Laboratory, UK. Patients with ABCC8 or KCNJ11 mutations were transferred from insulin to oral SU. Clinical characteristics, molecular genetics, and annual data relating to glycemic control, SU dose, severe hypoglycemia, and side effects were collected. The main outcomes of interest were SU dose, SU failure (defined as permanent reintroduction of daily insulin), and glycemic control (HbA1c). Results: Fifty-four of 70 patients (77%) with NDM harbored a genetic mutation and of these; 27 (50%) had activating heterozygous mutations in ABCC8 or KCNJ11. A total of 21 pathogenic mutations were identified in the 27 patients, including 13 mutations in ABCC8 and 8 mutations in KCNJ11. Overall, 51% had low birth weight (below 3rd percentile), 23 (85%) were diagnosed before 3 months of age, and 23 (85%) presented with diabetic ketoacidosis. At diagnosis, clinical and biochemical findings (mean ± SD) were pH 7.16 ± 0.16; HC O 3 − , 7.9 ± 7.4 mmol/L; BE, −17.9 ± 9.1 mmol/L; HbA1C, 7.98% ± 2.93%; blood glucose, 36.2 ± 12.3 mmol/L; and C-peptide median, 0.09 (range, 0–1.61 nmol/l). Twenty-six patients were successfully transferred from insulin to SU therapy. In the remaining case, remission of diabetes occurred prior to transfer. Glycemic control on SU treatment was better than on insulin treatment: HbA1c and blood glucose level decreased from 7.58% ± 4.63% and 19.04 ± 14.09 mmol/L when treated with insulin to 5.8 ± 0.94% and 6.87 ± 3.46 mmol/L when treated with SU, respectively. Conclusions: This is the first case series of NDM patients with ABCC8/KCNJ11 mutations reported in Vietnam. SU is safe in the short term for these patients and more effective than insulin therapy, consistent with all studies to date. This is relevant for populations where access to and cost of insulin are problematic, reinforcing the importance of genetic testing for NDM. [ABSTRACT FROM AUTHOR]

Background: Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach. Methods: A total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset. Results: Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10−8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10−7), Alzheimer's disease (0.80, [0.72, 0.89], P = 3.0 × 10−5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10−14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10−9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite. Conclusions: The present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations. [ABSTRACT FROM AUTHOR]

This study explores how early career academics negotiate precarity in the higher education sector in the United Kingdom under the amplified uncertainties brought by the COVID-19 pandemic. Our preliminary findings based on the semi-structured interviews with nine early career academics (six women and three men) shed light on varying experiences of early career academic precarity with regard to working and life routines, and their participation in the job market. We argue that early career academics' gender, employment status, and their university affiliations influence the degree to which they are able to instrumentalise and negotiate precarity during the pandemic in the UK. [ABSTRACT FROM AUTHOR]

Objectives: To investigate factors affecting the haemostatic success of non‐dissolvable intranasal packs in the management of acute epistaxis presenting to the emergency department (ED). Design: Prospective cohort study. Setting: A nationwide prospective audit examining epistaxis management at 113 sites in the UK over a 30‐day period. Participants: Patients 16 years or older, presenting to the ED with acute epistaxis managed with non‐dissolvable intranasal packs. Main outcome measures: The primary outcome was pack success, defined as successful haemostasis following nasal pack removal, not requiring further packing or surgical intervention or interventional radiology. Results: A cohort of 969 patients presented with epistaxis to the ED, with nasal packs being inserted in 54.4% by ED staff and by ENT in a further 18.9%. Overall, nasal packs were successful in 87.5%. Longer duration packs (≥21 hours) were more successful than shorter‐duration packs (89.9% vs. 84.3%, χ2P =.028). A patient survey supported longer packing duration. The most significant predictors of treatment failure were shorter packing duration (Odds Ratio (OR) = 2.3; 95% Confidence Interval (CI) = 1.4‐3.8), alongside ischaemic heart disease (OR = 1.9; 95% CI = 1.1‐3.3), normal admission haemoglobin (OR = 2.0; 95% CI = 1.2‐3.4) and no attempt at cautery following pack removal (OR = 2.5; 95% CI = 1.4‐4.2). Conclusions: The majority of epistaxis patients are packed by the ED prior to referral to ENT. Once inserted, nasal packs are highly successful, with data supporting the British Rhinological Society guidance of maintaining nasal packs for around 24 hours. Further work is needed to explore alternatives to non‐dissolvable intranasal packs to improve patient experience in epistaxis. [ABSTRACT FROM AUTHOR]

Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank. Transcriptome-wide association studies integrate GWAS and transcriptome data to examine the molecular mechanisms underlying disease etiology. Here the authors present PMR-Egger, a powerful TWAS method based on probabilistic Mendelian Randomization. [ABSTRACT FROM AUTHOR]

Introduction: The number of elderly patients taken to intensive care unit (ICU) is gradually increasing due to the prolongation of life expectancy. According to UK data, the majority of newly diagnosed cancer patients are people over the age of 65, and the highest incidence of cancer is in people between the ages of 85 and 89. The aim of our study is to reveal the ICU outcomes, mortality in oncological patients over 65 years of age, and to document the predisposing factors that cause mortality. Materials and Methods: After the ethics committee approval was obtained, the data of oncology patients over the age of 65 who were treated in ICU between 01/01/2020 and 12/31/2021 were retrospectively analyzed. Results: Of the total 706 patients treated in ICU, 174 were oncology patients over the age of 65. There were 98 people in the 65-74 age range and 76 people over the age of 75. Although patients over 75 years of age had higher APACHE II scores, hospital and ICU mortality rates were similar to those of the other age group. Among the factors affecting ICU and hospital mortality, it was significant that patients used vasoactive drugs at any time and needed invasive mechanical ventilation support. Hospital mortality was found to be lower in cancer patients who underwent surgery in the last 6 months than in patients who did not undergo surgery. Conclusion: Mortality is quite high in ICU treatment of elderly critically ill patients with cancer. In this retrospective study, it was seen that the mortality rate of oncological patients over 65 years of age who were treated in ICU was over 70%. It was found that the mortality risk was more than 2 times higher in patients requiring invasive mechanical ventilation and vasoactive drugs. There was no difference in mortality between solid and hematological cancers. [ABSTRACT FROM AUTHOR]

The article focuses on the Brexit Referendum signed in 2016. Topics discussed include anthropology about Brexit; political, economic and ideological challenges being faced by both, Europe and the world; and economics of inequality. Also being discussed is the electoral withdrawal in England's poor neighbourhoods.

The article focuses on the applications for permission to present a claim from outside the jurisdiction of the European Union and to serve for a person who is not permanent resident of the jurisdiction. It mentions three qualifier tests to serve out permission granted including the applicant having a reasonable prospect of success for which he or she seeks permission, good arguable case and the court's decision to grant permission to serve out.

To advance the on-going debate on Securitisation Theory (ST), we argue that the important questions of audience and attention can be addressed through careful historical study. In an analysis of the securitising moves concerning the American military base on Diego Garcia, we are able to demonstrate that the Copenhagen and Paris Schools are not methodologically incompatible, and empirically that public attention for security issues has a tendency to dissipate without continual discursive investment. [ABSTRACT FROM PUBLISHER]

The article focuses on a judicial review over a court case, which deals with the refusal of the Upper Tribunal to appeal decisions of the First-tier Tribunal on grounds for conventional review. It says that England's Supreme Court has expected the success of such reviews to be the exception rather than the norm. It mentions that the proposed appeal would raise important point of practice or principle.

The article discusses the legislation of conditional fee agreements (CFA) and human rights to the court case MGN Ltd. v. Great Britain. It mentions that the case revolves around supermodel Naomi Campbell's right to privacy. It tackles the decision of the European Court of Human Rights (ECtHR), noting that it carries potential implications for costs in non-media civil cases. It also explores the breach of confidence issue and costs issue as well as the illegitimacy of CFA success fees in defamation or privacy cases.

The article discusses the human rights case in the British Supreme Court concerning with Private Jason Smith who died of hypothermia at the British army base Camp Abu Naji in August 2003 wherein the Oxfordshire Assistant Deputy Coroner argues that the European Convention for the Protection of Human Rights and Fundamental Freedom is not applicable. It highlights the jurisdiction and inquiry issues which investigates the interpretation of the articles 1 and 2 of the European Convention. It presents the interpretation of the Bankovic case wherein civilians were killed by the United Nations (UN) air strikes on a radio and television center in Belgrade, Serbia in 1999 and the Al-Skeini case wherein British soldiers killed six Iraqi civilians in Iraq.

The new risk assessment model in which the second-order reliability method and the importance sampling Monte Carlo (ISMC) simulations were interrelated was implemented to Wiseman’s Bridge, Newport, and Broadhaven revetments in the Pembrokeshire Coast National Park, southwest Wales, United Kingdom. The tidal range of the site and the storm surge were randomly generated at the first stage of ISMC simulation from the probability distributions describing the phenomena. At the second stage, the damage probability was predicted by approximating the limit-state surface by a quadratic one having the identical curvature at the design point. Newport and Broadhaven revetments were safe, but the revetment at Wiseman’s Bridge needed strong maintenance. The risk assessment model reflected the effect of water level changes (circa 6 m above ordnance datum) on the reliability of rubble mound revetments by simulating the environmental conditions at the sites. As the uncertainties inherent in design parameters were extensive, such as variations associated with wave data, tidal range and storm surge, it was suggested to determine the reliability of revetments by using Monte Carlo simulation methods. On the other hand, such hard engineering structures in a National Park Coast where the emphasis is on natural beauty are questionable, especially when they protect just two buildings, such as the Wiseman’s Bridge revetment. It is ironic that pebble beaches abound in the area, and these are probably the best protection that can be given both to nature and structures. [ABSTRACT FROM AUTHOR]

• Medical errors harm patients and staff in dynamic and complex healthcare systems. • Machine learning algorithms (RF and GB) were developed to evaluate medical errors. • Using hospital-level survey data, RF and GB provided similar prediction accuracy. • Health and wellbeing and work-related stress were leading factors affecting errors. Medical errors constitute a significant challenge affecting patient and staff safety in complex and dynamic healthcare systems. While various organizational factors may contribute to such errors, limited studies have addressed patient and staff safety issues simultaneously in the same study setting. To evaluate this, we conduct an exploratory analysis using two types of tree-based machine learning algorithms, random forests and gradient boosting, and the hospital-level aggregate staff experience survey data from UK hospitals. Based on staff views and priorities, the results from both algorithms suggest that "health and wellbeing" is the leading theme associated with the number of reported errors and near misses harming patient and staff safety. Specifically, "work-related stress" is the most important survey item associated with safety outcomes. With respect to prediction accuracy, both algorithms provide similar results with comparable values in error metrics. Based on the analytical results, healthcare risk managers and decision-makers can develop and implement policies and practices that address staff experience and prioritize resources effectively to improve patient and staff safety. [ABSTRACT FROM AUTHOR]

Human melanocortin MC1 and MC3 receptors expressed on C-20/A4 chondrocytes exhibit chondroprotective and anti-inflammatory effects when activated by melanocortin peptides. Nearly 9 million people in the UK suffer from osteoarthritis, and bacterial infections play a role in its development. Here, we evaluate the effect of a panel of melanocortin peptides with different selectivity for human melanocortin MC1 (α-MSH, BMS-470539 dihydrochloride) and MC3 ([DTrp8]-γ-MSH, PG-990) receptors and C-terminal peptide α-MSH 11-13 (KPV), on inhibiting LPS-induced chondrocyte death, pro-inflammatory mediators and induction of anti-inflammatory proteins. C-20/A4 chondrocytes were treated with a panel of melanocortin peptides prophylactically and therapeutically in presence of LPS (0.1 μg/ml). The chondroprotective properties of these peptides determined by cell viability assay, RT-PCR, ELISA for detection of changes in inflammatory markers (IL-6, IL-8 and MMP-1, -3 and -13) and western blotting for expression of the anti-inflammatory protein heme-oxygenase-1. C-20/A4 expressed human melanocortin MC1 and MC3 receptors and melanocortin peptides elevated cAMP. LPS stimulation caused a reduction in C-20/A4 viability, attenuated by the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride, and MC3 receptor agonists PG-990 and [DTrp8]-γ-MSH. Prophylactic and therapeutic regimes of [DTrp8]-γ-MSH significantly inhibited LPS-induced modulation of cartilage-damaging IL-6, IL-8, MMPs −1,-3 and −13 mediators both prophylactically and therapeutically, whilst human melanocortin MC1 and MC3 receptor agonists promoted an increase in HO-1 production. In the presence of LPS, activation of human melanocortin MC1 and MC3 receptors provided potent chondroprotection, upregulation of anti-inflammatory proteins and downregulation of inflammatory and proteolytic mediators involved in cartilage degradation, suggesting a new avenue for osteoarthritis treatment. • LPS activated chondrocytes display characteristic markers related to OA. • Melanocortins exhibit prophylactic and therapeutic chondroprotection. • Melanocortins inhibit inflammatory cytokines and matrix metalloproteinases. • Targeting human melanocortin MC3 receptor induces HO-1. • Data suggests activation of human MC3 receptor may have therapeutic potential in OA. [ABSTRACT FROM AUTHOR]

ObjectivesTo evaluate the effect of issuing a patient reminder plus a confirmation slip on the attendance of orthodontic new patients.SettingDepartment of Orthodontics, University Dental Hospital of Manchester.DesignA randomised controlled trial.MethodNew patients were randomly allocated to:receive a reminder letter and return a confirmation slip ornot receive a reminder.Outcome measuresPatient attendance at the clinic.ResultsA total of 232 patients were entered into the study between June 18, 2001 and August 29, 2001. These were randomly allocated to 115 (49.8%) in the reminder group and 116 (50.2%) in the no reminder group. If the patient received a reminder and returned the confirmation they were less likely to fail the appointment than if they did not receive a reminder (OR 0.4, 95% CI 0.2 to 0.96) There was an effect of social deprivation, if the patients lived in an area of high social deprivation they were 2.7 (95% CI 1.1 to 6.5) times more likely to fail to attend an appointment than people who were more affluent.ConclusionsThe use of postal reminders for orthodontic consultation appointments appears to result in a useful increase of appointments that are kept or cancelled in advance. [ABSTRACT FROM AUTHOR]

Over the past two decades, genome-wide association studies (GWASs) have successfully advanced our understanding of the genetic basis of complex traits. Despite the fruitful discovery of GWASs, most GWAS samples are collected from European populations, and these GWASs are often criticized for their lack of ancestry diversity. Trans-ancestry association mapping (TRAM) offers an exciting opportunity to fill the gap of disparities in genetic studies between non-Europeans and Europeans. Here, we propose a statistical method, LOG-TRAM, to leverage the local genetic architecture for TRAM. By using biobank-scale datasets, we showed that LOG-TRAM can greatly improve the statistical power of identifying risk variants in under-represented populations while producing well-calibrated p values. We applied LOG-TRAM to the GWAS summary statistics of various complex traits/diseases from BioBank Japan, UK Biobank, and African populations. We obtained substantial gains in power and achieved effective correction of confounding biases in TRAM. Finally, we showed that LOG-TRAM can be successfully applied to identify ancestry-specific loci and the LOG-TRAM output can be further used for construction of more accurate polygenic risk scores in under-represented populations. We introduce LOG-TRAM, a method to leverage the local genetic architecture for trans-ancestry association mapping. Not only can LOG-TRAM control type I errors at the nominal level, but it also can improve the statistical power of identifying risk variants in under-represented populations. [ABSTRACT FROM AUTHOR]

The development of polygenic risk scores (PRSs) has proved useful to stratify the general European population into different risk groups. However, PRSs are less accurate in non-European populations due to genetic differences across different populations. To improve the prediction accuracy in non-European populations, we propose a cross-population analysis framework for PRS construction with both individual-level (XPA) and summary-level (XPASS) GWAS data. By leveraging trans-ancestry genetic correlation, our methods can borrow information from the Biobank-scale European population data to improve risk prediction in the non-European populations. Our framework can also incorporate population-specific effects to further improve construction of PRS. With innovations in data structure and algorithm design, our methods provide a substantial saving in computational time and memory usage. Through comprehensive simulation studies, we show that our framework provides accurate, efficient, and robust PRS construction across a range of genetic architectures. In a Chinese cohort, our methods achieved 7.3%–198.0% accuracy gain for height and 19.5%–313.3% accuracy gain for body mass index (BMI) in terms of predictive R 2 compared to existing PRS approaches. We also show that XPA and XPASS can achieve substantial improvement for construction of height PRSs in the African population, suggesting the generality of our framework across global populations. [ABSTRACT FROM AUTHOR]

Background: Biological ageing markers are useful to risk stratify morbidity and mortality more precisely than chronological age. In this study, we aimed to develop a novel deep-learning-based biological ageing marker (referred to as RetiPhenoAge hereafter) using retinal images and PhenoAge, a composite biomarker of phenotypic age., Methods: We used retinal photographs from the UK Biobank dataset to train a deep-learning algorithm to predict the composite score of PhenoAge. We used a deep convolutional neural network architecture with multiple layers to develop our deep-learning-based biological ageing marker, as RetiPhenoAge, with the aim of identifying patterns and features in the retina associated with variations of blood biomarkers related to renal, immune, liver functions, inflammation, and energy metabolism, and chronological age. We determined the performance of this biological ageing marker for the prediction of morbidity (cardiovascular disease and cancer events) and mortality (all-cause, cardiovascular disease, and cancer) in three independent cohorts (UK Biobank, the Singapore Epidemiology of Eye Diseases [SEED], and the Age-Related Eye Disease Study [AREDS] from the USA). We also compared the performance of RetiPhenoAge with two other known ageing biomarkers (hand grip strength and adjusted leukocyte telomere length) and one lifestyle factor (physical activity) for risk stratification of mortality and morbidity. We explored the underlying biology of RetiPhenoAge by assessing its associations with different systemic characteristics (eg, diabetes or hypertension) and blood metabolite levels. We also did a genome-wide association study to identify genetic variants associated with RetiPhenoAge, followed by expression quantitative trait loci mapping, a gene-based analysis, and a gene-set analysis. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and corresponding 95% CIs for the associations between RetiPhenoAge and the different morbidity and mortality outcomes., Findings: Retinal photographs for 34 061 UK Biobank participants were used to train the model, and data for 9429 participants from the SEED cohort and for 3986 participants from the AREDS cohort were included in the study. RetiPhenoAge was associated with all-cause mortality (HR 1·92 [95% CI 1·42-2·61]), cardiovascular disease mortality (1·97 [1·02-3·82]), cancer mortality (2·07 [1·29-3·33]), and cardiovascular disease events (1·70 [1·17-2·47]), independent of PhenoAge and other possible confounders. Similar findings were found in the two independent cohorts (HR 1·67 [1·21-2·31] for cardiovascular disease mortality in SEED and 2·07 [1·10-3·92] in AREDS). RetiPhenoAge had stronger associations with mortality and morbidity than did hand grip strength, telomere length, and physical activity. We identified two genetic variants that were significantly associated with RetiPhenoAge (single nucleotide polymorphisms rs3791224 and rs8001273), and were linked to expression quantitative trait locis in various tissues, including the heart, kidneys, and the brain., Interpretation: Our new deep-learning-derived biological ageing marker is a robust predictor of mortality and morbidity outcomes and could be used as a novel non-invasive method to measure ageing., Funding: Singapore National Medical Research Council and Agency for Science, Technology and Research, Singapore., Competing Interests: Declaration of interests THR and GL own stocks in MediWhale, to whom RetiAge was licensed. ZZ holds a National Health and Medical Research Council Investigator Grant (2010072) and owns two patents for biological age prediction from ocular images (AU2023903213A0 and CN114782361A). T-YW is a consultant for Aldropika Therapeutics, Bayer, Boehringer Ingelheim, Carl Zeiss, Genentech, Iveric Bio, Novartis, Oxurion, Plano, Roche, Sanofi, and Shanghai Henlius; is an inventor, holds patents, and is a co-founder of the start-up companies EyRiS and Visre; and has interests in, and develops digital solutions for, eye diseases, including diabetic retinopathy, outside of the submitted work. C-YC holds licences and receives consultation fees from MediWhale. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: People with mental health conditions were potentially more vulnerable than others to the neuropsychiatric effects of the COVID-19 pandemic and the global efforts taken to contain it. The aim of this multinational study was to examine the changes in psychotropic drug prescribing during the pandemic among people with depressive and anxiety disorders., Methods: This study included electronic medical records and claims data from nine databases in six countries (France, Germany, Italy, the UK, South Korea, and the USA) of patients with a diagnosis of depressive or anxiety disorders between 2016 and 2021. The outcomes were monthly prevalence rates of antidepressant, antipsychotic, and anxiolytic drug prescribing. The associations between the pandemic and psychotropic drug prescribing were examined with interrupted time series analyses for the total sample and stratified by sex and age group. People with lived experience were not involved in the research and writing process., Findings: Between Jan 1, 2016 and Dec 31, 2020, an average of 16 567 914 patients with depressive disorders (10 820 956 females [65·31%] and 5 746 958 males [34·69%]) and 15 988 451 patients with anxiety disorders (10 688 788 females [66·85%] and 5 299 663 males [33·15%]) were identified annually. Most patients with depressive disorders and anxiety disorders were aged 45-64 years. Ethnicity data were not available. Two distinct trends in prescribing rates were identified. The first pattern shows an initial surge at the start of the pandemic (eg, antipsychotics among patients with depressive disorders in MDCD&#95;US (rate ratio [RR] 1·077, 95% CI 1·055-1·100), followed by a gradual decline towards the counterfactual level (RR 0·990, 95% CI 0·988-0·992). The second pattern, observed in four databases for anxiolytics among patients with depressive disorders and two for antipsychotics among patients with anxiety disorders, shows an immediate increase (eg, antipsychotics among patients with anxiety disorders in IQVIA&#95;UK: RR 1·467, 95% CI 1·282-1·675) without a subsequent change in slope (RR 0·985, 95% CI 0·969-1·003). In MDCD&#95;US and IQVIA&#95;US, the anxiolytic prescribing rate continued to increase among patients younger than 25 years for both disorders., Interpretation: The study reveals persistently elevated rates of psychotropic drug prescriptions beyond the initial phase of the pandemic. These findings underscore the importance of enhanced mental health support and emphasise the need for regular review of psychotropic drug use among this patient group in the post-pandemic era., Funding: University Grants Committee, Research Grants Council, The Government of the Hong Kong Special Administrative Region., Competing Interests: Declaration of interests HL reports grants from Research Grants Council of Hong Kong, outside the submitted work. WCYL reports research grants from AIR@InnoHK administered by Innovation and Technology Commission, outside the submitted work. JH reports grants from UKRI, Consultancy Fees from Wellcome Trust and Juli Health, and patents pending and stock from Juli Health, outside the submitted work. COT reports stock or stock options and other financial or non-financial interests from Roche Pharmaceutical as an employee, outside the submitted work. XL reports grants from IQVIA, outside the submitted work. SF and DMK report stock or stock options and other financial or non-financial interests from Johnson and Johnson as employees, outside the submitted work. JL reports stock or stock options and other financial or non-financial interests from IQVIA as an employee, outside the submitted work. KKCM reports grants from the CW Maplethorpe Fellowship, National Institute of Health Research, UK, Hong Kong Research Grant Council, and the European Commission Horizon 2020 Framework, outside the submitted work. ICKW reports grants from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK and Novartis, the Hong Kong RGC, and the Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, and National Health and Medical Research Council in Australia, consulting fees from IQVIA, payment for expert testimony and a role as an independent non-executive director of Jacobson Medical, Hong Kong, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: To evaluate the association between regular glucosamine intake and heart failure (HF) and to explore whether the association is mediated by relevant cardiovascular disease., Patients and Methods: We included 479,650 participants with data available for supplement use and without HF at baseline from the UK Biobank study. Using 12 single-nucleotide polymorphisms linked to HF, a weighted genetic risk score was calculated. We evaluated the association between glucosamine use and HF by Cox regression models after inverse probability of treatment weighting. A validation and mediation analysis were performed through two-sample Mendelian randomization. The study was from May 18, 2006, to February 16, 2018., Results: During a median follow-up of 9.0 (IQR, 8.3-9.8) years, we documented 5501 incident cases of HF. In multivariable analysis, the HR of glucosamine users for HF was 0.87 (95% CI, 0.81 to 0.94). The inverse associations were stronger in males and participants with unfavorable lifestyle (P<.05 for interaction). Genetic risk categories did not modify this association (P>.05 for interaction). Multivariable Mendelian randomization showed that taking glucosamine was protective against HF (HR, 0.92; 95% CI, 0.87 to 0.96). The mediated proportion of coronary heart disease and stroke were 10.5% (95% CI, 7.6% to 13.4%) and 14.4% (95% CI, 10.8% to 18.0%), respectively. The two-mediator combination accounted for 22.7% (95% CI, 17.2% to 28.2%) of the effect of glucosamine use., Conclusion: Regular glucosamine supplementation was associated with a lower risk of HF regardless of genetic risk status, and to a lesser extent, coronary heart disease and stroke mediated this effect. The results may inform novel pathway for prevention and intervention toward HF., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose/background: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis., Methods: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions., Findings/results: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year., Implications/conclusions: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The COVID-19 pandemic has significantly affected all spheres of life, including the healthcare workforce. While the COVID-19 pandemic has started driving organizational and societal shifts, it is vital for healthcare organizations and decision-makers to analyze patterns in the changing workforce. In this study, we aim to identify patterns in healthcare job postings during the pandemic to understand which jobs and associated skills are trending after the advent of COVID-19. Content analysis of job postings was conducted using data-driven approaches over two-time intervals in the pandemic. The proposed framework utilizes Latent Dirichlet Allocation (LDA) for topic modeling to evaluate the patterns in job postings in the US and the UK. The most demanded jobs, skills and tasks for the US job postings are presented based on job posting data from popular job posting websites. This is obtained by mapping the job postings to the jobs, skills and tasks defined in the O*NET database for the healthcare occupations in the US. The topic modeling results clearly show increased hiring for telehealth services in both the US and UK. This study also presents an increase in demand for specific occupations and skills in the USA healthcare industry. The results and methods used in the study can help monitor rapid changes in the job market due to pandemics and guide decision-makers to make organizational shifts in a timely manner., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Upadhyay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)