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Abstract Background Multiple psychosocial factors have been associated with dementia, while the individual or joint effects of various psychosocial states on dementia remain unrevealed due to the complex interplay between those factors. Here, the authors examined the associations of psychosocial factors and patterns with subsequent risk of dementia, and if the associations could be modified by genetic susceptibility to dementia. Methods UK Biobank dementia-free participants were followed from one year after recruitment (median date: 24 January, 2010) until 31 October, 2022. Psychosocial states were measured by 22 items related to five dimensions, including psychiatric history, recent stressful life events, current psychiatric symptoms, social contact, and individual socioeconomic state. We identified clusters of individuals with distinct psychosocial patterns using latent class analysis. Cox proportional hazards models were used to evaluate the association between psychosocial items, as well as psychosocial patterns, and risk of dementia. We further performed stratification analyses by apolipoprotein E (APOE) genotype, polygenic risk score (PRS) of dementia, and family history of dementia. Results Of 497,787 included participants, 54.54% were female. During a median follow-up of 12.70 years, we identified 9,858 (1.98%) patients with newly diagnosed dementia. We identified seven clusters with distinct psychosocial patterns. Compared to individuals with a pattern of ‘good state’, individuals with other unfavorable patterns, featured by varying degrees of poor psychological state (‘fair state’ and ‘mildly, moderately, and extremely poor psychological state’), low social contact or socioeconomic state (‘living alone’ and ‘short education years’), were all at an increased risk of dementia (hazard ratios [HR] between 1.29 and 2.63). The observed associations showed no significant differences across individuals with varying APOE genotypes, levels of PRS, and family histories of dementia. Conclusion Unfavorable psychosocial patterns are associated with an increased risk of dementia, independent of genetic susceptibility. The findings highlight the importance of surveillance and prevention of cognitive decline among individuals with suboptimal psychosocial state.

Abstract Exposure to adverse life events is linked to somatic disorders. The study aims to evaluate the association between adverse events at varying life stages and the risk of chronic kidney disease (CKD), a condition affecting about 10% population worldwide. This prospective cohort study included 140,997 participants from the UK Biobank. Using survey items related to childhood maltreatment, adulthood adversity and catastrophic trauma, we performed latent class analysis to summarize five distinct patterns of exposure to adverse life events, namely “low-level exposure”, “childhood exposure”, “adulthood exposure”, “sexual abuse” and “child-to-adulthood exposure”. We used Cox proportional hazard regression to evaluate the association of patterns of exposure to adverse life events with CKD, regression-based mediation analysis to decompose the total effect, and gene-environment-wide interaction study (GEWIS) to identify interactions between genetic loci and adverse life events. During a median follow-up of 5.98 years, 2734 cases of incident CKD were identified. Compared with the “low-level exposure” pattern, “child-to-adulthood exposure” was associated with increased risk of CKD (hazard ratio 1.37, 95% CI 1.14 to 1.65). BMI, smoking and hypertension mediated 11.45%, 9.79%, and 4.50% of this total effect, respectively. Other patterns did not show significant results. GEWIS and subsequent analyses indicated that the magnitude of the association between adverse life events and CKD differed according to genetic polymorphisms, and identified potential underlying pathways (e.g., interleukin 1 receptor activity). These findings underscore the importance of incorporating an individual’s psychological encounters and genetic profiles into the precision prevention of CKD.

Abstract Background Psychological and trauma-related factors are associated with many diseases and mortality. However, a comprehensive assessment of the association between psycho-trauma exposures and aging acceleration is currently lacking. Methods Using data from 332,359 UK Biobank participants, we calculated biological aging acceleration, indexed by the presence of leukocyte telomere length (LTL) deviation (i.e., the difference between genetically determined and observed LTL > 0). The acceleration of facial aging (i.e., looking older than the chronological age) was assessed using a self-report question. Then, we estimated the associations of each psycho-trauma factor with biological and facial aging acceleration, using logistic regression models adjusted for multiple important covariates. Furthermore, restricted to 99,180 participants with complete psychological and trauma-related data, we identified clusters of individuals with distinct psycho-trauma patterns using the latent class analysis method and assessed their associations with aging acceleration using similar models. Results We observed most of the studied psycho-trauma factors were associated with biological and facial aging acceleration. Compared to the “Absence of trauma and psychopathology” cluster, the “adverse childhood experiences (ACEs) with psychopathology” cluster showed strong associations with those aging measurements (odds ratio [OR] = 1.13 [1.05 − 1.23] for biological and 1.52 [1.18 − 1.95] for facial aging acceleration), while no such association was observed for the “ACEs without psychopathology” cluster (1.04 [0.99 − 1.09] and 1.02 [0.84 − 1.24]. Conclusions Our study demonstrated significant associations of psycho-trauma factors with both biological and facial aging acceleration. The differential aging consequences observed among ACEs exposed individuals with and without psychopathology prompt interventions aimed to improve individuals’ psychological resilience to prevent aging acceleration.

Abstract Background Childhood maltreatment (CM) has been indicated in adverse health outcomes across the lifespan, including severe infection-related outcomes. Yet, data are scarce on the potential role of CM in severe COVID-19-related outcomes as well as on mechanisms underlying this association. Methods We included 151,427 individuals in the UK Biobank who responded to questions on the history of CM in 2016 and 2017 and were alive on January 31, 2020. Binomial logistic regression models were performed to estimate the association between a history of CM and severe COVID-19 outcomes (i.e. hospitalization or death due to COVID-19), as well as COVID-19 diagnosis and vaccination as secondary outcomes. We then explored the potential mediating roles of socio-economic status, lifestyle and pre-pandemic comorbidities, and the effect modification by polygenic risk score for severe COVID-19 outcomes. Results The mean age of the study population at the start of the pandemic was 67.7 (SD = 7.72) years, and 56.5% were female. We found the number of CM types was associated with the risk of severe COVID-19 outcomes in a graded manner (p for trend 0.05). Mediation analysis revealed that 50.9% of the association between CM and severe COVID-19 outcomes was explained by suboptimal socio-economic status, lifestyle, and pre-pandemic diagnosis of psychiatric disorders or other chronic medical conditions. In contrast, any CM exposure was only weakly associated with COVID-19 diagnosis (1.06 [1.01–1.12]) while significantly associated with not being vaccinated for COVID-19 (1.21 [1.13–1.29]). Conclusions Our results add to the growing knowledge base indicating the role of childhood maltreatment in negative health outcomes across the lifespan, including severe COVID-19-related outcomes. The identified factors underlying this association represent potential intervention targets for mitigating the harmful effects of childhood maltreatment in COVID-19 and similar future pandemics.

Introduction While changes in the prevalence of depressive symptoms during the COVID-19 pandemic have been described across populations, few studies have incorporated multidimensional variables to characterise the varying effects of the pandemic on the population’s mental health.Methods This cohort study included 6423 participants aged ≥18 years from the Icelandic COVID-19 National Resilience Cohort. Data on depressive symptoms and pandemic-related and non-pandemic-related factors were obtained during three pandemic assessment periods (baseline, follow-up wave 1 and follow-up wave 2; April 2020–December 2021), while health outcomes were obtained during the post-pandemic assessment period (follow-up wave 3; September 2022–February 2023). We used latent growth mixture models to identify variation in depressive symptom trajectories during the pandemic. We then used XGBoost models with 37 pandemic-related and non-pandemic-related factors to characterise these trajectories. Moreover, we performed linear regression to assess the association between the identified trajectories and post-pandemic health outcomes.Results Of the included participants, we identified four depressive symptom trajectories, including consistently low (83.7%), consistently high (5.3%), initially high (5.1%) and late-onset high (5.9%) symptom trajectories. Individuals who exercised frequently (≥3 days/week) and enjoyed social and family support were more likely to experience a consistently low symptom trajectory. In contrast, individuals with a history of psychiatric disorders, women and young adults (18–39 years) were less likely to follow the consistently low symptom trajectory. Moreover, compared with the consistently low symptom trajectory, the other trajectories were associated with significantly higher levels of depressive, anxiety and somatic symptoms and cognitive problems during the post-pandemic period.Conclusions Our results underscore the long-lasting impact of the COVID-19 pandemic on population mental health. Interventions focusing on exercise, social support and family support may mitigate the adverse mental health effects of future pandemics.

Abstract Mortality rates due to lung cancer are high worldwide. Although PD‐1 and PD‐L1 immune checkpoint inhibitors boost the survival of patients with non‐small‐cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build‐up and potential lysine‐lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non‐histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi‐omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl‐APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti‐APOC2K70‐lac antibody that sensitized anti‐PD‐1 therapy in vivo is developed. This findings highlight the potential of anti lactyl‐APOC2‐K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.

Objective To construct applicable models suitable for predicting the risk of suicidal behavior among individuals with depression, particularly on the progression from no history of suicidal behavior to suicide attempts, as well as from suicidal ideation to suicide attempts. Methods Based on a prospective cohort from the UK Biobank, a total of 55,139 individuals aged 50 and above with depression were enrolled in the study, among whom 29,528 exhibited suicidal behavior. Specifically, they were divided into control (25,611), suicidal ideation (24,361), and suicide attempt (5167) groups. Least absolute shrinkage and selection operator (LASSO) regression was used to identify a subset of important features for distinguishing suicidal ideation and suicide attempts. We used the Gradient Boosting Decision Tree (GBDT) algorithm with stratified 10-fold cross-validation and grid-search to construct the prediction models for suicidal ideation or suicide attempts. To address the dataset imbalance in classifying suicide attempts, we used random under-sampling. The SHapley Additive exPlanations (SHAP) were used to estimate the important variables in the GBDT model. Results Significant differences in sociodemographic, economic, lifestyle, and psychological factors were observed across the three groups. Each classifier optimally utilized 8–11 features. Overall, the algorithms predicting suicide attempts demonstrated slightly higher performance than those predicting suicidal ideation. The GBDT classifier achieved the highest accuracy, with AUROC scores of 0.914 for suicide attempts and 0.803 for suicidal ideation. Distinctive predictive factors were identified for each group: while depression's inherent characteristics crucially distinguished the suicidal ideation group from controls, some key predictors, including the age of depression onset and childhood trauma events, were identified for suicide attempts. Conclusions We established applicable machine learning-based models for predicting suicidal behavior, particularly suicide attempts, in individuals with depression, and clarified the differences in predictors between suicidal ideation and suicide attempts.

Plant architecture determines canopy coverage, photosynthetic efficiency, and ultimately productivity in soybean (Glycine max). Optimizing plant architecture is a major goal of breeders to develop high yield soybean varieties. Over the past few decades, the yield per unit area of soybean has not changed significantly; however, rice and wheat breeders have succeeded in achieving high yields by generating semi‐dwarf varieties. Semi-dwarf crops have the potential to ensure yield stability in high-density planting environments because they can significantly improve responses to fertilizer input, lodging resistance, and enhance resistance to various abiotic and biotic stresses. Soybean has a unique plant architecture, with leaves, inflorescences, and pods growing at each node; internode number greatly affects the final yield. Therefore, producing high-yielding soybean plants with an ideal architecture requires the coordination of effective node formation, effective internode formation, and branching. Dozens of quantitative trait loci (QTLs) controlling plant architecture have been identified in soybean, but only a few genes that control this trait have been cloned and characterized. Here, we review recent progress in understanding the genetic basis of soybean plant architecture. We provide our views and perspectives on how to breed new high-yielding soybean varieties.

Abstract The complexity of repairing large segment defects and eradicating residual tumor cell puts the osteosarcoma clinical management challenging. Current biomaterial design often overlooks the crucial role of precisely regulating innervation in bone regeneration. Here, we develop a Germanium Selenium (GeSe) co-doped polylactic acid (PLA) nanofiber membrane-coated tricalcium phosphate bioceramic scaffold (TCP-PLA/GeSe) that mimics the bone-periosteum structure. This biomimetic scaffold offers a dual functionality, combining piezoelectric and photothermal conversion capabilities while remaining biodegradable. When subjected to ultrasound irradiation, the US-electric stimulation of TCP-PLA/GeSe enables spatiotemporal control of neurogenic differentiation. This feature supports early innervation during bone formation, promoting early neurogenic differentiation of Schwann cells (SCs) by increasing intracellular Ca2+ and subsequently activating the PI3K-Akt and Ras signaling pathways. The biomimetic scaffold also demonstrates exceptional osteogenic differentiation potential under ultrasound irradiation. In rabbit model of large segment bone defects, the TCP-PLA/GeSe demonstrates promoted osteogenesis and nerve fibre ingrowth. The combined attributes of high photothermal conversion capacity and the sustained release of anti-tumor selenium from the TCP-PLA/GeSe enable the synergistic eradication of osteosarcoma both in vitro and in vivo. This strategy provides new insights on designing advanced biomaterials of repairing large segment bone defect and osteosarcoma.

Background The associations between cardiovascular disease (CVD) and multiple psychiatric disorders and suicide attempt, and whether different genetic susceptibilities affect such links, have not been investigated clearly. Methods and Results Based on the UK Biobank, we conducted a matched cohort study involving 63 923 patients who were first hospitalized with a CVD diagnosis between 1997 and 2020, and their 127 845 matched unexposed individuals. Cox models were used to examine the subsequent risk of psychiatric disorders and suicide attempt (ie, anxiety, depression, stress‐related disorder, substance misuse, psychotic disorder, and suicide behaviors) following CVD. We further performed stratified analyses by polygenic risk score for each studied psychiatric condition to detect the possible effects of genetic susceptibility on the observed associations. We found an increased risk of any psychiatric disorders and suicide attempt among CVD patients, compared with matched unexposed individuals, particularly within 1 year following the CVD (fully adjusted hazard ratio [HR] within 1 year, 1.83 [95% CI, 1.58–2.12]; HR after 1 year, 1.24 [95% CI, 1.16–1.32]). By subtype, the risk elevations existed for any psychiatric disorders and suicide attempt following most categories of CVDs. Analyses stratified by polygenic risk score revealed little impact of genetic predisposition to studied psychiatric conditions on these observed links. Conclusions Patients hospitalized for CVD were at increased subsequent risk of multiple types of psychiatric disorders and suicide attempt, especially in the first year after hospitalization, irrespective of their genetic susceptibilities to studied psychiatric conditions, and these findings underscore the necessity of developing timely psychological interventions for this vulnerable population.

Abstract BackgroundLarge language models (LLMs) have achieved great progress in natural language processing tasks and demonstrated the potential for use in clinical applications. Despite their capabilities, LLMs in the medical domain are prone to generating hallucinations (not fully reliable responses). Hallucinations in LLMs’ responses create substantial risks, potentially threatening patients’ physical safety. Thus, to perceive and prevent this safety risk, it is essential to evaluate LLMs in the medical domain and build a systematic evaluation. ObjectiveWe developed a comprehensive evaluation system, MedGPTEval, composed of criteria, medical data sets in Chinese, and publicly available benchmarks. MethodsFirst, a set of evaluation criteria was designed based on a comprehensive literature review. Second, existing candidate criteria were optimized by using a Delphi method with 5 experts in medicine and engineering. Third, 3 clinical experts designed medical data sets to interact with LLMs. Finally, benchmarking experiments were conducted on the data sets. The responses generated by chatbots based on LLMs were recorded for blind evaluations by 5 licensed medical experts. The evaluation criteria that were obtained covered medical professional capabilities, social comprehensive capabilities, contextual capabilities, and computational robustness, with 16 detailed indicators. The medical data sets include 27 medical dialogues and 7 case reports in Chinese. Three chatbots were evaluated: ChatGPT by OpenAI; ERNIE Bot by Baidu, Inc; and Doctor PuJiang (Dr PJ) by Shanghai Artificial Intelligence Laboratory. ResultsDr PJ outperformed ChatGPT and ERNIE Bot in the multiple-turn medical dialogues and case report scenarios. Dr PJ also outperformed ChatGPT in the semantic consistency rate and complete error rate category, indicating better robustness. However, Dr PJ had slightly lower scores in medical professional capabilities compared with ChatGPT in the multiple-turn dialogue scenario. ConclusionsMedGPTEval provides comprehensive criteria to evaluate chatbots by LLMs in the medical domain, open-source data sets, and benchmarks assessing 3 LLMs. Experimental results demonstrate that Dr PJ outperforms ChatGPT and ERNIE Bot in social and professional contexts. Therefore, such an assessment system can be easily adopted by researchers in this community to augment an open-source data set.

Abstract 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 (

Abstract Background Peripheral vertigo is often comorbid with psychiatric disorders. However, no longitudinal study has quantified the association between peripheral vertigo and risk of psychiatric disorders. Furthermore, it remains unknown how the white matter integrity of frontal-limbic network relates to the putative peripheral vertigo-psychiatric disorder link. Methods We conducted a cohort study including 452,053 participants of the UK Biobank with a follow-up from 2006 through 2021. We assessed the risks of depression and anxiety disorders in relation to a hospitalization episode involving peripheral vertigo using Cox proportional hazards models. We also examined the associations of peripheral vertigo, depression, and anxiety with MRI fractional anisotropy (FA) in a subsample with brain MRI data (N = 36,087), using multivariable linear regression. Results Individuals with an inpatient diagnosis of peripheral vertigo had elevated risks of incident depression (hazard ratio (HR) 2.18; 95% confidence interval (CI) 1.79–2.67) and anxiety (HR 2.11; 95% CI 1.71–2.61), compared to others, particularly within 2 years after hospitalization (HR for depression 2.91; 95% CI 2.04–4.15; HR for anxiety 4.92; 95% CI 3.62–6.69). Depression was associated with lower FA in most studied white matter regions, whereas anxiety and peripheral vertigo did not show statistically significant associations with FA. Conclusions Individuals with an inpatient diagnosis of peripheral vertigo have increased subsequent risks of depression and anxiety disorders, especially within 2 years after hospitalization. Our findings further indicate a link between depression and lower microstructural connectivity as well as integrity beyond the frontal-limbic network.

Abstract Anxiety/stress-related disorders have been associated with multiple diseases, whereas a comprehensive assessment of the structure and interplay of subsequent associated diseases and their genetic underpinnings is lacking. Here, we first identify 136, out of 454 tested, medical conditions associated with incident anxiety/stress-related disorders attended in specialized care using a population-based cohort from the nationwide Swedish Patient Register, comprising 70,026 patients with anxiety/stress-related disorders and 1:10 birth year- and sex-matched unaffected individuals. By combining findings from the comorbidity network and disease trajectory analyses, we identify five robust disease clusters to be associated with a prior diagnosis of anxiety/stress-related disorders, featured by predominance of psychiatric disorders, eye diseases, ear diseases, cardiovascular diseases, and skin and genitourinary diseases. These five clusters and their featured diseases are largely validated in the UK Biobank. GWAS analyses based on the UK Biobank identify 3, 33, 40, 4, and 16 significantly independent single nucleotide polymorphisms for the link to the five disease clusters, respectively, which are mapped to several distinct risk genes and biological pathways. These findings motivate further mechanistic explorations and aid early risk assessment for cluster-based disease prevention among patients with newly diagnosed anxiety/stress-related disorders in specialized care.

Background: We sought to establish a prospective hospital-based cohort, featuring detailed multidimensional data of trauma patients with active follow-ups, which can be a reliable data source for all studies focusing on the effects or underlying mechanistic pathways of environmental and biological factors on multiple interested trauma-related outcomes, particularly the incidence and trajectory of trauma-related psychopathology, in a Chinese population. Methods: The China Severe Trauma Cohort (CSTC) enrolled all traumatized individuals aged 12 to 80 years admitted to the Trauma Center of West China Hospital between March 1st, 2020 and July 8th, 2022. The bio-sample and detailed questionnaire data were collected at recruitment, and phone/internet follow-ups were scheduled at 1, 3, 6, and 12 months after the baseline. Long-term health outcomes are planned to be obtained from administrative databases through data linkage. Results: A total of 2,500 trauma patients were enrolled (response rate = 87.1%) with an average age of 46.01 years, and most of the participants were males (62.6%). The proportions of participants with blood and fecal sample collected at baseline were 93.8% and 66.3%, respectively. As of August 31st, 2022, the follow-up rate was 90.0%, 77.0%, 76.5%, and 89.0% for 1-, 3-, 6-, and 12-month follow-ups, respectively. Fall/wrench (47.6%) and traffic accident (26.2%) were the top causes of current trauma. The most common psychopathology at recruitment was sleep disturbance (39.4%), followed by depression (22.6%), anxiety (18.2%), and acute stress reaction (7.8%), all of which showed recovering trajectories during the follow-up period, particularly the first 3 months after baseline. Conclusion: CSTC provides a platform with multidimensional data to study both short-term and long-term trauma-related health consequences, prompting early identification and intervention for individuals with high risk of health decline after trauma exposures.

Background Hearing loss and tinnitus have been proposed as potential indicators of impaired mental health and brain morphological changes. Aims To assess the associations of hearing loss and tinnitus with the risk of depression and anxiety and with brain volume. Method We conducted a community-based cohort study including 129 610 participants aged 40−69 years at recruitment to the UK Biobank with a follow-up period during 2006–2021 to estimate the risk of depression and anxiety after detection of hearing loss and reported tinnitus. We also assessed the associations of hearing loss and tinnitus with brain volume in a subsample with available brain magnetic resonance imaging data (N = 5222). Results We observed an increased risk of depression among individuals with hearing loss (hazard ratio [HR] 1.14, 95% CI 1.03–1.26), tinnitus (HR 1.30, 95% CI 1.21–1.41) or both (HR 1.32, 95% CI 1.15–1.52), compared with individuals with neither hearing loss nor tinnitus. Similar results were noted for anxiety (HR 1.18, 95% CI 1.07–1.30 for hearing loss; HR 1.32, 95% CI 1.22–1.43 for tinnitus; and HR 1.48, 95% CI 1.30–1.68 for both). Hearing loss was associated with decreased overall brain volume as well as decreased volume of different brain regions. The latter associations disappeared after adjustment for whole intracranial volume. Tinnitus was associated with greater left accumbens and right occipital pole volume after adjustment for the whole intracranial volume. Conclusions Individuals with tinnitus are at increased risk of depression and anxiety. Hearing loss, on the other hand, is associated with both mood disorders and altered brain morphology.

Abstract Background and Aims We sought to identify novel molecular subtypes of ulcerative colitis (UC) based on large-scale cohorts and establish a clinically applicable subtyping system for the precision treatment of the disease. Methods Eight microarray profiles containing colon samples from 357 patients were utilized. Expression heterogeneity was screened out and stable subtypes were identified among UC patients. Immune infiltration pattern and biological agent response were compared among subtypes to assess the value in guiding treatment. The relationship between PRLR and TNFSF13B genes with the highest predictive value was further validated by functional experiments. Results Three stable molecular subtypes were successfully identified. Immune cell infiltration analysis defined three subtypes as innate immune activated UC (IIA), whole immune activated UC (WIA), and immune homeostasis like UC (IHL). Notably, the response rate towards biological agents (infliximab/vedolizumab) in WIA patients was the lowest (less than 10%), while the response rate in IHL patients was the highest, ranging from 42 to 60%. Among the featured genes of subtypes, the ratio of PRLR to TNFSF13B could effectively screen for IHL UC subtype suitable for biological agent therapies (Area under curve: 0.961–0.986). Furthermore, we demonstrated that PRLR expressed in epithelial cells could inhibit the expression of TNFSF13B in monocyte-derived macrophages through the CXCL1-NF-κB pathway. Conclusions We identified three stable UC subtypes with a heterogeneous immune pattern and different response rates towards biological agents for the first time. We also established a precise molecular subtyping system and classifier to predict clinical drug response and provide individualized treatment strategies for UC patients.

Background: This study aimed to explore the time-varying impact of COVID-19 on acute kidney disorders, including acute kidney injury and other acute kidney diseases. Methods: From the UK Biobank, 10,121 participants with COVID-19 were matched with up to 3 historically unexposed controls by age, sex, Townsend deprivation index, and the status of hospitalization or receiving critical care. We investigated the association between COVID-19 and incidence of acute kidney disorders, within the first 4 weeks after infection, using conditional and time-varying Cox proportional hazard regression. In addition, one-sample Mendelian randomization, utilizing the polygenic risk score for COVID-19 as an instrumental variable, was conducted to explore the potential causality of the association. Results: In the matched cohort study, we observed a significant association between COVID-19 and acute kidney disorders predominantly within the first 3 weeks. The impact of COVID-19 was time dependent, peaking in the second week (hazard ratio, 12.77; 95% confidence interval, 5.93 to 27.70) and decreasing by the fourth week (hazard ratio, 2.28; 95% confidence interval, 0.75 to 6.93). In subgroup analyses, only moderate to severe COVID-19 cases were associated with acute worsening of renal function in a time-dependent pattern. One-sample Mendelian randomization analyses further showed that COVID-19 might exert a “short-term” causal effect on the risk of acute kidney disorders, primarily confined to the first week after infection. Conclusions: The risk of acute kidney disorders following COVID-19 demonstrates a time-varying pattern. Hazard effects were observed only in patients with moderate or severe but not mild COVID-19.

ABSTRACTParkinson’s disease (PD) is recognized as a multisystem disease concerning gastrointestinal (GI) dysfunction and microbiota dysbiosis. However, the mechanism by which microbial dysbiosis contributes to pathogenesis of PD and the relationship between gut microbes and metabolites remain to be deeply elucidated. This study aims to explore the altered microflora and serum metabolites in PD mice and their role in PD etiology. Herein, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg) was injected intraperitoneally to establish the PD mice model. 16S rRNA sequencing and ultrahigh-performance liquid chromatography coupled with Q Exactive HF-X mass spectrometry were used to depict the profile of gut bacteria and metabolites. Phylogenetic investigation of communities by reconstruction of unobserved states 2 analysis was performed to elucidate the functional link between the microbe-metabolite axis and PD. We confirmed the MPTP-induced dopaminergic (DA) neuron loss accompanied by the GI dysfunction. Higher abundances of Aerococcus, Staphylococcus, and Ruminococcaceae, and lower abundances of Lactobacillus, Lachnospiraceae, and Adlercreutzia were identified in PD mice. Meanwhile, the differential metabolites concerning “taurine and hypotaurine metabolism” were markedly downregulated in PD mice. Furthermore, Lactobacillus, Adlercreutzia, and taurine-related metabolites showed the most significant correlation with pathological and GI performance of PD mice. The abundances of microbial transporter and enzymes participating in the degeneration of taurine were disturbed in PD mice. More importantly, taurine supplement is protected from MPTP-induced motor deficits and DA neuron loss. The detection of disturbed taurine metabolism in PD mice suggests a mechanism whereby dysregulation of the microbiota-metabolism axis contributes to the etiology of MPTP-treated mice.IMPORTANCEPD is recognized as a multisystem disease concerning GI dysfunction and microbiota dysbiosis but still lacks ideal therapies. Recently, aberrant microbiota-derived metabolites are emerging as important participants in PD etiology. However, the alterations of gut microbiota community and serum untargeted metabolite profile have not been fully investigated in a PD mice model. Here, we discover sharply reduced levels of Lactobacillus and taurine in MPTP-treated mice. Moreover, Lactobacillus, Adlercreutzia, and taurine-related metabolites showed the most significant correlation with pathological and GI performance of PD mice. The abundances of microbial transporter and enzymes participating in the degeneration of taurine were disturbed in PD mice. Most importantly, taurine supplement ameliorates MPTP-induced motor deficits, DA neuron loss, and microglial activation. Our data highlight the impaired taurine-based microbiome-metabolism axis during the progression of PD and reveal a novel and previously unrecognized role of genera in modulating taurine metabolism.

Summary: Age-related functional impairments (ARFIs) contribute to the loss of independence in older adults, but their progressions, interrelations, and combined relations with mortality are largely unknown. We conducted a prospective study among 17,914 participants in the Health and Retirement Study (2000–2020). The incidence rates of visual impairment, hearing impairment, physical frailty, and cognitive impairment increased exponentially with age, while those of restless sleep and depression increased relatively slowly. These ARFIs were associated with each other in temporal sequence and constituted a hazard network. We observed a dose-response relationship between the number of ARFIs and mortality risk, and the dyads involving physical frailty demonstrated the strongest associations with mortality. Our findings may assist in the identification of individuals at higher mortality risk and highlight the potential for future investigations to explore the impact of multiple ARFIs in aging.

Epitranscriptome studies have shown that critical RNA modifications drive tumorigenicity; however, the role of 5-methylcytosine (m5C) RNA methylation remains poorly understood. We extracted 17 m5C regulators and clustered distinct m5C modification patterns by consensus clustering analysis. Gene set variation and single-sample gene set enrichment analysis were applied to quantify functional analysis and immune infiltration. The least absolute shrinkage and selection operator was employed to develop a prognostic risk score. Kaplan-Meier with log-rank test was used for survival analysis. Differential expression analysis was performed with the “limma” R package. Wilcoxon signed ranked test or Kruskal-Wallis test was used to compare groups. We observed that m5C RNA methylation was commonly upregulated in gastrointestinal cancer and related to prognosis. Clusters were identified for m5C patterns, with distinct immune infiltrations and functional pathways. The risk scores of m5C regulators were independent risk factors. Differentially expressed mRNAs (DEmRNAs) in m5C clusters were involved in cancer-related pathways. The methylation-based m5Cscore showed a significant effect on the prognosis. Patients with a lower m5Cscore exhibited more therapeutic efficiency on anti-CTLA4 therapy in liver cancer, while the combination of anti-CTLA4 therapy and pd1 was more efficient for patients with a lower m5Cscore in pancreatic cancer. We uncovered dysregulations of m5C-related regulators in gastrointestinal cancer and their associations with overall survival. Some immune cells were differently infiltrated in distinct m5C modification patterns, indicating their potential impacts on gastrointestinal cancer cell-immune. Moreover, an m5Cscore, derived from DEmRNAs in specific clusters, can serve as a classifier for immunotherapy.

Abstract Background To determine whether serum gamma‐glutamyl transpeptidase (GGT) level is associated with pancreatic cancer risk in a large prospective cohort. Methods The study analyzed serum GGT concentration at baseline of 421,032 participants recruited in the UK Biobank since 2006 through 2010. Information on incidence of pancreatic cancer was obtained from cancer and death registers, updated until 2015 in Scotland or 2016 in England and Wales. Adjusted Cox proportional hazards models were used to measure the association between serum GGT and pancreatic cancer risk. Results The study identified 586 cases of pancreatic cancer over a median follow‐up period of 7.16 years. In the multivariable‐adjusted Cox model, serum GGT level was associated with 14% higher pancreatic cancer risk (hazard ratio (HR) per one standard deviation increment of log2 GGT level = 1.14, 95% confidence interval (CI) 1.02–1.28, p = 0.025). In the total population, the HR for the highest GGT group was 1.68 (95%CI: 1.22–2.30) versus the lowest GGT group. The HR for the highest GGT group in men (≥50.2 U/L) was 1.72 (95%CI: 1.14–2.61) and that in women (≥31.6 U/L) was 1.75 (95%CI: 1.06–2.88) versus the lowest GGT group. Conclusion Our findings suggested a positive association of serum GGT in pancreatic cancer etiology, implying the potential of monitoring GGT level for identifying at‐risk individuals for pancreatic cancer.

Abstract Serious concerns have been raised about the negative effects of the COVID-19 pandemic on population psychological well-being. However, limited data exist on the long-term effects of the pandemic on incident psychiatric morbidities among individuals with varying exposure to the pandemic. Leveraging prospective data from the community-based UK Biobank cohort, we included 308,400 participants free of diagnosis of anxiety or depression, as well as 213,757 participants free of anxiolytics or antidepressants prescriptions, to explore the trends in incident diagnoses and drug prescriptions for anxiety and depression from 16 March 2020 to 31 August 2021, compared to the pre-pandemic period (i.e., 1 January 2017 to 31 December 2019) and across populations with different exposure statuses (i.e., not tested for COVID-19, tested negative and tested positive). The age- and sex-standardized incidence ratios (SIRs) were calculated by month which indicated an increase in incident diagnoses of anxiety or depression among individuals who were tested for COVID-19 (tested negative: SIR 3.05 [95% confidence interval 2.88–3.22]; tested positive: 2.03 [1.76–2.34]), especially during the first six months of the pandemic (i.e., March-September 2020). Similar increases were also observed for incident prescriptions of anxiolytics or antidepressants (tested negative: 1.56 [1.47–1.67]; tested positive: 1.41 [1.22–1.62]). In contrast, individuals not tested for COVID-19 had consistently lower incidence rates of both diagnoses of anxiety or depression (0.70 [0.67–0.72]) and prescriptions of respective psychotropic medications (0.70 [0.68–0.72]) during the pandemic period. These data suggest a distinct rise in health care needs for anxiety and depression among individuals tested for COVID-19, regardless of the test result, in contrast to a reduction in health care consumption for these disorders among individuals not tested for and, presumably, not directly exposed to the disease.

Abstract Background Whether a genetic predisposition to psychiatric disorders is associated with coronavirus disease 2019 (COVID-19) is unknown. Methods Our analytic sample consisted of 287,123 white British participants in UK Biobank who were alive on 31 January 2020. We performed a genome-wide association study (GWAS) analysis for each psychiatric disorder (substance misuse, depression, anxiety, psychotic disorder, and stress-related disorders) in a randomly selected half of the study population (“base dataset”). For the other half (“target dataset”), the polygenic risk score (PRS) was calculated as a proxy of individuals’ genetic predisposition to a given psychiatric phenotype using discovered genetic variants from the base dataset. Ascertainment of COVID-19 was based on the Public Health England dataset, inpatient hospital data, or death registers in UK Biobank. COVID-19 cases from hospitalization records or death records were considered “severe cases.” The association between the PRS for psychiatric disorders and COVID-19 risk was examined using logistic regression. We also repeated PRS analyses based on publicly available GWAS summary statistics. Results A total of 143,562 participants (including 10,868 COVID-19 cases) were used for PRS analyses. A higher genetic predisposition to psychiatric disorders was associated with an increased risk of any COVID-19 and severe COVID-19. The adjusted odds ratio (OR) for any COVID-19 was 1.07 (95% confidence interval [CI] 1.02–1.13) and 1.06 (95% CI 1.01–1.11) among individuals with a high genetic risk (above the upper tertile of the PRS) for substance misuse and depression, respectively, compared with individuals with a low genetic risk (below the lower tertile). Slightly higher ORs were noted for severe COVID-19, and similar result patterns were obtained in analyses based on publicly available GWAS summary statistics. Conclusions Our findings suggest a potential role of genetic factors in the observed phenotypic association between psychiatric disorders and COVID-19. Our data underscore the need for increased medical surveillance for this vulnerable population during the COVID-19 pandemic.

Abstract Background Experimental studies indicate that neuroendocrine pathways might play a role in progression of breast cancer. We aim to test the hypothesis that somatic mutations in the genes of neuroendocrine pathways influence breast cancer prognosis, through dysregulated gene expression in tumor tissue. Methods We conducted an extreme case–control study including 208 breast cancer patients with poor invasive disease-free survival (iDFS) and 208 patients with favorable iDFS who were individually matched on molecular subtype from the Breast Cancer Cohort at West China Hospital (WCH; N = 192) and The Cancer Genome Atlas (TCGA; N = 224). Whole exome sequencing and RNA sequencing of tumor and paired normal breast tissues were performed. Adrenergic, glucocorticoid, dopaminergic, serotonergic, and cholinergic pathways were assessed for differences in mutation burden and gene expression in relation to breast cancer iDFS using the logistic regression and global test, respectively. Results In the pooled analysis, presence of any somatic mutation (odds ratio = 1.66, 95% CI: 1.07–2.58) of the glucocorticoid pathway was associated with poor iDFS and a two-fold increase of tumor mutation burden was associated with 17% elevated odds (95% CI: 2–35%), after adjustment for cohort membership, age, menopausal status, molecular subtype, and tumor stage. Differential expression of genes in the glucocorticoid pathway in tumor tissue (P = 0.028), but not normal tissue (P = 0.701), was associated with poor iDFS. Somatic mutation of the adrenergic and cholinergic pathways was significantly associated with iDFS in WCH, but not in TCGA. Conclusion Glucocorticoid pathway may play a role in breast cancer prognosis through differential mutations and expression. Further characterization of its functional role may open new avenues for the development of novel therapeutic targets for breast cancer.

Abstract. Background:. The risk for chronic kidney disease (CKD) is influenced by genetic predisposition, sex, and lifestyle. Previous research indicates that coffee is a potentially protective factor in CKD. The current study aims to investigate whether sex disparity exists in the coffee–CKD association, and whether genetic risk of CKD or genetic polymorphisms of caffeine metabolism affect this association. Methods:. A total of 359,906 participants from the UK Biobank who were enrolled between 2006 and 2010 were included in this prospective cohort study, which aimed to estimate the hazard ratios for coffee intake and incident CKD using a Cox proportional hazard model. Allele scores of CKD and caffeine metabolism were additionally adjusted for in a subsample with qualified genetic data (n = 255,343). Analyses stratified by genetic predisposition, comorbidities, and sex hormones were performed. Tests based on Bayesian model averaging were conducted to ascertain the robustness of the results. Results:. Coffee was inversely associated with CKD in a dose-dependent manner. The effects of coffee did not differ across different strata of genetic risk for CKD, but were more evident among slower genetically predicted caffeine metabolizers. Significant sex disparity was observed (P value for interaction = 0.013), in that coffee drinking was only associated with the risk reduction of CKD in females. Subgroup analysis revealed that testosterone and sex hormone-binding globulin (SHBG), but not estradiol, modified the coffee–CKD association. Conclusions:. In addition to the overall inverse coffee–CKD association that was observed in the general population, we could also establish that a sex disparity existed, in that females were more likely to experience the benefit of the association. Testosterone and SHBG may partly account for the sex disparity.

The massive frost that occurs each year in autumn and spring across subtropical and temperate regions cause severe damage to horticultural crops, therefore, the research for frost formation and estimation of frost amount are important for monitoring and regulation of frost damage. In this study, a predictive model of frost formation on leaf surface with the interaction of wet air phase and frost phase was established by Euler multiphase flow model. According to the variation of phase volume fraction, the evolution process of frost under non-stationary conditions was simulated using Fluent calculations based on leaf surface frosting mechanism. In addition, the influence of different surface temperatures, air velocities and humidity on frost amount were investigated deeply during simulation by building frost amount measurement device combined with microscopic image processing. The results showed that the frost amount increased mainly with decreased surface temperature under time-varying conditions, and reduce the velocity or increase humidity also has a beneficial effect. The estimation of frost thickness fell within confidence intervals up to 90%, with overall deviations in frost mass ranging from −8.4% to 23.8%. Eventually, the model was demonstrated that it could provide an acceptable prediction of frost formation and estimate of frost amount.

Abstract Extensive changes of circRNA expression underscore their essential contributions to multiple hallmarks of cancers; however, their functions and mechanisms of action in esophageal squamous cell carcinoma (ESCC) remain undetermined. Here, we adopted a three-stage approach by first screening for significantly differentially expressed circRNAs in ESCC and performing an external validation study, followed by the functional analyses. The properties of circRNAs were evaluated using Sanger sequencing, RNase R digestion, actinomycin D treatment, subcellular localization analysis, and fluorescence in situ hybridization. Target transcripts were predicted using online tools and verified by dual-luciferase, RNA immunoprecipitation, qRT-PCR, and western blot. Biotin-labeled RNA-protein pull-down, mass spectrometry, and RNA immunoprecipitation were employed to identify proteins interacting with circRNAs. Gain- and loss-of-function experiments were performed to uncover the roles of circRNAs, their target genes, and binding proteins in the proliferation, metastasis, and invasion. We observed that circFAM120B (hsa_circ_0001666) was frequently downregulated in cancer tissues and patient plasma, and its expression level was related to overall survival in ESCC patients. Overexpression of circFAM120B inhibited the proliferation, metastasis, and invasion of ESCC while silencing it enhanced malignant phenotypes. Mechanistically, circFAM120B was predominantly located in the cytoplasm, guarantying its sponging for miR-661 to restore the expression of PPM1L, a tumor suppressor. We observed that circFAM120B could reduce the stability of RNA-dependent protein kinase (PKR) by promoting its ubiquitination-dependent degradation and subsequently regulating the p38 MAPK signaling pathway, resulting in the repression of EMTs in ESCC cells. Our findings suggest that circFAM120B is a promising biomarker of ESCC, which acts as a tumor suppressor via the circFAM120B/miR-661/PPM1L axis and PKR/p38 MAPK/EMT pathway, supporting its significance as a candidate therapeutic target.

Abstract Background Studies investigating breast cancer polygenic risk score (PRS) in Chinese women are scarce. The objectives of this study were to develop and validate PRSs that could be used to stratify risk for overall and subtype-specific breast cancer in Chinese women, and to evaluate the performance of a newly proposed Artificial Neural Network (ANN) based approach for PRS construction. Methods The PRSs were constructed using the dataset from a genome-wide association study (GWAS) and validated in an independent case-control study. Three approaches, including repeated logistic regression (RLR), logistic ridge regression (LRR) and ANN based approach, were used to build the PRSs for overall and subtype-specific breast cancer based on 24 selected single nucleotide polymorphisms (SNPs). Predictive performance and calibration of the PRSs were evaluated unadjusted and adjusted for Gail-2 model 5-year risk or classical breast cancer risk factors. Results The primary PRSANN and PRSLRR both showed modest predictive ability for overall breast cancer (odds ratio per interquartile range increase of the PRS in controls [IQ-OR] 1.76 vs 1.58; area under the receiver operator characteristic curve [AUC] 0.601 vs 0.598) and remained to be predictive after adjustment. Although estrogen receptor negative (ER−) breast cancer was poorly predicted by the primary PRSs, the ER− PRSs trained solely on ER− breast cancer cases saw a substantial improvement in predictions of ER− breast cancer. Conclusions The 24 SNPs based PRSs can provide additional risk information to help breast cancer risk stratification in the general population of China. The newly proposed ANN approach for PRS construction has potential to replace the traditional approaches, but more studies are needed to validate and investigate its performance.

Background: The purpose of this meta-analysis (PROSPERO number: CRD42021243204) is to perform extensive and penetrating analyses on the risk factors associated with reactivation or reinfection. Methods: We searched PubMed and Embase using search terms. Risk factors (including gender, length of time between first onset and recurrent diagnosis, extrapulmonary tuberculosis, sputum smear, pulmonary cavity, Beijing family strains, diabetes, HIV infection, history of imprisonment, and immigration) were analyzed. The pooled risk ratio (RR) and 95% confidence interval (CI) were calculated with STATA 15.1. Heterogeneity was evaluated by I2 and P values. Results: The meta-analysis included 25 studies with a total of 1,477 recurrent patients. After subgroup analysis, sensitivity analysis, and testing for publication bias, it was concluded that time spanning less than two years (RR = 1.56, 95% CI: 1.33-1.85) was a risk factor for endogenous reactivation, whereas coinfection with HIV (RR = 0.72, 95% CI: 0.63-0.83), Beijing family genotype (RR = 0.46, 95% CI: 0.32-0.67), history of imprisonment (RR = 0.36, 95% CI: 0.16-0.81), and immigration (RR = 0.66, 95% CI: 0.53-0.82) were associated with exogenous reinfection. Conclusions: The recurrence interval is a risk factor for the endogenous reactivation of tuberculosis. Infection with Beijing family strains, coinfection with HIV, imprisonment, and immigration contribute to the risk of exogenous reinfection.

Abstract 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.

Enhancing teacher retention in underdeveloped regions of Central and Western China is an important issue for high-quality education development. By investigating 1558 teachers from nine provinces and municipalities in these regions, this study uses quantitative research methods to analyze the relationship between principals’ instructional leadership and teacher retention and introduces a moderated chain-mediated model. The results show that principals’ instructional leadership and teacher retention are at a relatively moderate to high level in these regions. Principals’ instructional leadership not only has direct effect on teacher retention, but also has indirect effects by three paths: through the separate mediating role of role stress, the separate mediating role of affective commitment, and the chain-mediating role of role stress and affective commitment. Teacher gender negatively moderates the relationship between principal’s instructional leadership and teacher role stress. The sample need to be extended to developed areas to form a comparison. Underdeveloped regions of Central and Western China also need to take more action.

Abstract Background An increased susceptibility to COVID-19 has been suggested for individuals with neurodegenerative diseases, but data are scarce from longitudinal studies. Methods In this community-based cohort study, we included 96,275 participants of the UK Biobank who had available SARS-CoV-2 test results in Public Health England. Of these, 2617 had a clinical diagnosis of neurodegenerative diseases in the UK Biobank inpatient hospital data before the outbreak of COVID-19 (defined as January 31st, 2020), while the remaining participants constituted the reference group. We then followed both groups from January 31st, 2020 to June 14th, 2021 for ascertainment of COVID-19 outcomes, including any COVID-19, inpatient care for COVID-19, and COVID-19 related death. Logistic regression was applied to estimate the association between neurogenerative disease and risks of COVID-19 outcomes, adjusted for multiple confounders and somatic comorbidities. Results We observed an elevated risk of COVID-19 outcomes among individuals with a neurodegenerative disease compared with the reference group, corresponding to a fully adjusted odds ratio of 2.47 (95%CI 2.25–2.71) for any COVID-19, 2.18 (95%CI 1.94–2.45) for inpatient COVID-19, and 3.67 (95%CI 3.11–4.34) for COVID-19 related death. Among individuals with a positive test result for SARS-CoV-2, individuals with neurodegenerative diseases had also a higher risk of COVID-19 related death than others (fully adjusted odds ratio 2.08; 95%CI 1.71–2.53). Conclusion Among UK Biobank participants who received at least one test for SARS-CoV-2, a pre-existing diagnosis of neurodegenerative disease was associated with a subsequently increased risk of COVID-19, especially COVID-19 related death.

Abstract Background Elderly care service projects (ECSPs) aim to provide care services with the help of market forces on the supply side to satisfy the huge demand of the elderly. Subsidies play an important role in motivating the investors to invest in the ECSPs immediately. The optimal subsidy scheme should balance the policy costs and the investors’ interests. Methods Based on the policy background of China, this study applied the real options theory to compare the effects of construction subsidy and operating subsidy on achieving policy goals from the perspective of uncertain actual demand. It introduced numerical examples to identify the optimal subsidy scheme and embedded the data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) to verify the uncertainty of actual demand. Results The results showed that in the context of uncertain actual demand, operating subsidy has greater advantages in reducing investment thresholds, saving subsidy costs and increasing spillover values. Moreover, a sound quality supervision system, a differentiated operating subsidy scheme and a sustainable growth market demand environment are conducive to increasing the long-term interests of the government and the investors. Conclusions The study emphasized the importance of subsidy selection in the context of uncertain actual demand, and provided a practical reference for policy designers in China and other developing countries to choose the optimal subsidy scheme for the ECSPs.

BackgroundSuicidal behaviors, including suicide deaths and attempts, are major public health concerns. However, previous suicide models required a huge amount of input features, resulting in limited applicability in clinical practice. ObjectiveWe aimed to construct applicable models (ie, with limited features) for short- and long-term suicidal behavior prediction. We further validated these models among individuals with different genetic risks of suicide. MethodsBased on the prospective cohort of UK Biobank, we included 223 (0.06%) eligible cases of suicide attempts or deaths, according to hospital inpatient or death register data within 1 year from baseline and randomly selected 4460 (1.18%) controls (1:20) without such records. We similarly identified 833 (0.22%) cases of suicidal behaviors 1 to 6 years from baseline and 16,660 (4.42%) corresponding controls. Based on 143 input features, mainly including sociodemographic, environmental, and psychosocial factors; medical history; and polygenic risk scores (PRS) for suicidality, we applied a bagged balanced light gradient-boosting machine (LightGBM) with stratified 10-fold cross-validation and grid-search to construct the full prediction models for suicide attempts or deaths within 1 year or between 1 and 6 years. The Shapley Additive Explanations (SHAP) approach was used to quantify the importance of input features, and the top 20 features with the highest SHAP values were selected to train the applicable models. The external validity of the established models was assessed among 50,310 individuals who participated in UK Biobank repeated assessments both overall and by the level of PRS for suicidality. ResultsIndividuals with suicidal behaviors were on average 56 years old, with equal sex distribution. The application of these full models in the external validation data set demonstrated good model performance, with the area under the receiver operating characteristic (AUROC) curves of 0.919 and 0.892 within 1 year and between 1 and 6 years, respectively. Importantly, the applicable models with the top 20 most important features showed comparable external-validated performance (AUROC curves of 0.901 and 0.885) as the full models, based on which we found that individuals in the top quintile of predicted risk accounted for 91.7% (n=11) and 80.7% (n=25) of all suicidality cases within 1 year and during 1 to 6 years, respectively. We further obtained comparable prediction accuracy when applying these models to subpopulations with different genetic susceptibilities to suicidality. For example, for the 1-year risk prediction, the AUROC curves were 0.907 and 0.885 for the high (>2nd tertile of PRS) and low (

Introduction: Bu-Fei-Huo-Xue capsule (BFHX) has been used to treat pulmonary fibrosis (PF) in clinic. However, the mechanism of Bu-Fei-Huo-Xue capsule on pulmonary fibrosis remains unclear. Recent studies have shown that the changes in gut microbiota were closely related to the progression of pulmonary fibrosis. Modulating gut microbiota provides new thoughts in the treatment of pulmonary fibrosis.Methods: In this study,a mouse model of pulmonary fibrosis was induced using bleomycin (BLM) and treated with Bu-Fei-Huo-Xue capsule. We firstly evaluated the therapeutic effects of Bu-Fei-Huo-Xue capsule on pulmonary fibrosis model mice. Besides,the anti-inflammatory and anti- oxidative effects of Bu-Fei-Huo-Xue capsule were evaluated. Furthermore, 16S rRNA sequencing was used to observe the changes in gut microbiota in pulmonary fibrosis model mice after Bu-Fei-Huo-Xue capsule treatment.Results: Our results showed that Bu-Fei-Huo-Xue capsule significantly reduced the collagen deposition in pulmonary fibrosis model mice. Bu-Fei-Huo-Xue capsule treatment also reduced the levels and mRNA expression of pro-inflammatory cytokines and inhibited the oxidative stress in lung. 16S rRNA sequencing showed that Bu-Fei-Huo-Xue capsule affected the diversity of gut microbiota and the relative abundances of gut microbiota such as Lactobacillus, Lachnospiraceae_NK4A136_group, and Romboutsia.Conclusion: Our study demonstrated the therapeutic effects of Bu-Fei-Huo-Xue capsule on pulmonary fibrosis. The mechanisms of Bu-Fei-Huo-Xue capsule on pulmonary fibrosis may be associated with regulating gut microbiota.

Both autophagy and apoptosis are mechanisms that maintain homeostasis in cells and that play essential roles in viral infections. Previous studies have demonstrated that autophagy and apoptosis pathways occurred with complex relationships in virus-infected cells. However, the regulation between these two processes in Pseudorabies virus (PRV) infection remains unclear. In the present study, we demonstrated that activated autophagy was induced at the early stage of PRV infection and that apoptosis was induced at the late stage of infection. Autophagy induction inhibited apoptosis and decreased viral replication, and autophagy inhibition promoted apoptosis and increased viral replication. We also found that viral infection resulted in an increase in the production of reactive oxygen species (ROS) and activation of apoptosis in autophagy-impaired cells, suggesting that ROS may participate in the cross-talk between autophagy and apoptosis in PRV-infected cells. Our studies provide possible molecular mechanisms for the cross-talk between apoptosis and autophagy induced by PRV infection in porcine cells. This suggests that these two cell death processes should be considered as the same continuum rather than as completely separate processes.

With the application and development of UAV technology and navigation and positioning technology, higher requirements are put forward for UAV maneuvering obstacle avoidance ability and real-time route planning. In this paper, for the problem of real-time UAV route planning in the unknown environment, we combine the ideas of artificial potential field method to modify the state observation and reward function, which solves the problem of sparse rewards of reinforcement learning algorithm, improves the convergence speed of the algorithm, and improves the generalization of the algorithm by step-by-step training based on the ideas of curriculum learning and transfer learning according to the difficulty of the task. The simulation results show that the improved SAC algorithm has fast convergence speed, good timeliness and strong generalization, and can better complete the UAV route planning task.

Abstract 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.

Objectives Given the role of intraocular pressure in glaucoma, the patient’s sleeping pattern might contribute to the development and progression of glaucoma. We performed a study to understand the association between sleep behaviours and glaucoma.Design Our study was a prospective cohort study.Setting This was a prospective cohort study in the UK Biobank. Self-reported data on five sleep behaviours were collected using a questionnaire at baseline. We identified four sleep patterns based on a cluster analysis of the sleep behaviours.Participants In the UK Biobank, 409 053 participants were recruited between 2006 and 2010 and followed for a diagnosis of glaucoma. We identified glaucoma as any hospital admission with a diagnosis of glaucoma, based on UK Biobank inpatient hospital data. Individuals who withdrew from the UK Biobank, or were diagnosed with glaucoma before recruitment, or had self-reported surgery or laser treatment for glaucoma, or had no information on sleep behaviors were excluded.Primary and secondary outcome measures We estimated hazard ratios (HRs) with 95% confidence intervals (CI) using Cox proportional hazards models to estimate the associations of different sleep behaviors, as well as identified sleep patterns, with the risk of glaucoma, adjusting for multiple confounders.Results Compared with individuals who had a healthy sleep pattern, an excess risk of any glaucoma was observed among individuals with snoring and daytime sleepiness (HR 1.11, 95% CI 1.03 to 1.19) or insomnia and short/long sleep duration (HR 1.13, 95% CI 1.06 to 1.20), but not late chronotype sleep pattern (HR 0.98, 95% CI 0.93 to 1.03).Conclusion Snoring, daytime sleepiness, insomnia, and short/long duration, individually or jointly, were all associated with the risk of glaucoma. These findings underscore the need for sleep intervention for individuals at high risk of glaucoma as well as potential ophthalmologic screening among individuals with chronic sleep problems for glaucoma prevention.

Background: The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated. Methods: We identified 869,056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910,178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N = 8,690,560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls. Results: The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to 30 years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6, and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62–2.87) and thereafter (1.45; 95% CI, 1.42–1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR, 1.55; 95% CI, 1.44–1.67). Conclusions: Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed CVD patients. Funding: This work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, grant no. 847776 to UV, PFS, and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no. 726413 to UV), Swedish Research Council (grant no. D0886501 to PFS), and US NIMH R01 MH123724 (to PFS).

Summary: Background: Prior research provides suggestive evidence on an association between stress-related disorders and mortality. No previous study has however addressed the role of familial confounding on such association. Methods: We conducted a nationwide cohort study of 189,757 individuals with a first-onset stress-related disorder between January 1, 1981 and December 31, 2016 in Sweden (i.e., exposed patients), 1,896,352 matched unexposed individuals, and 207,479 unaffected full siblings of the exposed patients. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and cause-specific mortality. Findings: During a mean follow-up of 9.42 years, an elevated risk of all-cause mortality was observed during the entire follow-up among patients with stress-related disorders, compared with either unexposed individuals or their unaffected full siblings. Such excess risk was most pronounced within the first year after diagnosis of stress-related disorders (HR, 3.19 [95% CI, 2.87-3.54] in population-based comparison; HR, 3.21 [95% CI, 2.56-4.02] in sibling-based comparison). The excess risk decreased but remained statistically significant thereafter (HR, 1.64 [95% CI, 1.60-1.67] in population-based comparison; HR, 1.61 [95% CI, 1.54-1.68] in sibling-based comparison). An increased risk was observed for almost all cause-specific mortality, with greater risk increase for deaths from unnatural causes, especially suicide, and potentially avoidable causes. Interpretation: Stress-related disorders were associated with an increased risk of all-cause mortality and multiple cause-specific mortality, and the risk elevation was independent of familial confounding. The excess mortality attributable to unnatural causes and potentially avoidable causes highlights the importance of clinical surveillance of major health hazards among patients with stress-related disorders. Funding: EU Horizon 2020 Research and Innovation Action Grant, 1.3.5 Project for Disciplines of Excellence at West China Hospital of Sichuan University, National Natural Science Foundation of China, Icelandic Research Fund (Grant of Excellence), ERC Consolidator Grant, and Swedish Research Council.

Background: The Global Health Security (GHS) Index has been developed to measure a country’s capacity to cope with a public health emergency; however, evidence for whether it corresponds to the response to a global pandemic is lacking. This study performed a multidimensional association analysis to explore the correlation between the GHS Index and COVID-19-associated morbidity, mortality, and disease increase rate (DIR) in 178 countries (regions). Methods: The GHS Index and COVID-19 pandemic data – including total cases per million (TCPM), total deaths per million (TDPM), and daily growth rate – were extracted from online databases. The Spearman correlation coefficient was applied to describe the strength of the association between the GHS Index, sociological characteristics, and the epidemic situation of COVID-19. DIRs were compared, and the impact of the GHS Index on the DIR by the time of “lockdown” was visualized. Results: The overall GHS Index was positively correlated with TCPM and TDPM, with coefficients of 0.34 and 0.41, respectively. Countries categorized into different GHS Indextiers had different DIRs before implementing lockdown measures. However, no significant difference was observed between countries in the middle and upper tiers after implementing lockdown measures. The correlation between GHS Index and DIR was positive five days before lockdown measures were taken, but it became negative 13 days later. Conclusions: The GHS Index has limited value in assessing a country's capacity to respond to a global pandemic. Nevertheless, it has potential value in determining the country’s ability to cope with a local epidemic situation.

Abstract Background Government procurement of elderly care services from market-oriented private providers has become an important way to respond to the growing demands of elderly care. However, the government cannot accurately identify the actual quality efforts of these providers, and the government pursues social benefits while the providers pursue economic interests. The existence of asymmetric information and goal divergence increases the quality risk of services. From the perspective of maximizing the government’s net benefits, this study aimed to analyze how to reduce the quality risk through ex ante policy design. Methods On the basis of the principal-agent theory, this study defined the asymmetric information of market-oriented private providers’ efforts on quality as a random variable, and constructed the theoretical model in the case of asymmetric information to compare with the one in the reference case of complete information, in both of which the government is the principal and market-oriented private providers are the agents. And the models also introduced several parameters to describe key factors that affect the contract results, including the physical health of the elderly, the spillover benefits to the government and market-oriented private providers, and the market risks. Results The optimal results of the models in the two cases were obtained respectively, and the validity of the theoretical models was verified in a numerical example. Taking the case of complete information as the basic frame of reference, the difference of the optimal results in both cases showed the extent of negative impacts of asymmetric information, and highlighted the role of ex ante policy design in minimizing asymmetric information and reducing its negative impacts. Some ex ante policies that can improve the supervision of market-oriented private providers and their quality efforts, as well as have positive effects on key factors, were also recommended. Conclusions The government should attach importance to ex ante policy design to reduce the quality risk of elderly care services supplied by market-oriented private providers in government procurement. Our study provides main framework and critical directions for ex ante policy design, which is conducive to the realization of real and sustained quality improvement.

Objectives To assess the trends in medication use indicative of physical and psychological morbidity following the 2010 volcanic eruption in Eyjafjallajökull immediately after and during a 3-year period following the eruption.Design Population-based register study.Setting Eyjafjallajökull eruption in Iceland, 2007–2013.Participants All residents in Iceland who received at least one medication dispensing were identified. Residents of exposed areas were classified into exposure groups (individual-level data) and residents in other parts of Iceland were included as a non-exposed group (aggregated data).Intervention/exposure Eyjafjallajökull erupted on 14 April 2010 and continued for 39 days, producing heavy ash fall in South Iceland.Main outcome measures Using interrupted time series analysis, we examined annual and quarterly changes in medicine use, measured as number of dispensed defined daily dose (DDD) per 1000 individuals. We calculated the level shift (immediate change) and change in slope from pre-eruption to post-eruption (long-term change) in medication dispensing.Results Among exposed residents, there was a 6% decrease (95% CI -7% to -4%) in the annual number of dispensed DDDs 1-year post-eruption in the overall medication class, including analgesics (−5%, 95% CI -6% to -3%), hypnotics and sedatives (−9%, 95% CI -11% to -7%) and respiratory medications (−7%, 95% CI -9% to -5%; −8%, 95% CI -11% to -4%). Simultaneously, there was a 9% decrease (95% CI -14% to -4%) in the overall medication class among non-exposed residents. Moreover, among exposed residents, we observed change in slope of −4% (95% CI -7% to -1%) in the overall medication class, including for analgesics (−6%, 95% CI -8% to -3%) and other respiratory drugs (−10%, 95% CI -16% to -4%).Conclusion Our findings indicate that the eruption did not lead to increases in medication dispensing among residents of exposed areas, rather decreases for some medicine classes. The results should be interpreted with caution since the content of each eruption differs.

BackgroundTuberculosis (TB) infection interferes with the health-related quality of life (HRQOL), including physical, social, mental, emotional and financial domains of individuals. The goal of this scoping review is to outline the most frequent mental issues encountered by TB patients and evaluate the effects of mental health on TB treatment outcomes. Our findings identify research gaps that could help bridge the overall treatment outcomes in the near future.MethodA systematic stepwise approach was adopted to search online resource databases like PubMed, Web of science, and gray literature to retrieve published scientific articles for the review. Titles and abstracts of selected studies were examined for their possible eligibility. The studies matching our eligibility criteria were taken into account for this scoping review.ResultsOne hundred and ninety three articles were retrieved out of which 26 met the final inclusion criteria. We found that studies adopting interventional approaches reported good mental wellbeing outcomes and better medical compliance as compared with studies that just investigated the subjects. The data represented 15 countries including three low-income countries (LICs), four low-middle-income-countries (LMICs), seven upper-middle-income countries (UMICs), and one high-income country (HIC).ConclusionDepression, anxiety, and poor social support, and stigma affect the wellbeing of individuals across the globe irrespective of age, race, demographic characteristics, geographical location, and social status.

BackgroundThe association between hyperuricemia/gout with cardiovascular diseases (CVD) have been investigated. However, whether the magnitude of associations differs between hyperuricemia and gout, and the causality of these associations, remains inconclusive.MethodsBased on UK Biobank, we conducted a cohort analysis including 431,967 participants, who were categorized as gout, hyperuricemia, and normal groups at recruitment, and followed up for CVD until December 2019. The phenotypic association of hyperuricemia/gout with CVD was estimated by Cox regression, adjusting for multiple confounders. Further exploration on the causality of such links was performed using Mendelian Randomization (MR) analysis, where we selected exclusive genetic variants for hyperuricemia and for gout based on summary GWAS data from independent populations.ResultsDuring mean 10.20 years of follow-up, hyperuricemia patients were associated with increased CVD (HR = 1.33, 95% CI: 1.29–1.36), compared to individuals who were free of hyperuricemia/gout. The risk elevation was even higher for gout patients (HR = 1.54, 95% CI: 1.48–1.62). Furthermore, we found significantly positive association between genetic liability for hyperuricemia and CVD in both one-sample (OR = 1.06, 95% CI: 1.02–1.11) and two-sample (OR = 1.09, 95% CI: 1.03–1.16) MR analysis. However, genetic liability for gout was not associated with CVD (OR = 0.89, 95% CI: 0.79–1.01 in one-sample, and OR = 0.92, 95% CI: 0.82–1.21 in two-sample MR analysis).ConclusionIndividuals with hyperuricemia/gout were at increased risk of various types of CVD. As the MR analyses suggest a causal effect of hyperuricemia, but not gout, on CVD, these results indicate the possible effects of other gout-associated factors on the development of CVD, in addition to the uric acid pathway.