Search

Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n = 130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n = 33,735). We found brain volumetric phenotypes share substantial genetic variants (74–96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and (3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest that altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development. acceptedVersion

Low vitamin D (vitD) levels have been consistently reported in schizophrenia (SCZ) suggesting a role in the etiopathology. However, little is known about the role of underlying shared genetic mechanisms. We applied a conditional/conjunctional false discovery rate approach (FDR) on large, nonoverlapping genome-wide association studies for SCZ (N cases = 53 386, N controls = 77 258) and vitD serum concentration (N = 417 580) to evaluate shared common genetic variants. The identified genomic loci were characterized using functional analyses and biological repositories. We observed cross-trait SNP enrichment in SCZ conditioned on vitD and vice versa, demonstrating shared genetic architecture. Applying the conjunctional FDR approach, we identified 72 loci jointly associated with SCZ and vitD at conjunctional FDR

Background and aim Schizophrenia (SCZ) and bipolar disorder (BD) have a high comorbidity of alcohol use disorder (AUD), and both comorbid AUD and excessive alcohol consumption (AC) have been linked to greater illness severity. We aimed to identify genomic loci jointly associated with SCZ, BD, AUD and AC to gain further insights into their shared genetic architecture. Design We analysed summary data (P values and Z scores) from genome-wide association studies (GWAS) using conjunctional false discovery rate (conjFDR) analysis, which increases power to discover shared genomic loci. We functionally characterized the identified loci using publicly available biological resources. Setting AUD and AC data provided by the Million Veteran Program, derived from the United States Department of Veterans Affairs Healthcare System. SCZ and BD data provided by the Psychiatric Genomics Consortium, based on cohorts from countries in Europe, North America and Australia. Participants AUD (34 658 cases, 167 346 controls), AC (n = 200 680), SCZ (31 013 cases and 38 918 controls), BD (20 352 cases and 31 358 controls). All participants were of European ancestry. Measurements Genomic loci shared between alcohol traits, SCZ and BD at conjFDR

Objective Autism Spectrum Disorder (ASD) is a highly heritable condition with a large variation in cognitive function. Here we investigated the shared genetic architecture between cognitive traits (intelligence (INT) and educational attainment (EDU)), and risk loci jointly associated with ASD and the cognitive traits. Methods We included data from genome-wide association studies (GWAS) of INT (n = 269,867), EDU (n = 766,345) and ASD (cases n = 18,381, controls n = 27,969). We used the bivariate causal mixture model (MiXeR) to estimate the total number of shared genetic variants, and conditional and conjunctional false discovery rate (cond/conjFDR) to identify specific overlapping loci. Results The MiXeR indicated 12.7k genetic variants associated with ASD, with 12.0k shared with EDU and 11.1k shared with INT (Dice: 0.90–0.91), with both positive and negative relationships within overlapping variants. The majority (59%-68%) of estimated shared loci have concordant effect directions, with a positive, albeit modest, genetic correlation between ASD and EDU (rg=0.21, p = 2e-13) and INT (rg=0.22, p = 4e-12). We discovered 43 loci jointly associated with ASD and cognitive traits (conjFDR

Personality and cognition are heritable mental traits, and their genetic determinants may be distributed across interconnected brain functions. However, previous studies have employed univariate approaches which reduce complex traits to summary measures. We applied the “pleiotropy-informed” multivariate omnibus statistical test (MOSTest) to genome-wide association studies (GWAS) of 35 item and task-level measures of neuroticism and cognition from the UK Biobank (n=336,993). We identified 431 significant genetic loci and found evidence of abundant pleiotropy across personality and cognitive domains. Functional characterisation implicated genes with significant tissue-specific expression in all tested brain tissues and enriched in brain-specific gene-sets. We conditioned independent GWAS of the Big 5 personality traits and cognition on our multivariate findings, which boosted genetic discovery in other personality traits and improved polygenic prediction. These findings advance our understanding of the polygenic architecture of complex mental traits, indicating a prominence of pleiotropic genetic effects across higher-order domains of mental function.Graphical abstract

This cross‐sectional and longitudinal descriptive analysis aimed to track the evolving landscape of global immuno‐oncology (IO) trials and provide insight into the resolution of IO‐related controversies. Clinical trials (n = 4510) registered on ClinicalTrials.gov in 2007 to 2019 studying immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), cancer vaccines and immune modulators were included. Most of IO trials are Phase 2 and focus on ICIs and multiple IO therapies. The United States leads global IO research, with stable growth and the best methodological quality. Mainland China ranks first in the number of ACT trials but has the lowest article publication rate (6.2%). A multiple‐arm comparative design is often adopted in multiple IO therapies trials (44.0%). Trials studying ICIs and multiple IO therapies are likely to use early registration (80.0% and 86.6%) and stringent corticosteroid‐/infection‐related criteria. Hospitals have provided the most extensive and strongest support for all IO categories. Big pharma prefers to fund Phase 3‐4 ICI trials (6.98%), while small pharma has a wider sponsorship favoring Phase 1‐2 trials. The “partial‐use‐of‐corticosteroids” strategy is generally well accepted in ICI trials with a definitive trend (32.5%; P, What's new? In recent decades, immunotherapy has emerged and advanced to become a key part of cancer‐fighting strategies. The rapid growth of immuno‐oncology, however, has been accompanied by controversy in suitable interventions and trial design. In this cross‐sectional and longitudinal analysis, disparities in design were found to be common in immuno‐oncology trials, with differences influenced by factors such as cancer type and trial sponsor. Trials with strict limitations on corticosteroid use had significantly higher publications rates than trials permitting partial corticosteroid administration. The data further suggest that timely publication of immuno‐oncology trials is the third year after trial completion.

Frontline power grid workers are always facing plenty of stressors such as aerial work and high job demands, which may lead them to be less satisfied with their job. Therefore, this study aims to investigate frontline power grid workers’ job satisfaction (JS) and explore how it can be improved by its relationship with personality traits and work–family support (WFS). Data from 535 frontline power grid workers were collected from two power supply bureaus in Guangdong Province, China. Structural equation modeling (SEM) was adopted to examine the structural relationship between personality traits taken as independent variables, JS as dependent variable, and WFS as mediator. The bootstrap method was used to test the significance of indirect effects. Results suggested the overall job satisfaction of our sample is 3.34 ± 0.55 on a scale ranging from 1 to 5, and significantly correlated with personality traits and WFS. Moreover, the results of SEM and bootstrap indicated that WFS partially mediates the effect of neuroticism on JS and fully mediates the effect of conscientiousness and extraversion on JS. These findings shed light on how personality traits and environmental factors jointly impact JS and highlight the important role of WFS among frontline power grid workers.

Background Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive impairment. The aggregation of amyloid β (Aβ) and hyperphosphorylated tau protein are two major pathological features of AD. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) has been indicated in Aβ pathology; however, whether and how it affects tau pathology are not yet clear. Methods The role of NOX2 in cognitive function, amyloid plaque formation, and tau hyperphosphorylation were examined in APP/PS1 transgenic mice mated with p47phox-deficient mice (with deletion of the gene of neutrophil cytosolic factor 1, Ncf1) and/or in p47phox-deficient mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ). The cognitive and non-cognitive functions in these mice were assessed by Morris water maze, Rotarod test, open field, and elevated plus maze. Aβ levels, amyloid plaques, p47phox expression, and astrocyte activation were evaluated using immunofluorescence staining, ELISA, and/or Western blotting. Cultured primary neuronal cells were treated with okadaic acid or conditioned media (CM) from high glucose-stimulated primary astrocytes. The alteration in tau pathology was determined using Western blotting and immunofluorescence staining. Results Deletion of the gene coding for p47phox, the organizer subunit of NOX2, significantly attenuated cognitive impairment and tau pathology in these mice. p47phox deficiency decreased the activation of astrocytes but had no effect on Aβ levels and amyloid plaque formation in the brains of aged APP/PS1 mice, which displayed markedly increased expression of p47phox in neurons and astrocytes. Cell culture studies found that neuronal p47phox deletion attenuated okadaic acid-induced tau hyperphosphorylation at specific sites in primary cultures of neurons. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in primary neurons, whereas this effect was absent from p47phox-deficient astrocytes. Conclusions These results suggest that p47phox is associated with cognitive function and tau pathology in AD. p47phox expressed in neurons contributes to tau hyperphosphorylation directly, while p47phox in astrocytes affect tau hyperphosphorylation by activating astrocytes indirectly. Our results provide new insights into the role of NOX2 in AD and indicate that targeted inhibition of p47phox may be a new strategy for the treatment of AD.

Recent genome-wide association studies of mood instability (MOOD) have found significant positive genetic correlation with major depression (DEP) and weak correlations with other psychiatric disorders. We investigated the polygenic overlap between MOOD and psychiatric disorders beyond genetic correlation to better characterize putative shared genetic determinants. GWAS summary statistics for schizophrenia (SCZ, n = 105,318), bipolar disorder (BIP, n = 413,466), DEP (n = 450,619), attention-deficit hyperactivity disorder (ADHD, n = 53,293), and MOOD (n = 363,705) were analyzed using the bivariate causal mixture model and conjunctional false discovery rate methods. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (rg = 0.10–0.62). Of 10.4 K genomic variants influencing MOOD, 4 K–9.4 K influenced psychiatric disorders. Furthermore, MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25. Fifty-three jointly associated loci were overlapping across two or more disorders, seven of which had discordant effect directions on psychiatric disorders. Genes mapped to loci associated with MOOD and all four disorders were enriched in a single gene-set, “synapse organization.” The extensive polygenic overlap indicates shared molecular underpinnings across MOOD and psychiatric disorders. However, distinct patterns of genetic correlation and effect directions may relate to differences in the core clinical features of each disorder. publishedVersion

Brain morphology has been shown to be highly heritable, yet only a small portion of the heritability is explained by the genetic variants discovered so far. Here we extended the Multivariate Omnibus Statistical Test (MOSTest) and applied it to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) cortical measures from N = 35,657 participants in the UK Biobank. We identified 695 loci for cortical surface area and 539 for cortical thickness, in total 780 unique genetic loci associated with cortical morphology robustly replicated in 8,060 children of mixed ethnicity from the Adolescent Brain Cognitive Development (ABCD) Study (R). This reflects more than 8-fold increase in genetic discovery at no cost to generalizability compared to the commonly used univariate GWAS methods applied to region of interest (ROI) data. Functional follow up including gene-based analyses implicated 10% of all protein-coding genes and pointed towards pathways involved in neurogenesis and cell differentiation. Power analysis indicated that applying the MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional univariate GWAS approaches. The large boost in power obtained with the vertex-wise MOSTest together with pronounced replication rates and highlighted biologically meaningful pathways underscores the advantage of multivariate approaches in the context of highly distributed polygenic architecture of the human brain.

Pathologic features of Alzheimer's disease (AD) include accumulation of amyloid β (Aβ) and hyperphosphorylated tau protein. We have shown previously that the chemokine-like receptor 1 (CMKLR1) is a functional receptor for Aβ, and CMKLR1 contributes to the uptake of Aβ. However, it is unclear whether CMKLR1 ameliorates or aggravates the process of AD. Here, we show that deletion of the gene coding for CMKLR1 significantly increased Aβ deposits in brains of both male and female amyloid β precursor protein/presenilin-1 mice. However, it markedly decreased the mortality of these mice. Behavioral studies found that CMKLR1 deficiency improved cognitive impairment of male and female amyloid β precursor protein/presenilin-1 mice and intracerebroventricular-streptozotocin injection AD mice. We further explored the effect of CMKLR1 on tau pathology. We found that CMKLR1 deficiency or inhibition attenuated the hyperphosphorylation of tau in brains of AD mice in vivo and in the neuronal cells in vitro. The expression of CMKLR1 on the neurons affected tau phosphorylation by participating in tau seeding. Together, these results uncover a novel mechanism of CMKLR1 in the pathologic process of AD and suggest that inhibiting the promotion effect of CMKLR1 on tau seeding may provide a new strategy for the treatment of AD. SIGNIFICANCE STATEMENT Evidence suggests that inflammation is involved in the pathologic progression of AD. The chemokine-like receptor 1 (CMKLR1), belonging to the family of GPCRs, is able to bind and uptake amyloid β. We show here, for the first time, that, although CMKLR1 deficiency increased amyloid β deposits in AD mice, it reduced the mortality and improved the cognitive deficits of AD mice. We furthermore show that CMKLR1 deficiency or inhibition attenuated tau hyperphosphorylation in brains of AD model mice in vivo and in neuronal cells in vitro. Finally, we first discovered that the expression of CMKLR1 on neurons affected tau phosphorylation by participating in tau seeding. These findings suggest that inhibition of CMKLR1 may provide a new strategy for the treatment of AD.

Background We studied patients with coronavirus disease 2019 (COVID-19) infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that originated in Wuhan, China, and is spreading over the country including Jiangsu Province. We studied the clinical characteristics and therapies of severe cases in Jiangsu Province. Methods A multicenter retrospective cohort study was conducted to analyze clinical, laboratory data and treatment of 60 severe cases with COVID-19 infection in Jiangsu Province between January 24, 2020 and April 20, 2020. The improvement and deterioration subgroups were compared to identify predictors of disease progression. Results A total of 653 infected cases with COVID-19 were reported in Jiangsu Province, of which 60 severe cases were included in this study. Up until April 20, 2020, the mortality of severe patients was 0%. The median age was 57 years. The average body mass index (BMI) of these patients was 25 kg/m². White blood cell counts decreased in 45.0% of patients, lymphopenia in 63.3%, thrombocytopenia in 13.3%, and procalcitonin levels in 88.3% of the patients were less than 0.5 ng/mL. There were no statistically significant differences in immunoglobulin therapy and glucocorticoids therapy between the improvement and deterioration subgroups. Logistic regression analysis identified higher levels of troponin T (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.00-1.08; P=0.04), antiviral therapy with aerosol inhalation of interferon (OR: 6.33; 95% CI: 1.18-33.98; P=0.03), and the application of non-invasive mechanical ventilation (OR: 1.99; 95%CI: 1.17-3.41; P=0.01) as predictors of disease progression, whereas higher lymphocyte count (OR: 0.11; 95% CI: 0.02-0.57; P=0.01) and early prone ventilation were associated with improvement (OR: 0.11; 95% CI: 0.01-0.98; P=0.04). Conclusions COVID-19 infection had a low mortality rate in Jiangsu Province, China. The higher levels of troponin T and lower lymphocyte count were predictors of disease progression. Early prone ventilation may be an effective treatment for severe cases.

In this paper we introduce a method for solving linear and nonlinear scattering problems for wave equations using a new hybrid approach. This new approach consists of a reformulation of the governing equations into a form that can be solved by a combination of a domain-based method and a boundary-integral method.Our reformulation is aimed at a situation where we have a collection of compact scattering objects located in an otherwise homogeneous unbounded space. The domain-based method is used to propagate the equations governing the wave field inside the scattering objects forward in time. The boundary integral method is used to supply the domain-based method with the required boundary values for the wave field. In this way the best features of both methods come into play; the response inside the scattering objects, which can be caused by both material inhomogeneity and nonlinearities, is easily taken into account using the domain-based method, and the boundary conditions supplied by the boundary integral method makes it possible to confine the domain based method to the inside of each scattering object., Comment: 31 pages, 5 figures

Background The psychometric properties of the simplified Chinese version of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) have not been assessed. Therefore, we aimed to assess its validity, reliability, and responsiveness. Patients and methods A Chinese version of the PRO-CTCAE and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) were distributed to 1580 patients from four cancer hospitals in China. Validity assessments included construct validity, measured by Pearson’s correlations and confirmatory factor analysis (CFA), and known-groups validity, measured by t-tests. The assessment of reliability included internal consistency, measured by Cronbach’s ɑ, and test-retest reliability, measured by the intraclass correlation (ICC). Responsiveness was assessed by standardized response means (SRMs). Results Data from 1555 patients who completed the instruments were analyzed. The correlations were high between PRO-CTCAE items and parallel QLQ-C30 symptom scales (r > 0.60, p r = 0.49). Moreover, CFA showed the PRO-CTCAE structure was a good fit with the data (Root Mean Square Error of Approximation = 0.046). Known-groups validity was also confirmed. Cronbach’s ɑ of all item clusters were greater than 0.9 and the median test-retest reliability coefficients of the 38 items were 0.85 (range = 0.71–0.91). In addition, the SRMs of PRO-CTCAE items were greater than 0.8, indicating strong responsiveness. Conclusion The simplified Chinese version of the PRO-CTCAE showed good reliability, validity, and responsiveness.

Mood instability (MOOD) is a transdiagnostic phenomenon with a prominent neurobiological basis. Recent genome-wide association studies found significant positive genetic correlation between MOOD and major depression (DEP) and weak correlations with other psychiatric disorders. We investigated the polygenic overlap between MOOD and psychiatric disorders beyond genetic correlation to better characterize putative shared genetic determinants. Summary statistics for schizophrenia (SCZ, n=105,318), bipolar disorder (BIP, n=413,466), DEP (n=450,619), attention-deficit hyperactivity disorder (ADHD, n=53,293) and MOOD (n=363,705), were analysed using the bivariate causal mixture model and conjunctional false discovery rate methods to estimate the proportion of shared variants influencing MOOD and each disorder, and identify jointly associated genomic loci. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (rg=0.10-0.62). Of 10.4K genomic variants influencing MOOD, 4K-9.4K were estimated to influence psychiatric disorders. MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25, with consistent genetic effects in independent samples. Fifty-three jointly associated loci were overlapping across two or more disorders (transdiagnostic), seven of which had discordant effect directions on psychiatric disorders. Genes mapped to loci associated with MOOD and all four disorders were enriched in a single gene-set, “synapse organization”. The extensive polygenic overlap indicates shared molecular underpinnings across MOOD and psychiatric disorders. However, distinct patterns of genetic correlation and effect directions of shared loci suggest divergent effects on corresponding neurobiological mechanisms which may relate to differences in the core clinical features of each disorder.

Anthocyanins play vital roles in plant stress tolerance and growth regulation. Previously, we reported that the photomorphogenesis-related transcription factor SlBBX20 regulates anthocyanin accumulation in tomato. However, the underlying mechanism remains unclear. Here, we showed that SlBBX20 promotes anthocyanin biosynthesis by binding the promoter of the anthocyanin biosynthesis gene SlDFR, suggesting that SlBBX20 directly activates anthocyanin biosynthesis genes. Furthermore, we found by yeast two-hybrid screening that SlBBX20 interacts with the COP9 signalosome subunit SlCSN5-2, and the interaction was confirmed by bimolecular fluorescence complementation and coimmunoprecipitation assays. SlCSN5 gene silencing led to anthocyanin hyperaccumulation in the transgenic tomato calli and shoots, and SlCSN5-2 overexpression decreased anthocyanin accumulation, suggesting thSlCSN5-2 enhanced the ubiquitination of SlBBX20 and promoted the degradation of SlBBX20 in vivo. Consistently, silencing the SlCSN5-2 homolog in tobacco significantly increased the accumulation of the SlBBX20 protein. Since SlBBX20 is a vital regulator of photomorphogenesis, the SlBBX20-SlCSN5-2 module may represent a novel regulatory pathway in light-induced anthocyanin biosynthesis.

Purpose The prevalence of hypertension continues to increase worldwide, raising an urgent need for novel and efficient methods for controlling hypertension. As the Internet and smartphones become more popular, their multiple functions and large user base make mobile health (mHealth) technology a potential tool for hypertension management. We aim to evaluate the use of mHealth technology to improve blood pressure and self-management behavior in people with hypertension and prehypertension. Intervention The mHealth intervention measures include health education, behavior promotion, group chatting and long-term blood pressure monitoring hierarchically delivered via WeChat application among 242 participants. The frequency, intensity and content of the hierarchical intervention are determined based on the cardiovascular risk stratification of the intervention subjects. Study design This cluster randomized controlled trial was carried out in two subdistricts in Guangzhou, China, among 492 smartphone users with hypertension or prehypertension, from August 2018 to September 2019. The intervention group received hierarchical intervention through WeChat for six months, while the control group received usual care in the community healthcare center during this period. Indicators are measured at three time points for each group, and a telephone follow-up is planned for two years after the intervention. The primary outcome is systolic blood pressure; secondary outcomes include BMI, CPAT score, improvements in behavior and diet, score of self-efficacy and self-management. Feasibility is evaluated by intervention participation. The cost-effectiveness is evaluated by ICER. Conclusion This study aims to evaluate the effect of the WeChat-based hierarchical management mode on improving blood pressure and self-management behavior in population with hypertension and prehypertension, based on health-related knowledge, self-efficacy and medication adherence. If successful, the management mode will serve as a feasible, economical and efficient hypertension management mode suitable for the community.Clinical trial identifier: ChiCTR1900023002.

Weiwei Ding,1 Tong Li,1 Qiying Su,2 Maohua Yuan,2 Aihua Lin1 1Department of Epidemiology and Health Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China; 2Department of Chronic Disease Management, Dadong Community Healthcare Center, Guangzhou, Guangdong, China Purpose: Hypertension is considered a major public health issue worldwide because of its high frequency and concomitant risk of cardiovascular disease (CVD). Chronic-disease self-management has been proven to be cost-effective, but influencing factors and pathways remain complex and unclear. The purpose of this study was to integrate factors associated with hypertension self-management to provide a theoretical reference for community hypertension management.Methods: A total of 268 community-dwelling hypertensive patients were enrolled in a cross-sectional study conducted from July to September in 2017. A questionnaire on demographic–disease characteristics, disease knowledge, social support, self-efficacy, and self-management was completed by patients. Structural equation modeling was performed to verify multiple factors in self-management based on the self-efficacy theory.Results: The final model showed a good fit to sample data, ie, younger patients with lower CVD risk, shorter disease course, and less disease knowledge and social support predicted less self-efficacy, less hypertension self-management, and less controlled hypertension. Furthermore, social support was negatively correlated with age, CVD risk, and disease course and positively with disease knowledge.Conclusion: Medication adherence is the lowest dimension in self-management, and self-efficacy is vital to consider in the development of self-management interventions. Self-management education and mutual-help groups may be potential solutions with the power of technology. Younger patients with lower CVD risk and shorter disease course are vulnerable and need more attention. Keywords: hypertension, self-management, associated factors, structural equation model, China, disease knowledge, social support, self-efficacy

Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipolar disorder (BD), major depression (MD), loneliness and CVD risk factors using bivariate causal mixture mode (MiXeR), which estimates the total amount of shared variants, and conditional false discovery rate to evaluate overlap in specific loci. We observed substantial genetic overlap between SMDs, loneliness and CVD risk factors, beyond genetic correlation. We identified 149 loci jointly associated with loneliness and SMDs (MD n = 67, SCZ n = 54, and BD n = 28), and 55 distinct loci jointly associated with loneliness and CVD risk factors. A total of 153 novel loneliness loci were found. Most of the shared loci possessed concordant effect directions, suggesting that genetic risk for loneliness may increase the risk of both SMDs and CVD. Functional analyses of the shared loci implicated biological processes related to the brain, metabolic processes, chromatin and immune system. Altogether, the study revealed polygenic overlap between loneliness, SMDs and CVD risk factors, providing new insights into their shared genetic architecture and common genetic mechanisms.

Asymptomatic SARS-CoV-2-infected individuals are thought to play major roles in virus transmission. This study aimed to analyze the characteristics of asymptomatic carriers with COVID-19 to control the spread of the virus. We retrospectively investigated the clinical characteristics of 648 consecutive subjects who were enrolled in the study and were divided into asymptomatic carriers, mild cases, ordinary cases, severe or critical cases, and evaluated their impact on disease severity by means of Spearman correlation and multiple regression analyses. Receiver operating characteristic curve analysis was conducted to determine the optimum cutoff levels of laboratory findings for diagnostic predictors of asymptomatic carriers of COVID-19. In our study, a total of 648 subjects on admission with a mean age of 45.61 y including 345 males and 303 females were enrolled in our study. The leukocyte, lymphocyte, eosinophil, platelet, C-reactive protein, interleukin-6, CD3+, CD4+, and CD8 + T lymphocyte levels, and the erythrocyte sedimentation rate differed significantly among the groups (all p ≤ 0.05). Disease severity was negatively associated with the CD3+ (r = −0.340; p

Brain morphology has been shown to be highly heritable, yet only a small portion of the heritability is explained by the genetic variants discovered so far. Here we exploit the distributed nature of genetic effects across the brain and apply the Multivariate Omnibus Statistical Test (MOSTest) to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) cortical measures from N=35,657 participants in the UK Biobank. We identified 695 loci for cortical surface area and 539 for cortical thickness, in total 780 unique genetic loci associated with cortical morphology. This reflects an approximate 10-fold increase compared to the commonly applied univariate GWAS methods. Power analysis indicates that applying MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional univariate GWAS approaches. Functional follow up including gene-based analyses implicate 10% of all protein-coding genes and point towards pathways involved in neurogenesis and cell differentiation.

Background The accumulation of astrocytes around senile plaques is one of the pathological characteristics in Alzheimer’s disease (AD). Serum amyloid A (SAA), known as a major acute-phase protein, colocalizes with senile plaques in AD patients. Here, we demonstrate the role of SAA in astrocyte migration. Methods The effects of SAA on astrocyte activation and accumulation around amyloid β (Aβ) deposits were detected in APP/PS1 transgenic mice mated with Saa3−/− mice. SAA expression, astrocyte activation, and colocalization with Aβ deposits were evaluated in mice using immunofluorescence staining and/or Western blotting. The migration of primary cultures of mouse astrocytes and human glioma U251 cells was examined using Boyden chamber assay and scratch-would assay. The actin and microtubule networks, protrusion formation, and Golgi apparatus location in astrocytes were determined using scratch-would assay and immunofluorescence staining. Results Saa3 expression was significantly induced in aged APP/PS1 transgenic mouse brain. Saa3 deficiency exacerbated astrocyte activation and increased the number of astrocytes around Aβ deposits in APP/PS1 mice. In vitro studies demonstrated that SAA inhibited the migration of primary cultures of astrocytes and U251 cells. Mechanistic studies showed that SAA inhibited astrocyte polarization and protrusion formation via disrupting actin and microtubule reorganization and Golgi reorientation. Inhibition of the p38 MAPK pathway abolished the suppression of SAA on astrocyte migration and polarization. Conclusions These results suggest that increased SAA in the brain of APP/PS1 mice inhibits the migration of astrocytes to amyloid plaques by activating the p38 MAPK pathway.

The purpose of this study was to synthesize the results of previously published observational studies through meta-analysis to clarify the association between smoking and noise-induced hearing loss (NIHL). We searched several databases as of October 2019. Based on the results of heterogeneity analysis (Q statistic and I2 statistic), a fixed effect model (for no heterogeneity; Q test P > 0.1 and I2 ≤ 50%) or a random effects model (for heterogeneity) was used to calculate the pooled odds ratios (ORs). We explored the potential dose-response relationship between smoking and NIHL as well. In total, 27 studies involving 30,465 participants were included. Compared with non-smokers, the pooled OR of current smokers was 2.05 (95% Confidence interval (CI): 1.71−2.46), and of former smokers was 1.11 (95% CI: 1.05−1.18). We found a curve linear association between an increasing number of pack-years (packages/day × smoking years) and risk of NIHL. The dose-response meta-analysis suggested that when the number of pack-years was less than fifteen, the risk of NIHL was increasing, and the highest combined OR was 5.25 (95% CI: 2.30−11.96) for pack-years of fifteen. After fifteen pack-years, the pooled OR had a slow decline. Our study indicated that smoking is a risk factor for NIHL. Current smokers have a higher risk than former smokers, and there is a positive dose-response relationship between smoking and NIHL.

Background: Patients with coronavirus disease 2019 (COVID-19) infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which originated in Wuhan, China, and spreading over the country including Jiangsu Province. Our study aimed to study the epidemiological, clinical characteristics and therapies of these severe cases in Jiangsu Province.Methods: A multicenter retrospective cohort study was conducted to extract and analyze epidemiological, clinical, laboratory data and treatment of 60 severe cases with COVID-19 infection from 12 large hospitals in Jiangsu Province between Jan 24 and Feb 23, 2020. Cases were identified by real-time reverse transcription polymerase chain reaction (RT-PCR). The improvement and deterioration subgroups were compared to identify predictors of disease progression. Clinical outcomes were followed up until Feb 23, 2020.Results: A total of 631 infected cases with COVID-19 in Jiangsu Province, 60 of which were severe cases. Up until Feb 23, 2020, the mortality rate of these severe patients was 0%. The median age was 57 years (range, 26 to 97), and 58.3% were man. The body mass index (BMI) of these patients was higher, with an average of 25 kg/m². More than 90 percent of the patients had a history of contact with an infected patient or dined together, and two patients were infected while staying in the same train compartment with a confirmed patient. 51.7% of severe cases had at least one underlying disease, and low fever (80.0%) and dry cough (51.7%) were the most common symptoms. Mean acute physiology and chronic health evaluation (APACHE) II score on admission was 14±5. Acute respiratory distress syndrome (ARDS) appeared in 15% of the patients. White blood cell counts decreased in 45.0% of patients, lymphopenia in 63.3%, thrombocytopenia in 13.3%, and procalcitonin levels in 88.3% of the patients were less than 0.5 ng/mL. There were no statistically significant differences in immunoglobulin therapy and glucocorticoids therapy between the improvement and deterioration subgroups (P>0.05). Logistic regression analysis indentified higher levels of troponin T (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.00-1.08; P=0.04), antiviral therapy with interferon (OR: 6.33; 95% CI: 1.18-33.98; P=0.03), and the application of non-invasive mechanical ventilation (OR: 1.99; 95%CI: 1.17-3.41; P=0.01) as predictors of disease progression, whereas higher lymphocyte count (OR: 0.11; 95% CI: 0.02-0.57; P=0.01) and early prone ventilation were associated with improvement (OR: 0.11; 95% CI: 0.01-0.98; P=0.04).Conclusions: The COVID-19 infection had a low mortality rate in Jiangsu Province, China. The higher levels of troponin T and lower lymphocyte count were predictors of disease progression. Antiviral therapy with interferon was not recommended. The early prone ventilation may be an effective treatment for severe cases.

Objective: To study the prevalence of depression and related factors among men who have sex with men (MSM) in Shenzhen China. Methods: Using a cross-sectional design, convenient sampling was applied to recruit participants at the AIDS(Acquired Immune Deficiency Syndrome)voluntary counseling and testing (VCT) clinic and gay clubs in 2015, thereby collecting data on sociodemographics, serological information, sexual behaviotablers, and depression. Descriptive analyses were conducted to determine the distribution of the measured variables. A chi-square test was applied to test the association between different levels of factors and depression status, alongside a binary logistic regression for multivariate analysis of depression. Results: A total of 334 MSM completed the survey. Their mean age was 29.88 &plusmn, 7.56, and 35.6% had at least college education, 44.9% considered themselves to be homosexual, and 43.4% considered themselves bisexual. The median score of depression was 12, with 116 people (34.7%) depressed. A total of 267 took the serological test. Of these 267, 60 (22.5%) were reported HIV(Human Immunodeficiency Virus) positive, 33 (12.4%) were syphilis positive, and none were hepatitis C positive. The multiple logistic regression analysis showed that a lack of awareness of AIDS knowledge (OR(Odds Ratio): 2.636, 95% CI(confidence interval): 1.384&ndash, 5.020), peer education (OR: 1.752, 95% CI: 1.055&ndash, 2.190), and lack of heterosexuality (OR: 1.805, 95% CI: 1.080&ndash, 3.018) increased the odds of depression. Conclusion: Raising awareness of AIDS and strengthening peer education can improve depression among men who have sex with men.

This study aimed to assess whether a WeChat-based self-management intervention would be effective for community middle-aged and elderly adults with hypertension in Guangzhou, China. We conducted a cluster-randomized control trial with a total of 464 participants (intervention, n = 186, control, n = 276) between March 2018 and May 2019. The self-management intervention lasted for 6 months, consisting of health education, health promotion, group chat, and blood pressure (BP) monitoring. All individuals in the baseline and follow-up surveys were assessed for BP and completed a hypertension knowledge questionnaire, self-efficacy scale, self-management scale, and social support scale. A total of 253 participants (intervention, n = 110, control, n = 143) completed the follow-up survey and were included in the analysis. The adjusted mean differences in the changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) between the intervention and control groups were &minus, 6.9 (95% Confidence Interval (CI) &minus, 11.2 to &minus, 2.6, p = 0.002) and &minus, 3.1 (95% CI &minus, 5.7 to &minus, 0.6, p = 0.016) mmHg, respectively. Individuals who participated in the intervention program had better BP monitoring, improved their hypertension self-management as well as parts of their disease knowledge and self-efficacy. The WeChat-based self-management intervention may be a feasible and efficient program to help Chinese community middle-aged and elderly hypertensive patients lower BP and improve self-management.

Objectives Baicalein is a Chinese traditional medicine that inhibits tumor migration and growth. Pancreatic neuroendocrine tumors (pNETs) have a high incidence in China, but there are still no effective treatments. The aim of our study was to investigate whether baicalein could inhibit pNETs. Methods In vitro, we used BON1—a cell line of pNETs—to analyze the apoptosis and migration and invasion after baicalein treatment via flow cytometry and Western blot. In vivo, we used a xenograft tumors model to evaluate the size of tumors after baicalein treatment. Western blot was used to analyze the expression of apoptosis and migration-related protein. Results In vitro, the Cell Counting Kit 8 assay showed that baicalein decreased BON1 viability, and flow cytometry demonstrated that baicalein induced BON1 apoptosis and protein changes. In addition, baicalein inhibited BON1 migration and invasion as shown via a Transwell assay. In vivo, baicalein inhibited tumor growth and migration and also increased apoptosis-related protein expression. Conclusions Baicalein could increase caspase-3 and Bax expression and decrease survivin and Bcl-2 to induce apoptosis. It inhibits migration and invasion by decreasing expression of vascular endothelial growth factor and matrix metalloproteinases 2 and 9.

Aim: The present study aimed to determine whether anatomical resection was necessary for early hepatocellular carcinoma. Methods: A log-rank test or two-stage test was used for univariate analysis. A Cox proportional hazards model was used for multivariable analysis. Results: For patients without microvascular invasion, a resection margin ≥1 cm provided the longest recurrence-free survival time regardless of whether they underwent anatomical resection (p = 0.005) or nonanatomical resection (p = 0.006). For patients with microvascular invasion, anatomical resection combined with a resection margin ≥1 cm provided the longest recurrence-free survival time compared with other treatments (p = 0.001). Conclusion: Anatomical resection was not necessary for patients without microvascular invasion. However, for patients with microvascular invasion, both anatomical resection and a resection margin ≥1 cm were necessary.

The Asn-Gly-Arg (NGR) motif has previously been demonstrated to specifically bind to CD13, which is selectively overexpressed in tumor vasculature and some tumor cells (e.g. HT1080). It was reported that NGR-modified stealth liposomes (NGR-SL) could be prepared with different lipid composition, such as 1,2-dipalmitoyl-sn-glycero-phosphatidylcholine (DPPC), hydrogenated soy posphatidylcholine (HSPC) and soy posphatidylcholine (SPC). In the present study, NGR-modified liposomes were prepared with DPPC, HSPC, SPC or the mixture of HSPC and SPC. The resultant liposomes with different lipid composition were compared in terms of cell uptake, antitumor efficacy and targeted drug delivery efficiency using HT1080 tumor model. It was found that NGR-SL composed of the mixture of HSPC and SPC was able to improve targeted drug delivery efficiency to tumor producing the most significant antitumor activity. Collectively, the NGR-modified liposomes composed of the mixture of HSPC and SPC are promising carriers for the treatment of tumor. Besides NGR ligand, lipid composition could also significantly affect the targeted delivery efficiency to the tumor.

In this paper we discuss some of the mathematical and numerical issues that have to be addressed when calculating wave scattering using the Ewald Oseen scattering (EOS) formulation which is newly developed for solving linear and nonlinear scattering problems. The discussion is framed in context of light scattering by objects whose optical response can be of a nonlinear and/or inhomogeneous nature. The discussions address two issues that, more likely than not, will be part of any investigation of wave scattering using the EOS approach.

Background: To investigate and analyze the hospitalization costs of inpatients with primary acute angle closure glaucoma (PACG), and to explores the influencing factors of hospitalization cost and to provide reference for specialized hospitals to carry out clinical pathways. Methods: The first page diagnostic data of PACG patients’ medical records were collected, and an Excel database was established according to the International Classification of Diseases (ICD-10) code. Statistical analysis of hospitalization data was performed using SPSS 17.0 software. Results: Hospitalization days and clinical pathway which affect the change of the hospitalization cost (P Conclusions: Hospitalization day is an important factor affecting the hospitalization cost, reducing unnecessary hospitalization time can control the increase of hospitalization cost.

Carotenoids play important roles in many biological processes, such as light harvesting, photoprotection and visual attraction in plants. However, the regulation of carotenoid biosynthesis is still not fully understood. Here, we demonstrate that SlBBX20, a B-box (BBX) zinc-finger transcription factor, is a positive regulator of carotenoid accumulation in tomato (Solanum lycopersicum). Overexpression of SlBBX20 leads to dark green fruits and leaves and higher levels of carotenoids relative to the wild-type. Interactions between SlBBX20 and DE-ETIOLATED 1 (SlDET1) lead to the ubiquitination and 26S proteasome-mediated degradation of SlBBX20. Moreover, deficiencies in the components of the CUL4-DDB1-DET1 complex enhanced the stability of the SlBBX20 protein. Thus, we conclude that SlBBX20 is a substrate of the CUL4-DDB1-DET1 E3 ligase. SlBBX20 can activate the expression of PHYTOENE SYNTHASE 1, encoding a key enzyme in carotenoid biosynthesis, by directly binding to a G-box motif in its promoter, which results in the elevated levels of carotenoids in SlBBX20 overexpression lines. We identified a key regulator of carotenoid biosynthesis and demonstrated that the stability of SlBBX20 is regulated by ubiquitination. These findings provide us a new target for the genetic improvement of the nutritional quality of tomato fruit.

In this paper we explore the possibility for solving the 3D Maxwell's equations in the presence of nonlinear and/or inhomogeneous material response. We propose using a hybrid approach which combines a bound- ary integral representation with a domain-based method. This hybrid approach has previously been successfully applied to 1D linear and non- linear transient wave scattering problems. The basic idea of the approach is to propagate the Maxwell's equations inside the scattering objects for- ward in time by using a domain-based method, while a boundary integral representation of the electromagnetic field is used to supply the domain- based method with the required surface values. Thus no grids outside the scattering objects are needed and this greatly reduces the computational cost and complexity., Comment: 23 pages, 2 figures

Background: The evidence of increased mortality attributable to extreme temperatures is widely characterized in climate-health studies. However, few of these studies have examined the role of humidity on temperature-mortality association. We investigated the joint effect between temperature and humidity on cardiovascular disease (CVD) mortality in Zhejiang Province, China. Methods: We collected data on daily meteorological and CVD mortality from 11 cities in Zhejiang Province during 2010-2013. We first applied time-series Poisson regression analysis within the framework of distributed lag non-linear models to estimate the city-specific effect of temperature and humidity on CVD mortality, after controlling for temporal trends and potential confounding variables. We then applied a multivariate meta-analytical model to pool the effect estimates in the 11 cities to generate an overall provincial estimate. The joint effects between them were calculated by the attributable fraction (AF). The analyses were further stratified by gender, age group, education level, and location of cities. Results: In total, 120,544 CVD deaths were recorded in this study. The mean values of temperature and humidity were 17.6 °C and 72.3%. The joint effect between low temperature and high humidity had the greatest impact on the CVD death burden over a lag of 0-21 days with a significant AF of 31.36% (95% eCI: 14.79-38.41%), while in a condition of low temperature and low humidity with a significant AF of 16.74% (95% eCI: 0.89, 24.44). The AFs were higher at low temperature and high humidity in different subgroups. When considering the levels of humidity, the AFs were significant at low temperature and high humidity for males, youth, those with a low level of education, and coastal area people. Conclusions: The combination of low temperature and high humidity had the greatest impact on the CVD death burden in Zhejiang Province. This evidence has important implications for developing CVD interventions.

Although evidence suggests that lifestyle interventions can reduce blood pressure (BP) and glucose levels, there is little information about the feasibility of such interventions when implemented in community settings. This study evaluated the effectiveness of a community-based lifestyle intervention on BP and glucose in the middle-aged and older Chinese population. By using a cluster randomisation approach, 474 participants from two communities were assigned to the intervention group which received intensive health education and behavioural intervention, or the control group which received conventional education. Linear mixed models were used to compare between-group differences on change in BP and fasting glucose after 6, 12 and 24 months. At the 12-month follow-up, the intervention group experienced significantly reductions in systolic BP (−4.9 vs. 2.4 mmHg, mean difference [MD] −7.3 mmHg, p &lt, 0.001), diastolic BP (−1.9 vs. 1.9 mmHg, MD −3.8 mmHg, 0.001) and fasting glucose (−0.59 vs. 0.08 mmol/L, MD −0.67 mmol/L, 0.001). These differences were sustained at the 24-month follow-up. With only two communities, it was not possible to adjust for potential clustering by site. This approach of lifestyle interventions conducted through primary care services may be a potential solution for combating hypertension and diabetes in a resource-limited country context in China.

In the past decades, various studies have suggested a possible link between thymidine phosphorylase (TP) level and colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)-based chemotherapy; however, they have arrived at inconsistent results. Therefore, the present meta-analysis aimed to disclose a more comprehensive evaluation of this relationship. PubMed, the Cochrane Library, Ovid MEDLINE, Embase and China National Knowledge Infrastructure were systematically searched for studies that evaluated the prognostic value of TP in CRC. Stata 12.0 software was used to test the heterogeneity and evaluate the overall test performance. A total of 15 studies, including 1,225 patients, were included. The summary estimates of TP for CRC treated with 5-FU-based chemotherapy indicated a moderately positive prognosis with a hazard ratio (HR) of 0.76 (P=0.031) for overall survival and a HR of 0.711 (P=0.022) for relapse-free survival. On the basis of the present meta-analysis, TP could be promising and meaningful in the prognosis of CRC treated with 5-FU-based chemotherapy.

Background Southern China is an endemic area for primary liver cancer (PLC), but it is unclear if rates have changed in recent decades. We evaluated PLC incidence and estimated the effects of age, period of diagnosis, and birth cohort in Sihui City, Guangdong Province, China. Methods Age-standardized rates (ASRs) of PLC were examined for both males and females from 1987 to 2011. Joinpoint regression analysis was conducted to estimate the annual percent changes in PLC incidence. The age-period-cohort (APC) model was used to investigate the effects of age, diagnosis period, and birth cohort on the relative risk (RR) of PLC. Results A total of 2988 PLC cases were identified in this period, with average ASRs of 51.1/100,000 for males and 11.7/100,000 for females. Joinpoint regression analysis revealed increasing PLC incidence throughout the entire period in both males (average annual change of 1.65 %) and females (0.20 %). RRs increased gradually in both sexes from the youngest age group (30–34 years) to the oldest (80–84 years). In males, the RR decreased during diagnosis period from 1987–1991 to 1997–2001 and remained stable thereafter. In females, RRs fluctuated with diagnosis period throughout the entire period. Incidence tended to increase with birth cohort from 1905–1909 to 1975–1979 in both males and females; however, female incidence plateaued in the youngest cohorts born between 1955 and 1974, while incidence in males increased sharply in the cohorts born between 1965 and 1974. According to APC analysis, the full age-period-cohort (APC) model fit the data best, and the period-cohort (PC) model would be enough to explain variability of rates in females. Conclusion The PLC incidence rate in males of Sihui City has increased more significantly than female over the last 25 years. Despite the age effect in male, this trend mainly reflects the effects of risk factors that are present in early life (birth cohort) and period change in both genders.