TRANSPARENT TESTA GLABRA2 defines trichome cell shape by modulating actin cytoskeleton in Arabidopsis thaliana.

The Arabidopsis (Arabidopsis thaliana) TRANSPARENT TESTA GLABRA2 (TTG2) gene encodes a WRKY transcription factor that regulates a range of development events like trichome, seed coat, and atrichoblast formation. Loss-of-function of TTG2 was previously shown to reduce or eliminate trichome specification and branching. Here, we report the identification of an allele of TTG2, ttg2-6. In contrast to the ttg2 mutants described before, ttg2-6 displayed unique trichome phenotypes. Some ttg2-6 mutant trichomes were hyper-branched, whereas others were hypo-branched, distorted, or clustered. Further, we found that in addition to specifically activating R3 MYB transcription factor TRIPTYCHON (TRY) to modulate trichome specification, TTG2 also integrated cytoskeletal signaling to regulate trichome morphogenesis. The ttg2-6 trichomes displayed aberrant cortical microtubules (cMTs) and actin filaments (F-actin) configurations. Moreover, genetic and biochemical analyses showed that TTG2 could directly bind to the promoter and regulate the expression of BRICK1 (BRK1), which encodes a subunit of the actin nucleation promoting complex suppressor of cyclic AMP repressor (SCAR)/Wiskott-Aldrich syndrome protein family verprolin homologous protein (WAVE). Collectively, taking advantage of ttg2-6, we uncovered a function for TTG2 in facilitating cMTs and F-actin cytoskeleton-dependent trichome development, providing insight into cellular signaling events downstream of the core transcriptional regulation during trichome development in Arabidopsis.

The metabolic signature of blood lipids: a causal inference study using twins.

Dyslipidemia is one of the cardiometabolic risk factors that influences mortality globally. Unraveling the causality between blood lipids and metabolites and the complex networks connecting lipids, metabolites, and other cardiometabolic traits can help to more accurately reflect the body's metabolic disorders and even cardiometabolic diseases. We conducted targeted metabolomics of 248 metabolites in 437 twins from the Chinese National Twin Registry. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) analysis was used for causal inference between metabolites and lipid parameters. Bidirectional mediation analysis was performed to explore the linkages between blood lipids, metabolites, and other seven cardiometabolic traits. We identified 44, 1, and 31 metabolites associated with triglyceride (TG), total cholesterol (TC), and high-density lipoprotein-cholesterol (HDL-C), most of which were gut microbiota-derived metabolites. There were 9, 1, and 14 metabolites that showed novel associations with TG, TC, and HDL-C, respectively. ICE FALCON analysis found that TG and HDL-C may have a predicted causal effect on 23 and six metabolites, respectively, and one metabolite may have a predicted causal effect on TG. Mediation analysis discovered 14 linkages connecting blood lipids, metabolites, and other cardiometabolic traits. Our study highlights the significance of gut microbiota-derived metabolites in lipid metabolism. Most of the identified cross-sectional associations may be due to the lipids having a predicted causal effect on metabolites, but not vice versa, nor are they due to family confounding. These findings shed new light on lipid metabolism and personalized management of cardiometabolic diseases.

A panel of janus kinase inhibitors identified with anti-inflammatory effects protect mice from lethal influenza virus infection.

Influenza remains a significant threat to public health. In severe cases, excessive inflammation can lead to severe pneumonia or acute respiratory distress syndrome, contributing to patient morbidity and mortality. While antivirals can be effective if administered early, current anti-inflammatory drugs have limited success in treating severe cases. Therefore, discovering new anti-inflammatory agents to inhibit influenza-related inflammatory diseases is crucial. Herein, we screened a drug library with known targets using a human monocyte U937 infected with the influenza virus to identify novel anti-inflammatory agents. We also evaluated the anti-inflammatory effects of the hit compounds in an influenza mouse model. Our research revealed that JAK inhibitors exhibited a higher hit rate and more potent inhibition effect than inhibitors targeting other drug targets in vitro. Of the 22 JAK inhibitors tested, 15 exhibited robust anti-inflammatory activity against influenza virus infection in vitro. Subsequently, we evaluated the efficacy of 10 JAK inhibitors using an influenza mouse model and observed that seven provided protection ranging from 40% to 70% against lethal influenza virus infection. We selected oclacitinib as a representative compound for an extensive study to further investigate the in vivo therapeutic potential of JAK inhibitors for severe influenza-associated inflammation. Our results revealed that oclacitinib effectively suppressed neutrophil and macrophage infiltration, reduced pro-inflammatory cytokine production, and ultimately mitigated lung injury in mice infected with lethal influenza virus without impacting viral titer. These findings suggest that JAK inhibitors can modulate immune responses to influenza virus infection and may serve as potential treatments for influenza.IMPORTANCEAntivirals exhibit limited efficacy in treating severe influenza when not administered promptly during the infection. Current steroidal and nonsteroidal anti-inflammatory drugs demonstrate restricted effectiveness against severe influenza or are associated with significant side effects. Therefore, there is an urgent need for novel anti-inflammatory agents that possess high potency and minimal adverse reactions. In this study, 15 JAK inhibitors were identified through a screening process based on their anti-inflammatory activity against influenza virus infection in vitro. Remarkably, 7 of the 10 selected inhibitors exhibited protective effects against lethal influenza virus infection in mice, thereby highlighting the potential therapeutic value of JAK inhibitors for treating influenza.

Five years of change in adult twins: longitudinal changes of genetic and environmental influence on epigenetic clocks.

BACKGROUND: Epigenetic clocks were known as promising biomarkers of aging, including original clocks trained by individual CpG sites and principal component (PC) clocks trained by PCs of CpG sites. The effects of genetic and environmental factors on epigenetic clocks are still unclear, especially for PC clocks. METHODS: We constructed univariate twin models in 477 same-sex twin pairs from the Chinese National Twin Registry (CNTR) to estimate the heritability of five epigenetic clocks (GrimAge, PhenoAge, DunedinPACE, PCGrimAge, and PCPhenoAge). Besides, we investigated the longitudinal changes of genetic and environmental influences on epigenetic clocks across 5 years in 134 same-sex twin pairs. RESULTS: Heritability of epigenetic clocks ranged from 0.45 to 0.70, and those for PC clocks were higher than those for original clocks. For five epigenetic clocks, the longitudinal stability was moderate to high and was largely due to genetic effects. The genetic correlations between baseline and follow-up epigenetic clocks were moderate to high. Special unique environmental factors emerged both at baseline and at follow-up. PC clocks showed higher longitudinal stability and unique environmental correlations than original clocks. CONCLUSIONS: For five epigenetic clocks, they have the potential to identify aging interventions. High longitudinal stability is mainly due to genetic factors, and changes of epigenetic clocks over time are primarily due to changes in unique environmental factors. Given the disparities in genetic and environmental factors as well as longitudinal stability between PC and original clocks, the results of studies with original clocks need to be further verified with PC clocks.

Association of psychological distress and DNA methylation: A 5-year longitudinal population-based twin study.

AIM: To identify the psychological distress (PD)-associated 5'-cytosine-phosphate-guanine-3' sites (CpGs), and investigate the temporal relationship between dynamic changes in DNA methylation (DNAm) and PD. METHODS: This study included 1084 twins from the Chinese National Twin Register (CNTR). The CNTR conducted epidemiological investigations and blood withdrawal twice in 2013 and 2018. These included twins were used to perform epigenome-wide association studies (EWASs) and to validate the previously reported PD-associated CpGs selected from previous EWASs in PubMed, Embase, and the EWAS catalog. Next, a cross-lagged study was performed to examine the temporality between changes in DNAm and PD in 308 twins who completed both 2013 and 2018 surveys. RESULTS: The EWAS analysis of our study identified 25 CpGs. In the validation analysis, 741 CpGs from 29 previous EWASs on PD were selected for validation, and 101 CpGs were validated to be significant at a false discovery rate <0.05. The cross-lagged analysis found a unidirectional path from PD to DNAm at 14 CpGs, while no sites showed significance from DNAm to PD. CONCLUSIONS: This study identified and validated PD-related CpGs in a Chinese twin population, and suggested that PD may be the cause of changes in DNAm over time. The findings provide new insights into the molecular mechanisms underlying PD pathophysiology.

Association between Fish Consumption and Risk of Chronic Obstructive Pulmonary Disease among Chinese Men and Women: an 11-Year Population-Based Cohort Study.

BACKGROUND: Epidemiological evidence on the relation between fish consumption and chronic obstructive pulmonary disease (COPD) is limited, especially among Chinese. OBJECTIVES: The aim was to explore the prospective association between fish consumption and COPD among a large population-based Chinese cohort. METHODS: The China Kadoorie Biobank recruited over 0.5 million participants from 10 geographically diverse regions across China from 2004 to 2008. Consumption frequency of fish at baseline was assessed by a validated food-frequency questionnaire. A total of 169,188 men and 252,238 women who had no prior COPD or other major chronic diseases at baseline were included in our analyses. Cox proportional hazard models were used to estimate HRs and 95% CIs for fish consumption categories in relation to incident COPD. RESULTS: During a median follow-up of 11.1 y, 11,292 incident COPD cases were documented. Fish consumption was inversely associated with COPD risk among women, with a 17% reduction in risk for participants who consumed fish ≥4 d/wk compared with nonconsumption (HR: 0.83; 95% CI: 0.70, 0.99; P-trend = 0.017), whereas we did not observe such a dose-response relation among men (HR: 0.89; 95% CI: 0.76, 1.05; P-trend = 0.373). The joint analysis showed that COPD risk was 38% and 48% lower in men and women who consumed fish ≥4 d/wk and had a healthy lifestyle [having ≥4 of the following healthy lifestyle factors: not smoking currently; never or rarely drinking alcohol; adequate physical activity; BMI (kg/m2): 18.5-23.9; normal waist circumference; reasonable diet], compared with participants with fish consumption <4 d/wk and an unhealthy lifestyle (≤1 factors). CONCLUSIONS: Higher fish consumption was associated with lower COPD risk among Chinese women but not men. This association was independent of lifestyle factors. Eating adequate fish with an overall healthy lifestyle might help lower the risk of COPD.

Genetic and Environmental Influences on Blood Pressure and Serum Lipids Across Age-Groups.

Aging plays a crucial role in the mechanisms of the impacts of genetic and environmental factors on blood pressure and serum lipids. However, to our knowledge, how the influence of genetic and environmental factors on the correlation between blood pressure and serum lipids changes with age remains to be determined. In this study, data from the Chinese National Twin Registry (CNTR) were used. Resting blood pressure, including systolic and diastolic blood pressure (SBP and DBP), and fasting serum lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) were measured in 2378 participants (1189 twin pairs). Univariate and bivariate structural equation models examined the genetic and environmental influences on blood pressure and serum lipids among three age groups. All phenotypes showed moderate to high heritability (0.37-0.59) and moderate unique environmental variance (0.30-0.44). The heritability of all phenotypes showed a decreasing trend with age. Among all phenotypes, SBP and DBP showed a significant monotonic decreasing trend. For phenotype-phenotype pairs, the phenotypic correlation (Rph) of each pair ranged from -0.04 to 0.23, and the additive genetic correlation (Ra) ranged from 0.00 to 0.36. For TC&SBP, TC&DBP, TG&SBP and TGs&DBP, both the Rph and Ra declined with age, and the Ra difference between the young group and the older adult group is statistically significant (p < .05). The unique environmental correlation (Re) of each pair did not follow any pattern with age and remained relatively stable with age. In summary, we observed that the heritability of blood pressure was affected by age. Moreover, blood pressure and serum lipids shared common genetic backgrounds, and age had an impact on the phenotypic correlation and genetic correlations.

Survival Prediction in Home Hospice Care Patients with Lung Cancer Based on LASSO Algorithm.

PURPOSE: The aim of the present study was to develop a nomogram for prognostic prediction of patients with lung cancer in hospice. METHODS: The data was collected from 1106 lung cancer patients in hospice between January 2008 and December 2018. The data were split into a training set, which was used to identify the most important prognostic factors by the least absolute shrinkage and selection operator (LASSO) and to build the nomogram, while the testing set was used to validate the nomogram. The performance of the nomogram was assessed by c-index, calibration curve and the decision curve analysis (DCA). RESULTS: A total of 1106 patients, including 835 (75%) from the training set and 271 (25%) from testing set, were retrospectively analyzed in this study. Using the LASSO regression, 5 most important prognostic predictors that included sex, Karnofsky Performance Scale (KPS), quality-of-life (QOL), edema and anorexia, were selected out of 28 variables. Validated c-indexes of training set at 15, 30, and 90 days were .778 [.737-.818], .776 [.743-.809], and .751 [.713-.790], respectively. Similarly, the validated c-indexes of testing set at 15, 30, and 90 days were .789 [.714-.864], .748 [.685-.811], and .757 [.691-.823], respectively. The nomogram-predicted survival was well calibrated, as the predicted probabilities were close to the expected probabilities. Moreover, the DCA curve showed that nomogram received superior standardized net benefit at a broad threshold. CONCLUSIONS: The study built a non-lab nomogram with important predictor to analyze the clinical parameters using LASSO. It may be a useful tool to allow clinicians to easily estimate the prognosis of the patients with lung cancer in hospice.

Exploring the Genetic Association between Obesity and Serum Lipid Levels Using Bivariate Methods.

It is crucial to understand the genetic mechanisms and biological pathways underlying the relationship between obesity and serum lipid levels. Structural equation models (SEMs) were constructed to calculate heritability for body mass index (BMI), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and the genetic connections between BMI and the four classes of lipids using 1197 pairs of twins from the Chinese National Twin Registry (CNTR). Bivariate genomewide association studies (GWAS) were performed to identify genetic variants associated with BMI and lipids using the records of 457 individuals, and the results were further validated in 289 individuals. The genetic background affecting BMI may differ by gender, and the heritability of males and females was 71% (95% CI [.66, .75]) and 39% (95% CI [.15, .71]) respectively. BMI was positively correlated with TC, TG and LDL-C in phenotypic and genetic correlation, while negatively correlated with HDL-C. There were gender differences in the correlation between BMI and lipids. Bivariate GWAS analysis and validation stage found 7 genes (LOC105378740, LINC02506, CSMD1, MELK, FAM81A, ERAL1 and MIR144) that were possibly related to BMI and lipid levels. The significant biological pathways were the regulation of cholesterol reverse transport and the regulation of high-density lipoprotein particle clearance (p < .001). BMI and blood lipid levels were affected by genetic factors, and they were genetically correlated. There might be gender differences in their genetic correlation. Bivariate GWAS analysis found MIR144 gene and its related biological pathways may influence obesity and lipid levels.

Blood DNA methylation markers associated with type 2 diabetes, fasting glucose, and HbA1c levels: An epigenome-wide association study in 316 adult twin pairs.

DNA methylation plays an important role in the development and etiology of type 2 diabetes; however, few epigenomic studies have been conducted on twins. Herein, a two-stage study was performed to explore the associations between DNA methylation and type 2 diabetes, fasting plasma glucose, and HbA1c. DNA methylation in 316 twin pairs from the Chinese National Twin Registry (CNTR) was measured using Illumina Infinium BeadChips. In the discovery sample, the results revealed that 63 CpG sites and 6 CpG sites were significantly associated with fasting plasma glucose and HbA1c, respectively. In the replication sample, cg19690313 in TXNIP was associated with both fasting plasma glucose (P = 1.23 × 10-17, FDR < 0.001) and HbA1c (P = 2.29 × 10-18, FDR < 0.001). Furthermore, cg04816311, cg08309687, and cg09249494 may provide new insight in the metabolic mechanism of HbA1c. Our study provides solid evidence that cg19690313 on TXNIP correlates with HbA1c and fasting plasma glucose levels.

Developmental Consequences of Prenatal Telbivudine Exposure during the Third Trimester.

Hepatitis B virus (HBV) infection is a global health issue. Mother-to-child transmission (MTCT) is the most prominent route for chronic HBV infection in Asian countries.1 Although standard immunoprophylaxis has been effective in preventing MTCT, a significantly higher rate of MTCT has been observed among mothers with high levels of viremia.2 Tenofovir disoproxil, telbivudine (LdT), and lamivudine, used in third trimester, have been shown to significantly reduce MTCT of HBV for highly viremic mothers.3 Although the efficacy and short-term safety of LdT in preventing MTCT have been demonstrated in several large cohort studies in recent years, fewer data exist on the safety assessment of infants' neurocognitive development after fetal exposure to LdT.4-6 Therefore, we conducted a prospective cohort study to investigate the effect of LdT on infants' neurocognitive development.

A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic aetiology with obesity.

BACKGROUND: Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking. METHODS: We included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects. RESULTS: We identified nine genome-wide significant novel loci for FEV1, six for FVC and three for FEV1/FVC in the CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV1 and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years. CONCLUSION: This large-scale GWAS of lung function identified novel loci and shared genetic aetiology between lung function and obesity. Change in BMI might affect change in lung function differently according to a subject's polygenic background. These findings may open new avenues for the development of molecular-targeted therapies for obesity and lung function improvement.

Outcome of Chinese patients with hepatitis B at 96 weeks after functional cure with IFN versus combination regimens.

BACKGROUND & AIMS: Nucleotides with add-on interferon treatment (NUC-IFN) provide significantly higher rates of hepatitis B surface antigen (HBsAg) loss in patients with chronic hepatitis B (CHB). This study aimed to investigate the sustainability of HBsAg loss and the prevention of clinical relapse. METHODS: Patients with CHB who achieved HBsAg loss and HBV DNA levels <20 IU/ml after IFN or NUC-IFN therapy were enrolled and followed up for 96 weeks. The primary outcome was HBsAg negativity without viremia at week 96. Secondary outcomes included virological or clinical relapse and predictors of relapse. RESULTS: 420 patients were included in intention-to-treat analysis with 290 and 130 in the IFN and NUC-IFN groups respectively. At week 96, the intention-to-treat analysis revealed similar outcomes between groups, including HBsAg seroreversion (24.83% vs. 23.08%, P = .70), viremia (16.90% vs 13.08%, P = .32) and clinical relapse (11.38% vs 10.00%, P = .68); the per-protocol analyses also showed HBsAg seroreversion, viremia and clinical relapse in IFN group (15.50%, 6.59% and 0.39%) did not differ from those in NUC-IFN group (15.25%, 4.24% and 0.85%, P > .05). These outcomes were similar between patients who received entecavir and those who received telbivudine/lamivudine/adefovir before the combination therapy. In NUC-IFN-treated patients, fibrosis regression was observed at week 96. Baseline HBsAb negativity was independent predictors of HBsAg sero-reversion and recurrence of viremia in IFN treated group. CONCLUSION: NUC-IFN and IFN therapies are equally effective in achieving sustained functional cure and fibrosis regression. (ClinicalTrials.gov, Number NCT02336399).

Exploring the needs and experiences of palliative home care from the perspectives of patients with advanced cancer in China: a qualitative study.

PURPOSE: The needs and experiences of palliative home care for patients with advanced cancer have received little research attention. We aimed to explore the needs and experiences of palliative home care among patients with advanced cancer in China. METHODS: This qualitative study was conducted using semi-structured interviews with patients with advanced cancer. Participants (n = 15) were recruited from an oncology palliative care unit and a hospice outpatient unit, and were selected using purposive sampling from October 2019 to March 2020. Interviews were audio-recorded, transcribed verbatim, and subjected to thematic analysis. Two researchers coded the interviews independently in NVivo 12 and developed major themes and subthemes by inductive and constant comparison. RESULTS: Five themes were identified: (1) physical need; (2) psychological experience; (3) spiritual need; (4) social need; and (5) information need. Patients need to manage their symptoms (especially cancer pain), prolong life as long as possible, reconstruct their attitudes to adapt to their roles, be socially supported, be respected, maintain spiritual peace, and obtain more information about illness and home care. CONCLUSIONS: The current palliative home care services are imperfect, and patients face substantial challenges, including physical symptoms, psychological/spiritual distress, and inadequate social support and information. Our findings may provide evidence and a reference for the development of palliative home care in China.

Associations of Obesity Measurements with Serum Metabolomic Profile: A Chinese Twin Study.

The objective of this study was to investigate how different obesity measures link to circulating metabolites, and whether the connections are due to genetic or environmental factors. A cross-sectional analysis was performed on follow-up survey data at the Chinese National Twin Registry (CNTR), which was conducted in four areas of China (Shandong, Jiangsu, Zhejiang and Sichuan) in 2013. The survey collected detailed questionnaire information and conducted physical examinations, fasting blood sampling and untargeted metabolomic measurements among 439 adult twins. Linear regression models and bioinformatics analysis were used to examine the relation of obesity measures, including body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) with serum metabolite levels and related pathways. A co-twin control study was additionally conducted among 15 obesity-discordant monozygotic (MZ) pairs (intrapair BMI difference >3 kg/m2) to examine any differences in metabolites controlling for genetic factors. Eleven metabolites were associated with BMI, WC and WHR after controlling for genetic and shared environmental factors. Pathway analysis identified pathways such as phenylalanine metabolism, purine metabolism, valine, leucine and isoleucine biosynthesis that were associated with obesity. A wide range of unfavorable alterations in the serum metabolome was associated with obesity. Obesity-discordant twin analysis suggests that these associations are independent of genetic liability.

A Comparison of Preterm Birth Rate and Growth from Birth to 18 Years Old between in Vitro Fertilization and Spontaneous Conception of Twins.

The aim of the present study was to compare the rate of preterm birth (PTB) and growth from birth to 18 years between twins conceived by in vitro fertilization (IVF) and twins conceived by spontaneous conception (SC) in mainland China. The retrospective cohort study included 1164 twins resulting from IVF and 25,654 twins conceived spontaneously, of which 494 from IVF and 6338 from SC were opposite-sex twins. PTB and low birth weight (LBW), and growth, including length/height and weight, were compared between the two groups at five stages: infancy (0 year), toddler period (1-2 years), preschool (3-5 years), primary or elementary school (6-11 years), and adolescence (10-18 years). Few statistically significant differences were found for LBW and growth between the two groups after adjusting for PTB and other confounders. Twins born by IVF faced an increased risk of PTB compared with those born by SC (adjusted odds ratio [aOR] 8.21, 95% confidence interval [CI] [3.19, 21.13], p < .001 in all twins and aOR 10.12, 95% CI [2.32, 44.04], p = .002 in opposite-sex twins). Twins born by IVF experienced a similar growth at five stages (0-18 years old) when compared with those born by SC. PTB risk, however, is significantly higher for twins conceived by IVF than those conceived by SC.

Association between adiposity measures and COPD risk in Chinese adults.

Bodyweight and fat distribution may be related to COPD risk. Limited prospective evidence linked COPD to abdominal adiposity. We investigated the association of body mass index (BMI) and measures of abdominal adiposity with COPD risk in a prospective cohort study.The China Kadoorie Biobank recruited participants aged 30-79 years from 10 areas across China. Anthropometric indexes were objectively measured at the baseline survey during 2004-2008. After exclusion of participants with prevalent COPD and major chronic diseases, 452 259 participants were included and followed-up until the end of 2016. We used Cox models to estimate adjusted hazard ratios relating adiposity to risk of COPD hospitalisation or death.Over an average of 10.1 years of follow-up, 10 739 COPD hospitalisation events and deaths were reported. Compared with subjects with normal BMI (18.5-<24.0 kg·m-2), underweight (BMI <18.5 kg·m-2) individuals had increased risk of COPD, with adjusted hazard ratio 1.78 (95% CI 1.66-1.89). Overweight (BMI 24.0-<28.0 kg·m-2) and obesity (BMI ≥28.0 kg·m-2) were not associated with an increased risk after adjustment for waist circumference. A higher waist circumference (≥85 cm for males and ≥80 cm for females) was positively associated with COPD risk after adjustment for BMI. Additionally, waist-to-hip ratio and waist-to-height ratio were positively related to COPD risk.Abdominal adiposity and underweight were risk factors for COPD in Chinese adults. Both BMI and measures of abdominal adiposity should be considered in the prevention of COPD.

A randomized, double-blind study to compare the efficacy and safety of two doses of mometasone furoate delivered via Breezhaler® or Twisthaler® in patients with asthma.

INTRODUCTION: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting ß2-agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 µg) and high (320 µg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 µg) and high (800 µg) doses respectively, delivered via Twisthaler®. METHODS: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 µg) and high (320 µg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 µg) and high (800 µg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV1), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 µg and 320 µg delivered via Breezhaler®, and MF 200 µg and 800 µg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment. RESULTS: The LS mean difference in trough FEV1 after four weeks of treatment between MF low dose 80 µg (Breezhaler®) and MF low dose 200 µg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 µg (Breezhaler®) and MF high dose 800 µg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events. CONCLUSION: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 µg) and high (320 µg) doses delivered with Breezhaler® with MF at low (200 µg) and high (800 µg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses.

Association of physical activity, sedentary behaviours and sleep duration with cardiovascular diseases and lipid profiles: a Mendelian randomization analysis.

BACKGROUND: Observational studies have shown that moderate-to-vigorous physical activity (MVPA), vigorous physical activity (VPA), sedentary behaviours, and sleep duration were associated with cardiovascular diseases (CVDs) and lipid levels. However, whether such observations reflect causality remain largely unknown. We aimed to investigate the causal associations of physical activity, sedentary behaviours, and sleep duration with coronary artery disease (CAD), myocardial infarction (MI), stroke and lipid levels. METHODS: We conducted a Mendelian randomization (MR) study using genetic variants as instruments which are associated with physical activity, sedentary behaviours, and sleep duration to examine the causal effects on CVDs and lipid levels. This study included analyses of 4 potentially modifiable factors and 7 outcomes. Thus, the threshold of statistical significance is P = 1.8 × 10- 3 (0.05/4 × 7) after Bonferroni correction. RESULTS: In the present study, there was suggestive evidence for associations of genetically predicted VPA with CAD (odds ratio, 0.65; 95% confidence intervals, 0.47-0.90; P = 0.009) and MI (0.74; 0.59-0.93; P = 0.010). However, genetically predicted VPA, MVPA, sleep duration and sedentary behaviours did not show significant associations with stroke and any lipid levels. CONCLUSIONS: Our findings from the MR approach provided suggestive evidence that vigorous exercise decreased risk of CAD and MI, but not stroke. However, there was no evidence to support causal associations of MVPA,sleep duration or sedentary behaviours with cardiovascular risk and lipid levels. TRANSLATIONAL PERSPECTIVE: The findings of this study did not point out specific recommendations on increasing physical activity required to deliver significant health benefits. Nevertheless, the findings allowed clinicians and public health practitioners to provide advice about increasing the total amount of excising time by demonstrating that such advice can be effective. Reliable assessment of the association of physical activity levels with different subtypes of CVDs is needed to provide the basis for a comprehensive clinical approach on CVDs prevention, which can be achieved through lifestyle interventions in addition to drug therapy.

A non-lab nomogram of survival prediction in home hospice care patients with gastrointestinal cancer.

BACKGROUND: Patients suffering from gastrointestinal cancer comprise a large group receiving home hospice care in China, however, little is known about the prediction of their survival time. This study aimed to develop a gastrointestinal cancer-specific non-lab nomogram predicting survival time in home-based hospice. METHODS: We retrospectively studied the patients with gastrointestinal cancer from a home-based hospice between 2008 and 2018. General baseline characteristics, disease-related characteristics, and related assessment scale scores were collected from the case records. The data were randomly split into a training set (75%) for developing a predictive nomogram and a testing set (25%) for validation. A non-lab nomogram predicting the 30-day and 60-day survival probability was created using the least absolute shrinkage and selection operator (LASSO) Cox regression. We evaluated the performance of our predictive model by means of the area under receiver operating characteristic curve (AUC) and calibration curve. RESULTS: A total of 1618 patients were included and divided into two sets: 1214 patients (110 censored) as training dataset and 404 patients (33 censored) as testing dataset. The median survival time for overall included patients was 35 days (IQR, 17-66). The 5 most significant prognostic variables were identified to construct the nomogram among all 28 initial variables, including Karnofsky Performance Status (KPS), abdominal distention, edema, quality of life (QOL), and duration of pain. In training dataset validation, the AUC at 30 days and 60 days were 0.723 (95% CI, 0.694-0.753) and 0.733 (95% CI, 0.702-0.763), respectively. Similarly, the AUC value was 0.724 (0.673-0.774) at 30 days and 0.725 (0.672-0.778) at 60 days in the testing dataset validation. Further, the calibration curves revealed good agreement between the nomogram predictions and actual observations in both the training and testing dataset. CONCLUSION: This non-lab nomogram may be a useful clinical tool. It needs prospective multicenter validation as well as testing with Chinese clinicians in charge of hospice patients with gastrointestinal cancer to assess acceptability and usability.