COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment: A Randomized Clinical Trial.

Importance: With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective: To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants: This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Interventions: Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. Main Outcomes and Measures: The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. Results: The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. Conclusions and Relevance: In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.

Do the same chlorinated organophosphorus flame retardants that cause cytotoxicity and DNA damage share the same pathway?

Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.

Kaposiform hemangioendothelioma presented with raynaud phenomenon: a case report.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm affecting infants or young children. KHE includes a spectrum of lesions, ranging from small and superficial tumors to large and invasive lesions with Kasabach-Merritt phenomenon (KMP). Currently, no published studies have reported a KHE presenting as thrombocytopenia and Raynaud phenomenon. CASE PRESENTATION: A 2-year-old boy with right hand swelling and thrombocytopenia was admitted to our hospital. His right hand turned swelling and red, even occasionally cyanotic. This condition became worse in response to cool environments and improved with warming, and platelet counts were between 50 ~ 80 × 10^9/L. Physical examination on admission revealed the swelling and frostbite-like rash of the right-hand fingers, and the skin temperature of the right hand was lower than the left. On day 3 of admission, chest CT results showed an irregular mass on the right side of the spine. The puncture biopsy demonstrated positive CD31, D2-40, and FLI1 immunohistochemical staining, but negative GLUT1 staining, confirming the diagnosis of KHE. Furthermore, endothelin-1 (ET1) expression levels significantly increased, and eNOS and A20 expression levels significantly decreased comparing with control patients. The patient received methylprednisolone and sirolimus treatments, and his condition gradually improved during the follow-up. CONCLUSIONS: We reported the first case of KHE presenting with thrombocytopenia and Raynaud phenomenon. The development of Raynaud phenomenon could be associated with increased ET-1 and reduced eNOS and A20 expressions. Careful differential diagnosis of hidden KHE should be considered in children with thrombocytopenia and Raynaud phenomenon.

Performance of interferon-gamma levels may lead to earlier diagnosing macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of rheumatic diseases, predominantly in systemic juvenile idiopathic arthritis (SJIA), and is considered as an autoinflammatory disease. Specific cytokine profiles could play a pivotal role in this inflammatory response. Gram-negative bacteremia, bacterial pneumonia, Kawasaki disease, and active SJIA exhibited similar cytokine profiles with elevated interleukin-6 (IL-6) and/or IL-10, further suggesting a correlation between them. Only when JIA is complicated by MAS can increased interferon-γ (IFN-γ) levels be observed. Therefore, increased serum IFN-γ levels could contribute to early diagnosing MAS in patients with SJIA in combination with other variables such as serum ferritin. A prospective multi-center study will be performed to further confirm the role of IFN-γ in the early recognition of MAS in SJIA.

Case report: Aggressive progression of acute heart failure due to juvenile tuberculosis-associated Takayasu arteritis with aortic stenosis and thrombosis.

Background: Takayasu arteritis (TA) is a chronic granulomatous vasculitis with unknown pathophysiology. TA with severe aortic obstruction has a poor prognosis. However, the efficacy of biologics and appropriate timing of surgical intervention remain controversial. We report a case of tuberculosis (TB)-associated TA with aggressive acute heart failure (AHF), pulmonary hypertension (PH), thrombosis, and seizure, who failed to survive after surgery. Case presentation: A 10-year-old boy who developed a cough with chest tightness, shortness of breath, hemoptysis with reduced left ventricular ejection fraction, PH, and increased C-reactive protein and erythrocyte sedimentation rate was hospitalized at the pediatric intensive care unit of our hospital. He had strongly positive purified protein derivative skin test and interferon-gamma release assay result. Computed tomography angiography (CTA) showed occlusion of proximal left subclavian artery and stenosis of descending aorta and upper abdominal aorta. His condition did not improve after administration of milrinone, diuretics, antihypertensive agents, and intravenous methylprednisolone pulse followed by oral prednisone. Intravenous tocilizumab was administered for five doses, followed by two doses of infliximab, but his HF worsened, and CTA on day 77 showed complete occlusion of the descending aorta with large thrombus. He had a seizure on day 99 with deterioration of renal function. Balloon angioplasty and catheter-directed thrombolysis were performed on day 127. Unfortunately, the child's heart function continued to deteriorate and died on day 133. Conclusion: TB infection may be related to juvenile TA. The biologics, thrombolysis, and surgical intervention failed to achieve the anticipated effect in our case with aggressive AHF due to severe aortic stenosis and thrombosis. More studies are needed to determine the role of biologics and surgery in such dire cases.

Passive sampling of diverse pesticides in water by hydrophilic-lipophilic balance sorbent-embedded cellulose acetate membrane: Kinetics, equilibrium partitioning and field application.

Pesticides are useful products for agriculture and human life, but they are often released into surface waters and are hazardous to aquatic ecosystems. Pesticides monitoring in surface waters is challenging due to the great variety, ultratrace levels and nonpoint source pollution of pesticides; however, continuous passive sampling may be conducive to solving these problems. This work evaluated the performance of a newly developed passive sampler (hydrophilic-lipophilic balance sorbent-embedded cellulose acetate membrane, HECAM) for six types of currently used/present pesticides. The uptake kinetics and equilibrium partitioning of nineteen pesticides in different dissolved concentrations were studied by dynamic accumulation and equilibrium partitioning experiments, respectively. In the dynamic accumulation experiments, pesticides gradually accumulated in the HECAM and followed a first-order kinetic model. The same type of pesticides had roughly comparable accumulation concentrations. The estimated uptake rate constants ranged from 1.04 to 13.5 L g-1 d-1, and sampling rates ranged from 0.02 to 0.31 L d-1 for the pesticides in the HECAM (size of 2 cm × 3 cm). Pesticide accumulation concentrations in the HECAM increased linearly with increasing dissolved concentrations, which means that varying concentrations can also be monitored by the HECAM. In the equilibrium partitioning experiments, the pesticide partitioning behavior at varying dissolved concentrations can be described by the Freundlich model. The calculated equilibrium partition coefficients (log KD) for pesticides ranged from 3.32 to 4.54, and different pesticide types showed different changes with log Kow. Comparable results were found when estimating chemical equilibrium partition coefficients by the dynamic accumulation and equilibrium partitioning methods. Field deployment of the HECAM in river waters resulted in the detection of four pesticides, and the measured results were comparable to those of active sampling coupled with liquid-liquid extraction. These results suggest that the HECAM would be a promising strategy for simultaneously monitoring diverse pesticides in waters.

First metabolic profiling of 4-n-nonylphenol in human liver microsomes by integrated approaches to testing and assessment: Metabolites, pathways, and biological effects.

4-n-nonylphenol (4-n-NP), a typical endocrine disrupting chemical, has been so far frequently detected in various environmental mediums and editable food. However, the specific metabolic pathways in human and potential adverse effects of metabolites have not been elucidated yet. Here, metabolic profiling of 4-n-NP in human liver microsome (HLM) was comprehensively characterized by integrated approaches of testing and assessment. A total of 21 metabolites were identified using nontarget analysis with high-resolution mass spectrum, including three groups of unique phase I metabolites first determined in HLM. Seven various metabolic pathways of 4-n-NP were identified by both in silico and in vitro, and CYP1A2, 2C19, and 2D6 were the mainly participating enzymes. Two secondary metabolites with carbonyl groups on side chains (M4, M7) presented most abundant in HLM, which were also predicted to have high binding affinities towards HPG-axis-related receptors (AR, ER, and PR). ESRs (estrogen receptors) were shared core protein targets for all metabolites revealed by protein-protein interaction networks. Biological functions enrichment analysis indicated that 4-n-NP metabolites might primarily involve in ESR-mediated signaling, GPCR ligand binding, Class A/1 (Rhodopsin-like receptors) and metabolism-related pathways. These findings of 4-n-NP metabolites, pathways, and biological effects provide insightful information for its environmental exposure and risk assessment.

Small-molecule anti-COVID-19 drugs and a focus on China's homegrown mindeudesivir (VV116).

The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral infection. So far, a few small-molecule antiviral drugs, including nirmatrelvir-ritonavir (Paxlovid), remdesivir, and molnupiravir have been marketed for the treatment of COVID-19. Nirmatrelvir-ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate COVID-19. However, the existing treatment options have limitations, and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still needed. To date, four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in China. These drugs include azvudine, simnotrelvir-ritonavir (Xiannuoxin), leritrelvir, and mindeudesivir (VV116). Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for progression. In this review, we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for COVID-19. These findings will expand our understanding and highlight the potential widespread application of China's homegrown anti-COVID-19 drugs.

Assessment of Thigh MRI Radiomics and Clinical Characteristics for Assisting in Discrimination of Juvenile Dermatomyositis.

Magnetic resonance imaging (MRI) is an important non-invasive examination in the early diagnosis of juvenile dermatomyositis (JDM). We aimed to evaluate the feasibility of radiomics to establish a quantitative analysis of MRI images. Radiomics and machine learning were used to retrospectively analyze MRI T2 fat suppression sequences and relevant clinical data. The model associated with radiomics features was established using a cohort of patients who underwent thigh MRI at the children's hospital from June 2014 to September 2021. In total, 75 patients with JDM and 75 control children were included in the training cohort (n = 102) and validation cohort (n = 48). The independent factors including lower muscle strength (OR, 0.75; 95% CI, 0.59-0.90), higher creatine kinase (CK) level (OR, 1.65; 95% CI, 1.20-2.38), and higher radiomics score (OR, 2.30; 95% CI, 1.63-3.62) were associated with a clinical diagnosis of JDM. The combined model achieved good discrimination performance compared the radiomics score model under linear discriminant analyses in the training cohort (AUC, 0.949; 95% CI, 0.912-0.986 vs. AUC, 0.912; 95% CI, 0.858-0.967; p = 0.02) and in the validation cohort (AUC, 0.945; 95% CI, 0.878-1 vs. AUC, 0.905; 95% CI, 0.812-0.998; p = 0.03). The combined model showed the diagnostic value was not weaker than the biopsy (AUC, 0.950; 95% CI, 0.919-0.981, n = 150 vs. AUC, 0.952; 95% CI, 0.889-1, n = 72; p = 0.95) and electromyogram (EMG) (AUC, 0.950; 95% CI, 0.919-0.981 vs. AUC, 0.900; 95% CI, 0.852-0.948; p = 0.10) among all the patients. The combination of radiomics features extracted from the MRI and non-invasive clinical characteristics obtained a pronounced discriminative performance to assist in discriminating JDM.

Exploration of the immune microenvironment of breast cancer in large population cohorts.

Tumor immune microenvironment is associated with tumor progression. However, previous studies have not fully explored the breast cancer (BC) immune microenvironment. All the data analyzed in this study were obtained from the open-access database, including The Cancer Genome Atlas, Gene Expression Omnibus (TCGA), and cBioPortal databases. R software v4.0 and SPSS 13.0 were used to perform all the statistical analysis. Firstly, the clinical and expression profile information of TCGA, GSE20685, GSE20711, GSE48390, GSE58812, and METABRIC cohorts was collected. Then, 53 immune terms were quantified using the single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm. A prognosis model based on HER2_Immune_PCA, IL12_score, IL13_score, IL4_score, and IR7_score was established, which showed great prognosis prediction efficiency in both training group and validation group. A nomogram was then established for a better clinical application. Clinical correlation showed that elderly BC patients might have a higher riskscore. Pathway enrichment analysis showed that the pathway of oxidative phosphorylation, E2F targets, hedgehog signaling, adipogenesis, DNA repair, glycolysis, heme metabolism, and mTORC1 signaling was activated in the high-risk group. Moreover, Tumor Immune Dysfunction and Exclusion and Genomics of Drug Sensitivity in Cancer analysis showed that low-risk patients might be more sensitive to PD-1 therapy, cisplatin, gemcitabine, paclitaxel, and sunitinib. Finally, four genes, XCL1, XCL2, TNFRSF17, and IRF4, were identified for risk group classification. In summary, our signature is a useful tool for the prognosis and prediction of the drug sensitivity of BC.

Diagnostic and Prognostic Nomograms for Lung Metastasis in Triple-Negative Breast Cancer.

Background: The lungs are one of the common sites of metastasis of triple-negative breast cancer (TNBC). Patients with lung metastases (LM) have a shorter duration of survival. This study is aimed at determining the prognostic factors of patients with TNBC with LM and constructing two nomograms to assess the risk of LM and the prognosis of patients with TNBC with LM. Methods: Clinicopathological and follow-up data of patients with TNBC between 2010 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression analyses were used to screen for independent predictors of LM in patients with TNBC and identify the independent prognostic factors of patients with TNBC with LM. The two nomograms were appraised using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Results: A total of 27,048 patients with TNBC were included in this study. Age, tumour size, T stage, and N stage were identified as independent risk factors for LM in patients with TNBC. Histological type, marital status, prior surgery, chemotherapy, bone metastases, brain metastases, and LM were confirmed as independent prognostic factors for patients with TNBC with LM. The area under the ROC curve (AUC) of the diagnostic nomogram was 0.838 (95% confidence interval 0.817-0.860) in the training cohort and 0.894 (95% confidence interval 0.875-0.917) in the verification cohort. The AUC values of the 6-, 12-, and 18-month prognostic nomograms in the training cohort were 0.809 (95% confidence interval 0.771-0.868), 0.779 (95% confidence interval 0.737-0.834), and 0.735 (95% confidence interval 0.699-0.811), respectively, and the corresponding AUC values in the validation cohort were 0.735(95% confidence interval 0.642-0.820), 0.672 (95% confidence interval 0.575-0.758), and 0.705 (95% confidence interval 0.598-0.782), respectively. According to the calibration curves and data analysis, both nomograms exhibited good performance. Conclusion: We successfully constructed and verified two valuable nomograms for predicting the incidence of LM and prognosis of patients TNBC with LM.

The Relative Body Weight Gain From Early to Middle Life Adulthood Associated With Later Life Risk of Diabetes: A Nationwide Cohort Study.

Aim: To determine the effect of decade-based body weight gain from 20 to 50 years of age on later life diabetes risk. Methods: 35,611 non-diabetic participants aged ≥ 50 years from a well-defined nationwide cohort were followed up for average of 3.6 years, with cardiovascular diseases and cancers at baseline were excluded. Body weight at 20, 30, 40, and 50 years was reported. The overall 30 years and each 10-year weight gain were calculated from the early and middle life. Cox regression models were used to estimate risks of incident diabetes. Results: After 127,745.26 person-years of follow-up, 2,789 incident diabetes were identified (incidence rate, 2.18%) in 25,289 women (mean weight gain 20-50 years, 7.60 kg) and 10,322 men (7.93 kg). Each 10-kg weight gain over the 30 years was significantly associated with a 39.7% increased risk of incident diabetes (95% confidence interval [CI], 1.33-1.47); weight gain from 20-30 years showed a more prominent effect on the risk of developing diabetes before 60 years than that of after 60 years (Hazard ratio, HR = 1.084, 95% CI [1.049-1.121], P <0.0001 vs. 1.015 [0.975-1.056], P = 0.4643; PInteraction=0.0293). It showed a stable effect of the three 10-year intervals weight gain on risk of diabetes after 60 years (HR=1.055, 1.038, 1.043, respectively, all P < 0.0036). Conclusions: The early life weight gain showed a more prominent effect on developing diabetes before 60 years than after 60 years; however, each-decade weight gain from 20 to 50 years showed a similar effect on risk developing diabetes after 60 years.

Discovery of METTL3 Small Molecule Inhibitors by Virtual Screening of Natural Products.

N6-Methyladenosine (m6A) is the most prevalent mRNA modification in mammalian cells that is mainly catalyzed by the methyltransferase complex of methyltransferase-like 3 and methyltransferase-like 14 (METTL3-METTL14). Many lines of evidence suggest that METTL3 plays important roles in several diseases such as cancers and viral infection. In the present study, 1,042 natural products from commercially available sources were chosen to establish a screening library, and docking-based high-throughput screening was performed to discover potential METTL3 inhibitors. The selected compounds were then further validated by an in vitro methyltransferase inhibition assay in which m6A content was determined by LC-MS/MS. A cellular assay of the inhibition of m6A methylation was performed to determine the METTL3 inhibitory activity of the selected compound. CCK-8 assay was applied to evaluate the effects of the selected compound on tumor cell viability. Additionally, binding mode analysis, molecular dynamics (MD) simulation, and binding free energy analysis were performed to study the process and characteristics of inhibitor binding. Finally, quercetin was identified as a METTL3 inhibitor with an IC50 value of 2.73 µM. The cellular assay of m6A methylation inhibition showed that quercetin decreased m6A level in a dose-dependent manner in MIA PaCa-2 pancreatic cancer cells. CCK-8 assay showed quercetin efficiently inhibited the proliferation of MIA PaCa-2 and Huh7 tumor cells, with IC50 values 73.51 ± 11.22 µM and 99.97 ± 7.03 µM, respectively. Molecular docking studies revealed that quercetin filled the pocket of the adenosine moiety of SAM but not the pocket of the SAM methionine in the METTL3 protein, and hydrogen bonds, hydrophobic interactions, and pi-stacking were formed. The values of the root mean square deviation (RMSD), the root mean square fluctuations (RMSF), and binding free energy suggested that quercetin can efficiently bind to the pocket of the METTL3 protein and form a stable protein-ligand complex. The present study is the first to identify METTL3 inhibitors from natural products, thus providing a basis for subsequent research and facilitating the development of METTL3-targeting drugs for diseases.

Metabolomics study reveals systematic metabolic dysregulation and early detection markers associated with incident pancreatic cancer.

Biomarkers for early detection of pancreatic cancer are in urgent need. To explore systematic circulating metabolites unbalance and identify potential biomarkers for pancreatic cancer in prospective Chinese cohorts, we conducted an untargeted metabolomics study in subjects with incident pancreatic cancer and matched controls (n = 192) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. We characterized 998 metabolites in baseline serum and calculated 156 product-to-precursor ratios based on the KEGG database. The identified metabolic profiling revealed systematic metabolic network disorders before pancreatic cancer diagnosis. Forty-Five metabolites or product-to-precursor ratios showed significant associations with pancreatic cancer (P < .05 and FDR < 0.1), revealing abnormal metabolism of amino acids (especially alanine, aspartate and glutamate), lipids (especially steroid hormones), vitamins, nucleotides and peptides. A novel metabolite panel containing aspartate/alanine (OR [95% CI]: 1.97 [1.31-2.94]), androstenediol monosulfate (0.69 [0.49-0.97]) and glycylvaline (1.68 [1.04-2.70]) was significantly associated with risk of pancreatic cancer. Area under the receiver operating characteristic curves (AUCs) was improved from 0.573 (reference model of CA 19-9) to 0.721. The novel metabolite panel was validated in an independent cohort with AUC improved from 0.529 to 0.661. These biomarkers may have a potential value in early detection of pancreatic cancer.

Non-alcoholic fatty liver disease, metabolic goal achievement with incident cardiovascular disease and eGFR-based chronic kidney disease in patients with prediabetes and diabetes.

AIMS/HYPOTHESIS: We aimed to evaluate the effect of NAFLD on the risk of incident cardiovascular disease (CVD) and estimated glomerular filtration rate (eGFR)-based chronic kidney disease (CKD), and further test the joint effects and interactions between NAFLD status and individual metabolic element, as well as the total 'ABCs' metabolic goal achievement, on the CVD and CKD risk among 101,296 patients with prediabetes or diabetes from a prospective cohort study. METHODS: We conducted the study based on the China Cardiometabolic Disease and Cancer Cohort (4C) study, a large-scale, population-based prospective cohort. After excluding alcohol abuse and other cause of hepatic diseases, we used fatty liver index (FLI) ≥ 60 as a proxy of NAFLD and stratified the probability of fibrosis by aspartate transaminase/alanine transaminase ratio (AAR) with cut-offs of 0.8 and 1.4. 'ABCs' metabolic goal was defined as subjects who had HbA1c < 6.5% (A), SBP/DBP < 130/80 mmHg (B), and LDL-C < 100 mg/dL (C). During 3.8 years follow-up, we validated 2340 CVD events based on medical records and identified 1943 participants developed CKD based on centrally tested eGFR. RESULTS: The multivariable adjusted hazard ratios (HRs) were 1.15 (95% confidence interval (CI), 1.05-1.27) for CVD events and 1.33 (95% CI, 1.20-1.48) for CKD among NAFLD patients, compared with participants without NAFLD. Of NAFLD patients, relative to individuals with low AAR (<0.8), those with high AAR (≥1.4) were more likely to experience CVD events [1.62 (1.21-2.18)] and CKD [1.63 (1.17-2.28)]. Participants with NAFLD and comorbid poorly controlled metabolic risk factors had higher risk of CVD events or CKD than having either alone, with a significant interaction between poor glycemic control and NAFLD on the risk of vascular complications. CONCLUSIONS: NAFLD was associated with incident CVD and CKD among patients with prediabetes or diabetes. Such associations were substantially modified by the comprehensive achievement of metabolic goal.

Age-specific modifiable risk factor profiles for cardiovascular disease and all-cause mortality: a nationwide, population-based, prospective cohort study.

BACKGROUND: National investigations on age-specific modifiable risk factor profiles for cardiovascular disease (CVD) and mortality are scarce in China, the country that is experiencing a huge cardiometabolic burden exacerbated by population ageing. METHODS: This is a nationwide prospective cohort study of 193,846 adults in the China Cardiometabolic Disease and Cancer Cohort Study, 2011-2016. Among 139,925 participants free from CVD at baseline, we examined hazard ratios and population-attributable risk percentages (PAR%s) for CVD and all-cause mortality attributable to 12 modifiable socioeconomic, psychosocial, lifestyle, and metabolic risk factors by four age groups (40-<55 years, 55-<65 years, 65-<75 years, and ≥75 years). FINDINGS: Metabolic risk factors accounted for 52·4%, 47·2%, and 37·8% of the PAR% for CVD events in participants aged 40-<55 years, 55-<65 years, and 65-<75 years, respectively, with hypertension being the largest risk factor. While in participants aged ≥75 years, lifestyle risk factors contributed to 34·0% of the PAR% for CVD, with inappropriate sleep duration being the predominant risk factor. Most deaths were attributed to metabolic risk factors (PAR% 25·3%) and lifestyle risk factors (PAR% 24·6%) in participants aged 40-<55 years, with unhealthy diet and diabetes being the main risk factors. While in participants aged ≥55 years, most deaths were attributed to lifestyle risk factors (PAR% 26·6%-41·0%) and socioeconomic and psychosocial risk factors (PAR% 26·1%-27·7%). In participants aged ≥75 years, lifestyle risk factors accounted for 41·0% of the PAR% for mortality, with inappropriate sleep duration being the leading risk factor. INTERPRETATION: We identified age-specific modifiable risk profiles for CVD and all-cause mortality in Chinese adults, with remarkable differences between adults aged ≥75 years and their younger counterparts. FUNDING: National Natural Science Foundation of China.

Age-related disparities in diabetes risk attributable to modifiable risk factor profiles in Chinese adults: a nationwide, population-based, cohort study.

BACKGROUND: National investigations of age-specific modifiable risk profiles for diabetes are crucial to promote personalised strategies for the prevention and control of diabetes, particularly in countries such as China, which is experiencing both a diabetes epidemic and a rapidly ageing population. We aimed to examine the associations of 12 potentially modifiable socioeconomic, lifestyle, and metabolic risk factors with diabetes in a nationwide prospective cohort of Chinese adults across four age groups. METHODS: We analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, a nationwide, population-based, cohort study done between Jan 1, 2011, and Dec 31, 2016. Among 93 781 participants without diabetes at baseline and with complete information available about risk factors and diabetes incidence, we examined the hazard ratios (HRs) and population-attributable risk percentages (PAR%s) of incident diabetes associated with 12 potentially modifiable risk factors: two socioeconomic risk factors (less education and intermediate or low grade occupation), five lifestyle risk factors (unhealthy diet, physical inactivity, current alcohol consumption, current smoking, and unhealthy sleep), and five metabolic risk factors (general or central obesity, insulin resistance, prediabetes, hypertension, and dyslipidaemia) across four age groups (40 to <55 years, 55 to <65 years, 65 to <75 years, and ≥75 years). FINDINGS: With 337 932 person-years' follow-up, 6171 participants developed diabetes. Although diabetes risk attributable to metabolic risk factors decreased slightly with age, metabolic risk factors accounted for most incident diabetes cases across all age groups (from a PAR% of 73·8% in participants aged 40 to <55 years to 65·5% in those aged ≥75 years), with prediabetes (ranging from a PAR% of 56·6% to 47·4%, with increasing age) and hypertension (PAR% of 16·8% to 28·6% with increasing age) being the leading risk factors across all age groups. By contrast, diabetes risk attributable to lifestyle risk factors increased substantially with age (with a PAR% of 9·9% in adults aged 40 to <55 years increasing to 29·7% in adults aged ≥75 years), and was especially evident in participants aged 75 years or older, in whom unhealthy sleep was the largest lifestyle factor, accounting for a PAR% of 17·0%. The impact of socioeconomic risk factors on diabetes was mainly driven by less education, which contributed to a PAR% of 7·1% to 12·4% in participants younger than 75 years but conferred no excess risk in participants aged 75 years or older. The risk of diabetes associated with unhealthy sleep significantly increased with age group (HR 1·04 [95% CI 0·95-1·13] among participants aged 40 to <55 years vs 1·36 [1·01-1·85] among participants aged ≥75 years; pinteraction=0·0054), but there was an age-related decrease in the risk of diabetes associated with obesity (1·35 [1·23-1·48] vs 0·99 [0·72-1·36]; pinteraction=0·0003), prediabetes (3·00 [2·67-3·37] vs 2·18 [1·41-3·37]; pinteraction=0·0014), and dyslipidaemia (1·23 [1·13-1·34] vs 0·90 [0·66-1·21]; pinteraction=0·016). INTERPRETATION: These findings provide novel insights into age-related modifiable risk factor profiles for diabetes in Chinese adults, highlighting the importance of prioritising risk factors according to age groups for effective prevention and management of diabetes. FUNDING: National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia.

Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.

Individual and Combined Associations of Modifiable Lifestyle and Metabolic Health Status With New-Onset Diabetes and Major Cardiovascular Events: The China Cardiometabolic Disease and Cancer Cohort (4C) Study.

OBJECTIVE: We aimed to determine the individual and combined associations of lifestyle and metabolic factors with new-onset diabetes and major cardiovascular events among a Chinese population aged ≥40 years. RESEARCH DESIGN AND METHODS: Baseline lifestyle information, waist circumference, blood pressure, lipid profiles, and glycemic status were obtained in a nationwide, multicenter, prospective study of 170,240 participants. During the up to 5 years of follow-up, we detected 7,847 individuals with new-onset diabetes according to the American Diabetes Association 2010 criteria and 3,520 cardiovascular events, including cardiovascular death, myocardial infarction, stroke, and hospitalized or treated heart failure. RESULTS: On the basis of 36.13% (population-attributable fraction [PAF]) risk attributed to metabolic risk components collectively, physical inactivity (8.59%), sedentary behavior (6.35%), and unhealthy diet (4.47%) moderately contributed to incident diabetes. Physical inactivity (13.34%), unhealthy diet (8.70%), and current smoking (3.38%) significantly contributed to the risk of major cardiovascular events, on the basis of 37.42% PAF attributed to a cluster of metabolic risk factors. Significant associations of lifestyle health status with diabetes and cardiovascular events were found across all metabolic health categories. Risks of new-onset diabetes and major cardiovascular events increased simultaneously according to the worsening of lifestyle and metabolic health status. CONCLUSIONS: We showed robust effects of lifestyle status on new-onset diabetes and major cardiovascular events regardless of metabolic status and a graded increment of risk according to the combination of lifestyle and metabolic health, highlighting the importance of lifestyle modification regardless of the present metabolic status.

Laparoscopic Management of Choledochal Cysts Associated with Aberrant Hepatic Ducts.

Introduction and objectives: This study assessed the diagnostic protocol and the outcomes of laparoscopic aberrant hepatic duct (AHD) reconstruction in choledochal cyst (CC) surgery. Methods: From January 2010 to January 2018, 275 laparoscopic CC excisions were conducted in our hospital. Seven patients of CC with associated AHD were recorded. AHDs that drained into the cystic duct were anastomosed to the Roux-en-Y loop. Clinical data of these 7 patients were retrospectively analyzed. Results: AHD is classified into four types according to the literature. The type where AHD drains into the cystic duct is the most commonly encountered one. The incidence of this type was 2.5% (7/275) in our series. Preoperative examination included magnetic resonance cholangiopancreatography (MRCP) (5 patients) and computed tomography (CT) scan (2 patients). Suspected AHD was diagnosed preoperatively in 4 out of the 5 patients who underwent MRCP. For the 2 patients who underwent CT scan only, AHD was not detected preoperatively. AHD was verified intraoperatively for all the 4 patients who had suspected diagnosis. Among them, AHD was well preserved in 3 patients, but damaged at exploration in the remaining 1. For the remaining 3 patients without preoperative AHD diagnosis, bile leakage was detected intraoperatively. Ductoplasty of the AHD with common hepatic duct was performed in 3 patients, and AHD was incorporated into the Roux-en-Y jejunal loop separately in 4 patients. Laparoscopic surgical procedures were completed in 6 of the 7 patients in this study, while 1 patient was converted into an open procedure. Postoperative recovery was uneventful in all patients. The duration of follow-up ranged from 6 months to 4 years (median 2 years) with no complication encountered. Conclusions: Routine preoperative MRCP examination of CC is recommended to detect variations of biliary tree. The laparoscopic approach is a feasible option in the experienced hands.