Identification of 8 Rare Deleterious Variants in ADAMTS13 by Next-generation Sequencing in a Chinese Population with Thrombotic Thrombocytopenic Purpura.

OBJECTIVE: Thrombotic thrombocytopenic purpura (TTP) is a rare and fatal disease caused by a severe deficiency in the metalloprotease ADAMTS13 and is characterized by thrombotic microangiopathy. The present study aimed to investigate the genes and variants associated with TTP in a Chinese population. METHODS: Target sequencing was performed on 220 genes related to complements, coagulation factors, platelets, fibrinolytic, endothelial, inflammatory, and anticoagulation systems in 207 TTP patients and 574 controls. Subsequently, logistic regression analysis was carried out to identify the TTP-associated genes based on the counts of rare deleterious variants in the region of a certain gene. Moreover, the associations between common variants and TTP were also investigated. RESULTS: ADAMTS13 was the only TTP-associated gene (OR = 3.77; 95% CI: 1.82-7.81; P=3.6×10È¡4) containing rare deleterious variants in TTP patients. Among these 8 variants, 5 novel rare variants that might contribute to TTP were identified, including rs200594025, rs782492477, c.T1928G (p.I643S), c.3336_3361del (p.Q1114Afs*20), and c.3469_3470del (p.A1158Sfs*17). No common variants associated with TTP were identified under the stringent criteria of correction for multiple testing. CONCLUSION: ADAMTS13 is the primary gene related to TTP. The genetic variants associated with the occurrence of TTP were slightly different between the Chinese and European populations.

Association of immune cell composition with the risk factors and incidence of acute coronary syndrome.

BACKGROUND: Although immune cells are involved in acute coronary syndrome (ACS), few studies have explored the association of incident ACS with the relative immune cell proportions. We aimed to investigate the association of immune cell proportions with the incidence and risk factors of ACS in the Dongfeng-Tongji cohort. METHODS: We conducted the analyses with 38,295 subjects from the first follow-up of the Dongfeng-Tongji cohort, including DNA methylation profiles for 1570 individuals. The proportions of immune cell types were observed from routine blood tests or estimated from DNA methylation profiles. For both observed and estimated immune cell proportions, we tested their associations with risk factors of ACS by multivariable linear regression models. In addition, the association of each immune cell proportion with incident ACS was assessed by the Cox regression model and conditional logistic regression model, respectively, adjusting for the risk factors of ACS. FINDINGS: The proportions of lymphocytes, monocytes, and neutrophils showed strong associations with sex, followed by diabetes. Moreover, sex and current smoking were the two factors with strongest association with the proportions of lymphocyte subtypes. The hazard ratio (HR) and 95% confidence interval (CI) of incident ACS per standard deviation (SD) increase in proportions of lymphocytes and neutrophils were 0.91 (0.85-0.96) and 1.10 (1.03-1.16), respectively. Furthermore, the OR (95% CI) of incident ACS per SD increase in proportions of NK cells, CD4+ T cells, and B cells were 0.88 (0.78-0.99), 1.15 (1.03-1.30), and 1.13 (1.00-1.26), respectively. INTERPRETATION: The proportions of immune cells were associated with several risk factors of ACS, including sex, diabetes, and current smoking. In addition, proportion of neutrophils had a risk effect, while proportion of lymphocytes had a protective effect on the incidence of ACS. The protective effect of lymphocytes was probably driven by NK cells.

Investigating the shared genetic architecture and causal relationship between pain and neuropsychiatric disorders.

Pain often occurs in parallel with neuropsychiatric disorders. However, the underlying mechanisms and potential causality have not been well studied. We collected the genome-wide association study (GWAS) summary statistics of 26 common pain and neuropsychiatric disorders with sample size ranging from 17,310 to 482,730 in European population. The genetic correlation between pair of pain and neuropsychiatric disorders, as well as the relevant cell types were investigated by linkage disequilibrium (LD) score regression analyses. Then, transcriptome-wide association study (TWAS) was applied to identify the potential shared genes by integrating the gene expression information and GWAS. In addition, Mendelian randomization (MR) analyses were conducted to infer the potential causality between pain and neuropsychiatric disorders. Among the 169 pairwise pain and neuropsychiatric disorders, 55 pairs showed positive correlations (median rg = 0.43) and 9 pairs showed negative correlations (median rg = -0.31). Using MR analyses, 26 likely causal associations were identified, including that neuroticism and insomnia were risk factors for most of short-term pain, and multisite chronic pain was risk factor for neuroticism, insomnia, major depressive disorder and attention deficit/hyperactivity disorder, and vice versa. The signals of pain and neuropsychiatric disorders tended to be enriched in the functional regions of cell types from central nervous system (CNS). A total of 19 genes shared in at least one pain and neuropsychiatric disorder pair were identified by TWAS, including AMT, NCOA6, and UNC45A, which involved in glycine degradation, insulin secretion, and cell proliferation, respectively. Our findings provided the evidence of shared genetic structure, causality and potential shared pathogenic mechanisms between pain and neuropsychiatric disorders, and enhanced our understanding of the comorbidities of pain and neuropsychiatric disorders.

Predictive Risk Factors at Admission and a "Burning Point" During Hospitalization Serve as Sequential Alerts for Critical Illness in Patients With COVID-19.

Background: We intended to establish a novel critical illness prediction system combining baseline risk factors with dynamic laboratory tests for patients with coronavirus disease 2019 (COVID-19). Methods: We evaluated patients with COVID-19 admitted to Wuhan West Union Hospital between 12 January and 25 February 2020. The data of patients were collected, and the illness severity was assessed. Results: Among 1,150 enrolled patients, 296 (25.7%) patients developed into critical illness. A baseline nomogram model consists of seven variables including age [odds ratio (OR), 1.028; 95% confidence interval (CI), 1.004-1.052], sequential organ failure assessment (SOFA) score (OR, 4.367; 95% CI, 3.230-5.903), neutrophil-to-lymphocyte ratio (NLR; OR, 1.094; 95% CI, 1.024-1.168), D-dimer (OR, 1.476; 95% CI, 1.107-1.968), lactate dehydrogenase (LDH; OR, 1.004; 95% CI, 1.001-1.006), international normalised ratio (INR; OR, 1.027; 95% CI, 0.999-1.055), and pneumonia area interpreted from computed tomography (CT) images (medium vs. small [OR, 4.358; 95% CI, 2.188-8.678], and large vs. small [OR, 9.567; 95% CI, 3.982-22.986]) were established to predict the risk for critical illness at admission. The differentiating power of this nomogram scoring system was perfect with an area under the curve (AUC) of 0.960 (95% CI, 0.941-0.972) in the training set and an AUC of 0.958 (95% CI, 0.936-0.980) in the testing set. In addition, a linear mixed model (LMM) based on dynamic change of seven variables consisting of SOFA score (value, 2; increase per day [I/d], +0.49), NLR (value, 10.61; I/d, +2.07), C-reactive protein (CRP; value, 46.9 mg/L; I/d, +4.95), glucose (value, 7.83 mmol/L; I/d, +0.2), D-dimer (value, 6.08 µg/L; I/d, +0.28), LDH (value, 461 U/L; I/d, +13.95), and blood urea nitrogen (BUN value, 6.51 mmol/L; I/d, +0.55) were established to assist in predicting occurrence time of critical illness onset during hospitalization. Conclusion: The two-checkpoint system could assist in accurately and dynamically predicting critical illness and timely adjusting the treatment regimen for patients with COVID-19.

Incubation period of coronavirus disease 2019: new implications for intervention and control.

The COVID-19 pandemic has been causing serious disasters to mankind. The incubation period is a key parameter for epidemic control and also an important basis for epidemic prediction, but its distribution law remains unclear. This paper analyzed the epidemiological information of 787 confirmed non-Wuhan resident cases, and systematically studied the characteristics of the incubation period of COVID-19 based on the interval-censored data estimation method. The results show that the incubation period of COVID-19 approximately conforms to the Gamma distribution with a mean value of 7.8 (95%CI:7.4-8.5) days and a median value of 7.0 (95%CI:6.7-7.3) days. The incubation period was positively correlated with age and negatively correlated with disease severity. Female cases presented a slightly higher incubation period than that of males. The proportion of infected persons who developed symptoms within 14 days was 91.6%. These results are of great significance to the prevention and control of the COVID-19 pandemic.

Deconvolution of Bulk Gene Expression Profiles with Single-Cell Transcriptomics to Develop a Cell Type Composition-Based Prognostic Model for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is one of the malignant hematologic cancers with rapid progress and poor prognosis. Most AML prognostic stratifications focused on genetic abnormalities. However, none of them was established based on the cell type compositions (CTCs) of peripheral blood or bone marrow aspirates from patients at diagnosis. Here we sought to develop a novel prognostic model for AML in adults based on the CTCs. First, we applied the CIBERSORT algorithm to estimate the CTCs for patients from two public datasets (GSE6891 and TCGA-LAML) using a custom gene expression signature reference constructed by an AML single-cell RNA sequencing dataset (GSE116256). Then, a CTC-based prognostic model was established using least absolute shrinkage and selection operator Cox regression, termed CTC score. The constructed prognostic model CTC score comprised 3 cell types, GMP-like, HSC-like, and T. Compared with the low-CTC-score group, the high-CTC-score group showed a 1.57-fold [95% confidence interval (CI), 1.23 to 2.00; p = 0.0002] and a 2.32-fold (95% CI, 1.53 to 3.51; p < 0.0001) higher overall mortality risk in the training set (GSE6891) and validation set (TCGA-LAML), respectively. When adjusting for age at diagnosis, cytogenetic risk, and karyotype, the CTC score remained statistically significant in both the training set [hazard ratio (HR) = 2.25; 95% CI, 1.20 to 4.24; p = 0.0119] and the validation set (HR = 7.97; 95% CI, 2.95 to 21.56; p < 0.0001]. We further compared the performance of the CTC score with two gene expression-based prognostic scores: the 17-gene leukemic stem cell score (LSC17 score) and the AML prognostic score (APS). It turned out that the CTC score achieved comparable performance at 1-, 2-, 3-, and 5-years timepoints and provided independent and additional prognostic information different from the LSC17 score and APS. In conclusion, the CTC score could serve as a powerful prognostic marker for AML and has great potential to assist clinicians to formulate individualized treatment plans.

Modelling the initial epidemic trends of COVID-19 in Italy, Spain, Germany, and France.

The Coronavirus Disease 2019 (COVID-19) has fast spread to over 200 countries and regions worldwide since its outbreak, while in March, Europe became the emerging epicentre. In this study, we aimed to model the epidemic trends and estimate the essential epidemic features of COVID-19 in Italy, Spain, Germany, and France at the initial stage. The numbers of daily confirmed cases and total confirmed cases were extracted from the Coronavirus disease (COVID-19) situation reports of WHO. We applied an extended Susceptible-Exposed-Infectious-Removed (SEIR) model to fit the epidemic trend and estimated corresponding epidemic features. The transmission rate estimates were 1.67 (95% credible interval (CrI), 1.64-1.71), 2.83 (2.72-2.85), 1.91 (1.84-1.98), and 1.89 (1.82-1.96) for Italy, Spain, Germany, and France, corresponding to the basic reproduction numbers (R0) 3.44 (3.35-3.54), 6.25 (5.97-6.55), 4.03 (3.84-4.23), and 4.00 (3.82-4.19), respectively. We found Spain had the lowest ascertainment rate of 0.22 (0.19-0.25), followed by France, Germany, and Italy of 0.45 (0.40-0.50), 0.46 (0.40-0.52), and 0.59 (0.55-0.64). The peaks of daily new confirmed cases would reach on April 16, April 5, April 21, and April 19 for Italy, Spain, Germany, and France if no action was taken by the authorities. Given the high transmissibility and high covertness of COVID-19, strict countermeasures, such as national lockdown and social distancing, were essential to be implemented to reduce the spread of the disease.

Integrative analysis of scRNA-seq and GWAS data pinpoints periportal hepatocytes as the relevant liver cell types for blood lipids.

Liver, a heterogeneous tissue consisting of various cell types, is known to be relevant for blood lipid traits. By integrating summary statistics from genome-wide association studies (GWAS) of lipid traits and single-cell transcriptome data of the liver, we sought to identify specific cell types in the liver that were most relevant for blood lipid levels. We conducted differential expression analyses for 40 cell types from human and mouse livers in order to construct the cell-type specifically expressed gene sets, which we refer to as construction of the liver cell-type specifically expressed gene sets (CT-SEGS). Under the assumption that CT-SEGS represented specific functions of each cell type, we applied stratified linkage disequilibrium score regression to determine cell types that were most relevant for complex traits and diseases. We first confirmed the validity of this method (of delineating functionally relevant cell types) by identifying the immune cell types as relevant for autoimmune diseases. We further showed that lipid GWAS signals were enriched in the human and mouse periportal hepatocytes. Our results provide important information to facilitate future cellular studies of the metabolic mechanism affecting blood lipid levels.

The effects of Japanese encephalitis virus antibodies on Zika virus infection.

Recently, Zika virus (ZIKV) has become more widespread, thus attracting global attention. The vaccine against Japanese encephalitis virus (JEV) is currently used in China, being included in planned immunisation regimes. Although ZIKV and JEV are closely related mosquito-borne Flaviviruses, and a complex cross-immune response within flaviviruses has been demonstrated, the effect of JEV vaccination on ZIKV infection has not been well described. Thus, this study aimed to explore the impact of different titres of anti-JEV antibodies (Abs) against ZIKV infection using sera from healthy human donors in Guangzhou and anti-JEV rabbit polyclonal antibodies (pAbs) in vitro and vivo. Human anti-JEV Ab titres were tested at decreasing concentrations as the age increased. A neutralising effect on ZIKV infection was observed when anti-JEV Ab titres in human sera or rabbit pAbs were high (the corresponding age was under 30 years). Even though a lower titre in human sera showed no apparent effect, whereas rabbit pAbs had an antibody-dependent enhancement(ADE)effect, we proved an ADE effect in vivo for the first time. This study suggests that individuals over 60 years of age are at high risk for JEV and ZIKV infection, and screening this age group for infection should strengthen. Furthermore, a deep exploration of the relationship between anti-JEV Abs and ZIKV infection is needed.