Objective To explore the safety and effects of alpha-lipoic acid (ALA) in patients with ischemic heart failure (IHF). Methods A randomized, double-blind, placebo-controlled trial was designed (ClinicalTrial.gov registration number NCT03491969). From January 2019 to January 2023, 300 patients with IHF were enrolled in four medical centers in China, and were randomly assigned at a 1∶1 ratio to receive ALA (600 mg daily) or placebo on top of standard care for 24 months. The primary outcome was the composite outcome of hospitalization for heart failure (HF) or all-cause mortality events. The second outcome included non-fatal myocardial infarction (MI), non-fatal stroke, changes of left ventricular ejection fraction (LVEF) and 6-minute walking distance (6MWD) from baseline to 24 months after randomization. Results Finally, 138 patients of the ALA group and 139 patients of the placebo group attained the primary outcome. Hospitalization for HF or all-cause mortality events occurred in 32 patients (23.2%) of the ALA group and in 40 patients (28.8%) of the placebo group (HR＝0.753, 95%CI 0.473-1.198, P＝0.231; Figure 1A-1C). The absolute risk reduction (ARR) was 5.6%, the relative risk reduction (RRR) associated with ALA therapy was approximately 19.4% compared to placebo, corresponding to a number needed to treat (NNT) of 18 patients to prevent one event. In the secondary outcome analysis, the composite outcome of the major adverse cardiovascular events (MACE) including the hospitalization for HF, all-cause mortality events, non-fatal MI or non-fatal stroke occurred in 35 patients (25.4%) in the ALA group and 47 patients (33.8%) in the placebo group (HR＝0.685, 95%CI 0.442-1.062, P＝0.091; Figure 1D). Moreover, greater improvement in LVEF (β＝3.20, 95%CI 1.14-5.23, P＝0.002) and 6MWD (β＝31.7, 95%CI 8.3-54.7, P＝0.008) from baseline to 24 months after randomization were observed in the ALA group as compared to the placebo group. There were no differences in adverse events between the study groups. Conclusions These results show potential long-term beneficial effects of adding ALA to IHF patients. ALA could significantly improve LVEF and 6MWD compared to the placebo group in IHF patients.

Hemophagocytic lymphohistiocytosis（HLH）is a complex，rapidly progressing，and highly fatal disease that can lead to during multiple organ dysfunctions.Coagulation disorders frequently occur during the course of HLH and are a significant cause of early mortality.Early diagnosis of coagulation disorders or disseminated intravascular coagulation（DIC）in such patients is particularly challenging，as HLH itself interferes with the diagnostic markers associated with coagulation disorders or DIC.This article summarized the current state of research on HLH complicated by coagulation disorders，including its pathogenesis and the common and novel coagulation markers used in the collaborative assessment of HLH complicated by coagulation disorders or DIC.The goal was to provide more opportunities for subsequent treatment of the underlying disease.

As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44-CXCR2- neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.
Humans ; Animals ; Mice ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Stomach Neoplasms/pathology* ; Neutrophils/pathology* ; Signal Transduction/genetics* ; YAP-Signaling Proteins ; Tumor Microenvironment ; Hyaluronan Receptors/genetics*

Existing traditional Chinese medicine (TCM)-related databases are still insufficient in data standardization, integrity and precision, and need to be updated urgently. Herein, an Encyclopedia of Traditional Chinese Medicine version 2.0 (ETCM v2.0, http://www.tcmip.cn/ETCM2/front/#/) was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books, 9872 Chinese patent drugs, 2079 Chinese medicinal materials and 38,298 ingredients. To facilitate the mechanistic research and new drug discovery, we improved the target identification method based on a two-dimensional ligand similarity search module, which provides the confirmed and/or potential targets of each ingredient, as well as their binding activities. Importantly, five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0, which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy, to summarize the rules of prescription use, and to find alternative drugs for endangered Chinese medicinal materials. Moreover, ETCM v2.0 provides an enhanced JavaScript-based network visualization tool for creating, modifying and exploring multi-scale biological networks. ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs, the TCM-derived drug discovery and repurposing, and the pharmacological mechanism investigation of TCMs against various human diseases.

OBJECTIVES: This population-based, prospective cohort study investigated the association between glaucoma and mortality in older adults. METHODS: Participants aged 45 years or older at baseline (47.9% male) were enrolled in 2011 for the China Health and Retirement Longitudinal Study (CHARLS). All-cause mortality was observed during 7 years of follow-up. The baseline data were collected in the 2011 CHARLS, and participants were followed up for 7 years (until 2018). The risk of all-cause mortality was investigated using Cox proportional-hazards regression with age as the time scale, adjusting for significant risk factors and comorbid conditions. RESULTS: Among the 14,803 participants included, the risk of all-cause death was significantly higher among people with glaucoma than among those without glaucoma, after adjustment for other confounders (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.04 to 2.03). In a subgroup analysis based on the mean age of death, among those who were 75 years and older (n=1,231), the risk of all-cause death was significantly higher in patients with glaucoma than in those without glaucoma (HR, 1.89; 95% CI, 1.24 to 1.89). CONCLUSIONS Participants with glaucoma had a higher risk of all-cause mortality, especially those aged 75 years and above. Our findings revealed potential mechanisms underlying an association between glaucoma and all-cause mortality. They also highlighted the importance of glaucoma management to prevent premature death in middle-aged and older adults.

OBJECTIVES: This study evaluated the association between obesity and glaucoma in middle-aged and older people. A population-based retrospective cohort study was conducted using data from the China Health and Retirement Longitudinal Study. METHODS: Glaucoma was assessed via self-reports. Multivariate logistic regression analysis and a Cox proportional hazards model were used to assess the relationship between obesity and glaucoma risk. RESULTS: Older males living in urban areas who were single, smokers, and non-drinkers were found to have a significantly higher incidence of glaucoma (all p<0.05). Diabetes, hypertension, and kidney disease were also associated with higher glaucoma risk, while dyslipidemia was associated with lower risk (all p<0.05). After the model was adjusted for demographic, socioeconomic, and health-related variables, obesity was significantly associated with a 10.2% decrease in glaucoma risk according to the Cox proportional hazards model (hazard ratio, 0.90; 95% confidence interval [CI], 0.83 to 0.97) and an 11.8% risk reduction in the multivariate logistic regression analysis (odds ratio, 0.88; 95% CI, 0.80 to 0.97). A further subgroup analysis showed that obesity was associated with a reduced risk of glaucoma in people living in rural areas, in smokers, and in those with kidney disease (all p<0.05). Obesity also reduced glaucoma risk in people with diabetes, hypertension, or dyslipidemia more than in healthy controls (all p<0.05). CONCLUSIONS This cohort study suggests that obesity was associated with a reduced risk of glaucoma, especially in rural residents, smokers, and people with kidney disease. Obesity exerted a stronger protective effect in people with diabetes, hypertension, or dyslipidemia than in healthy people.

Christianson syndrome is a rare X-linked disease caused by mutations in the SLC9A6 gene. The clinical manifestations are male developmental delay, language disorder, seizures, mental retardation, ataxia, microcephaly and so on. Two cases of male children with Christianson syndrome were reported. The proband was 1 year and 11 months old. Clinical manifestations include microcephaly, global developmental delay, and seizures. The electroencephalogram showed that the central midline region of spikes and slow waves were emitted, and all exons sequencing detected a mutation in the SLC9A6 gene chrX: 135084373 [c.803+1(IVS6)G>A]. The proband′s brother was 4 years and 8 months old. The clinical manifestations were similar. The electroencephalogram showed spikes and spines in the Rolandic area on both sides. Slow waves and spiny slow waves were emitted. Magnetic resonance imaging suggested brain atrophy. The genetic verification results were consistent with the proband. The SLC9A6 gene c.803+1(IVS6) G>A splicing mutation was a pathogenic mutation in this family.

Objective:To investigate the clinical characteristics and genotypes of neurodevelopmental disorders of microcephaly-epilepsy-cortical atrophy caused by VARS1 gene mutation.Methods:The clinical data of a child with VARS1 gene mutation who visited Anhui Children′s Hospital in December 2021 were reviewed and followed up. Using "VARS1" "VARS" "VALYL-tRNA synthetase" "Valyl-tRNA synthetase" as the search terms, the Chinese data bases (China National Knowledge Infrastructure database, Wanfang database) and PubMed database (the database establishment until 2022). Articles related to genetic diseases were searched and clinical phenotypes and genotypes were summarized.Results:This case was a 3-month-old girl. After birth, she suffered from repeated convulsions and feeding difficulties, and gradually developed microcephaly, hypotonia, and overall developmental delay. Brain imaging showed cortical atrophy, corpus callosum dysplasia, and craniosynostosis. The results of whole exome sequencing indicated a new homozygous gene mutation in VARS1: gene mutation in exon 27 of chromosome 6 c.3203C>T(p.Thr1068 Met), which was from the patient 's parents. She took phenobarbital, levetiracetam, and sodium valproate for anti-epileptic treatment regularly, and then convulsed as a seizure every few days. A total of 19 patients were reported in 5 literatures that met the search criteria, all of whom presented with neurodevelopmental disorders. A total of 20 VARS1 gene mutation sites have been found so far. Conclusions:Neurodevelopmental disorders of microcephaly-epilepsy-cortical atrophy should be considered for children with neurodevelopmental disorders such as microcephaly, epilepsy, developmental delay, and cortical atrophy. Gene sequencing plays an important role in the diagnosis of the disease.

Animals ; Antibodies, Neutralizing/biosynthesis* ; Antibodies, Viral/biosynthesis* ; Body Weight/immunology* ; COVID-19/virology* ; Disease Models, Animal ; Disease Progression ; Humans ; Immunohistochemistry ; Lung/virology* ; Male ; Mesocricetus ; Nasal Cavity/virology* ; RNA, Viral/immunology* ; SARS-CoV-2/pathogenicity* ; Severity of Illness Index ; Viral Load

Objective:To explore the clinical characteristics of children with severe tuberculosis (TB) in pediatric intensive care unit (PICU) and the diagnostic viability of metagenomic next-generation sequencing (mNGS).Methods:The clinical data and mNGS results of 3 children with severe TB admitted to PICU of Anhui Provincial Children′s Hospital from January 2018 to December 2020 were retrospectively analyzed.The literature reporting children with TB diagnosed by applying mNGS were searched in China National Knowledge Infrastructure, Wanfang data, VIP and PubMed data bases, all of which were searched from the establishment of the database to March 2021, and the relevant literature was reviewed.Results:(1)All of 3 cases, including 2 males and 1 female, all had fever.One case was diagnosed with X-linked severe combined immunodeficiency (X-SCID). Acid-fast stain tests of body fluid, purified protein derivative (PPD) tests and T-cell spot tests of tuberculosis infection (T-SPOT.TB) were conducted in 3 cases, with the test results being negative, and the early diagnosis was confirmed with mNGS.Two cases were discharged from the hospital after being switched to special anti-TB treatment.(2)A total of 3 articles were retrieved, in which 7 children were reported.One male with X-SCID combined with bacillus Calmette-Guérin-associated hemophagocytic syndrome and 6 children with tuberculous meningitis were subject to early diagnosis with mNGS (detection of Mycobacterium tuberculosis complex).Conclusions:It is promising for the application of mNGS in rapid pathogen diagnosis of children with severe TB, especially in children with immunodeficiency.It could optimize early diagnosis and treatment to improve prognosis.