Genetics, environmental stress, and amino acid supplementation affect lactational performance via mTOR signaling pathway in bovine mammary epithelial cells.

Mammary glands are known for their ability to convert nutrients present in the blood into milk contents. In cows, milk synthesis and the proliferation of cow mammary epithelial cells (CMECs) are regulated by various factors, including nutrients such as amino acids and glucose, hormones, and environmental stress. Amino acids, in particular, play a crucial role in regulating cell proliferation and casein synthesis in mammalian epithelial cells, apart from being building blocks for protein synthesis. Studies have shown that environmental factors, particularly heat stress, can negatively impact milk production performance in dairy cattle. The mammalian target of rapamycin complex 1 (mTORC1) pathway is considered the primary signaling pathway involved in regulating cell proliferation and milk protein and fat synthesis in cow mammary epithelial cells in response to amino acids and heat stress. Given the significant role played by the mTORC signaling pathway in milk synthesis and cell proliferation, this article briefly discusses the main regulatory genes, the impact of amino acids and heat stress on milk production performance, and the regulation of mTORC signaling pathway in cow mammary epithelial cells.

Engineered circular guide RNAs boost CRISPR/Cas12a- and CRISPR/Cas13d-based DNA and RNA editing.

BACKGROUND: The CRISPR/Cas12a and CRISPR/Cas13d systems are widely used for fundamental research and hold great potential for future clinical applications. However, the short half-life of guide RNAs (gRNAs), particularly free gRNAs without Cas nuclease binding, limits their editing efficiency and durability. RESULTS: Here, we engineer circular free gRNAs (cgRNAs) to increase their stability, and thus availability for Cas12a and Cas13d processing and loading, to boost editing. cgRNAs increases the efficiency of Cas12a-based transcription activators and genomic DNA cleavage by approximately 2.1- to 40.2-fold for single gene editing and 1.7- to 2.1-fold for multiplexed gene editing than their linear counterparts, without compromising specificity, across multiple sites and cell lines. Similarly, the RNA interference efficiency of Cas13d is increased by around 1.8-fold. In in vivo mouse liver, cgRNAs are more potent in activating gene expression and cleaving genomic DNA. CONCLUSIONS: CgRNAs enable more efficient programmable DNA and RNA editing for Cas12a and Cas13d with broad applicability for fundamental research and gene therapy.

RNA-seq reveals the role of miR-223 in alleviating inflammation of bovine mammary epithelial cells.

Bovine mammary epithelial cells (bMECs) are involved in the early defense against the invasion of intramammary pathogens and are essential for the health of bovine mammary gland. MicroRNA (MiRNA) is a key factor that regulates cell state and physiological function. In the present study, the transcriptome profiles of miR-223 inhibitor transfection group (miR-223_Inhibitor) and negative control inhibitor transfection group (NC_Inhibitor) within bMECs were detected via the RNA sequencing (RNA-seq) platform. Based on these experiments, the differentially expressed mRNAs (DE-mRNAs) of the miR-223_Inhibitor transfection group were screened, and the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analyses of DE-mRNAs were performed. The results revealed that compared with the NC_Inhibitor, 224 differentially expressed genes (DEGs) were identified in the miR-223_Inhibitor, including 184 upregulated and 40 downregulated genes. The functional annotation of the above DEGs indicated that some of these genes are involved in the immune response generated by extracellular substance stimulation, regulation of the activity of cytokines and chemokines, and the immune signaling pathways of NF-κB and TNF. Meanwhile, miR-223_inhibitor upregulated the immune key genes IRF1 and NFκBIA, cytokines IL-6 and IL-24, as well as chemokines CXCL3, CXCL5, and CCR6, triggering a signaling cascade response that exacerbated inflammation in bMECs. These results suggested that miR-223 plays an important role in inhibiting the inflammatory response and maintaining the stability of bMECs, and is a potential target for treating mastitis in dairy cows.

[Investigation and clarification of traditional measuring units of Tibetan medicine].

Quantity is the key factor to ensure the safety and effectiveness of medicines. It is very important to study and determine the traditional measuring units and their quantity values of Tibetan medicine. Based on the literature records of Tibetan medicine and combined with modern experimental verification and investigation research, this study determined the reference, name, and conversion rate of traditional measuring units of Tibetan medicine. Meanwhile, through large sample sampling and repeated quantification of refe-rence of basic units, its weight and volume were clarified. The modern SI volume and weight unit values corresponding to the traditional volume and weight units of Tibetan medicine were deduced, and the correctness, reliability, and practicability of these determination results were demonstrated. This study also put forward some specific suggestions and reference values for formulating the standards of measuring units of weight and volume of Tibetan medicine. It is of great significance in guiding the processing, production, and clinical treatment of Tibetan medicine, and promoting the standardization and standardized development of Tibetan medicine.

The clinical characteristics of anemia in native adults living at different altitudes of the Tibetan Plateau.

To provide evidence-based medicine references for formulating prevention and control policies in plateau areas, we explore the characteristics of anemia patients in Tibet (the plateau areas of China), especially those located at an altitude above 4500 m. We collected clinical data from 379 Tibetan anemia patients over the age of 18 years. We found those female patients accounted for the majority of Tibetan anemia patients. Almost half of the anemia patients aged from 28 to 47 years. The percentage of severe anemia and extremely severe anemia was 45.4% and 2.4%, respectively. 88.7% of patients are engaged in agriculture and animal husbandry, and 81.5% of patients just graduated from primary school or below. The most common causes of anemia were nutritional anemia, especially iron-deficiency anemia. At high-altitude localities, folic acid-deficiency anemia needs more attention. Overall, this study showed that altitude influences the incidence, severity, and cause of anemia. Peasants and herdsmen, low education levels, young and middle-aged women, and nutrition status should be paid attention to in future anemia control.

Quantitative evaluation of density variability in the lesion-lung boundary zone to differentiate pulmonary subsolid nodules.

Background: Transition of the CT values from nodule to peripheral normal lung is related to pathological changes and may be a potential indicator for differential diagnosis. This study investigated the significance of the standard deviation (SD) values in the lesion-lung boundary zone when differentiating between benign and neoplastic subsolid nodules (SSNs). Methods: From January 2012 to July 2021, a total of 229 neoplastic and 84 benign SSNs confirmed by pathological examination were retrospectively and nonconsecutively enrolled in this study. The diagnostic study was not registered with a clinical trial platform, and the study protocol was not published. Computed tomography (CT) values of the ground-glass component (CT1), adjacent normal lung tissue (CT2), and lesion-lung boundary zone (CT3) were measured consecutively. The SD of CT3 was recorded to assess density variability. The CT1, CT2, CT3, and SD values were compared between benign and neoplastic SSNs. Results: No significant differences in CT1 and CT2 were observed between benign and neoplastic SSNs (each P value >0.05). CT3 (-736.1±51.0 vs. -792.6±73.9; P<0.001) and its SD (135.6±29.6 vs. 83.6±20.6; P<0.001) in neoplastic SSNs were significantly higher than those in benign SSNs. Moreover, the SD increased with the invasiveness degree of neoplastic SSNs (r=0.657; P<0.001). The receiver operating characteristic (ROC) curve revealed that the area under the curve was 0.927 (95% CI: 0.896-0.959) when using the SD (cutoff value =106.98) as a factor to distinguish SSNs, which increased to 0.966 (95% CI: 0.934-0.985) when including nodules with a CT1 of ≥-715 Hounsfield units (HU) only (cutoff of SD 109.9, sensitivity 0.930, and specificity 0.914). Conclusions: The SD as an objective index is valuable for differentiating SSNs, especially for those with a CT1 of ≥-715 HU, which have a higher possibility of neoplasm if the SD is >109.9.

Fecal fungal microbiota alterations associated with clinical phenotypes in Crohn's disease in southwest China.

Although previous studies reported that gut fungal microbiota was associated with Crohn's disease (CD), only a few studies have focused on the correlation between gut fungi and clinical phenotypes of CD. Here, we aimed to analyze the association between intestinal fungi and the occurrence of CD, disease activity, biological behaviors, and perianal lesions. Stool samples from subjects meeting the inclusion and exclusion criteria were collected for running internal transcribed spacer 2 (ITS2) high-throughput sequencing. Then, correlation analysis was conducted between intestinal fungi and different clinical groups. There were 45 patients with CD and 17 healthy controls (HCs) enrolled. Results showed that two phyla, Rozellomycota and Mortierellomycota, were not present in patients with CD compared to HCs. At the same time, there was a higher abundance of fungal genera and species belonging to the phylum Ascomycota in patients with CD. SparCC network analysis showed fewer interactions among the fungal communities in patients with CD compared to HCs. Exophiala dermatitidis was positively associated with the clinical active stage and platelet count. The genus Candida was with significantly higher abundance in the non-B1 CD group based on the Montreal classification. Clonostachys, Humicola, and Lophiostoma were significantly enriched in patients with CD with perianal lesions. Our results demonstrated that the composition of the intestinal fungal microbiota in patients with CD and HCs was markedly different, some of which might play a pathogenic role in the occurrence of CD and perianal lesions. Exophiala dermatitidis and genus Candida might be associated with active disease stage and type non-B1 CD (CD with intestinal stenosis or penetrating lesions, or both), respectively.

Clinical and Computed Tomography Characteristics of Solitary Pulmonary Nodules Caused by Fungi: A Comparative Study.

Purpose: To clarify the clinical and computed tomography (CT) indicators in distinguishing pulmonary nodules caused by fungal infection from lung cancers. Methods: From January 2013 to April 2022, 68 patients with solitary fungal nodules (64 were solid and 4 were mixed ground-glass nodules) and 140 cases with solid cancerous nodules with similar size were enrolled. Their clinical characteristics and CT manifestations of the solid nodules were summarized and compared, respectively. Results: Compared with patients with lung cancers, cases were younger (51.2 ± 11.5 vs 61.3 ± 10.2 years) and non-smokers (72.1% vs 57.9%) and immunocompromised (44.1% vs 17.9%) individuals were more common in patients with fungal nodules (each P < 0.05). The air crescent sign (ACS) (34.4% vs 0%), halo sign (HS) (23.4% vs 4.3%), and satellite lesions (45.3% vs 2.9%) were more frequently detected in fungal nodules than in cancerous ones (each P < 0.05). Air bronchogram similarly occurred in fungal and cancerous nodules, whereas the natural ones were more common in the former (100% vs 16.7%, P = 0.000). However, the fungal nodules had a lower enhancement degree (29.0 ± 19.2 HU vs 40.3 ± 28.3 HU, P = 0.038) and frequency of hilar and/or mediastinal lymph node enlargement (2.9% vs 14.3%, P = 0.013) compared with the cancerous nodules. Conclusion: In the younger, non-smoking and immunocompromised patients, a solitary pulmonary solid nodule with ACS, HS, satellite lesions and/or natural air bronchogram but without significant enhancement, fungal infection is a probable diagnosis.

RNA-seq reveals the role of miR-199a-3p in regulating inflammation of bovine mammary epithelial cells.

MicroRNAs (miRNAs) are involved in the regulation of a variety of biological processes. However, the research on the regulatory role of bovine mammary epithelial cells (bMECs) is scarce. To date, there are no reports about the role of miR-199a-3p in bMECs. In this study, RNA sequencing (RNA-seq) technology was used to detect the transcriptomes of the miR-199a-3p overexpression and negative control (NC) groups of bMECs. Then, the screening and functional annotation of differentially expressed genes (DEGs) were conducted. The results showed that there were 140 DEGs (109 up-regulated and 31 down-regulated) in the miR-199a-3p overexpression group. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that the DEGs might regulate the immune and inflammatory responses via the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, transforming growth factor-beta (TGF-ß) signaling pathway, and interleukin-17 (IL-17) signaling pathway, which revealed that miR-199a-3p might participate in regulating bMECs inflammation via affecting the expression of related genes and the above signaling pathways. This study may provide a new reference for potential therapeutic targets of cow mastitis.

Sensitivity and specificity of computed tomography hypodense sign when differentiating pulmonary inflammatory and malignant mass-like lesions.

Background: Hypodense sign (HyS) reportedly is associated with pulmonary fungal infection, while it also common in many non-fungal lesions. This study aims to determine the significance of a HyS presented on contrast-enhanced computed tomography (CECT) when distinguishing pulmonary inflammatory from malignant mass-like lesions. Methods: From January 2013 to January 2021, we retrospectively evaluated the clinical and computed tomography (CT) data of patients with pathologically confirmed pulmonary inflammatory lesions (ILs) and malignant lesions (MLs). We analyzed and compared the CT features of the HyS in MLs and ILs, and then evaluated whether the HyS helped to differentiate MLs and ILs. Results: There were significant differences in age and tumor markers between patients with ILs and MLs (both P<0.05). Compared with that in MLs, the occurrence of the HyS in ILs was higher (62.81% vs. 28.81%; P<0.0001). In ILs, more HyS were single, round or oval, well-defined, and had lower enhancement (ΔCT). Logistic regression analysis revealed that an ill-defined boundary, peripheral fibrosis, presence of a well-defined HyS, and a ΔCT value of the HyS <9.5 Hounsfield units (HU) were independent indicators for predicting ILs. After including the HyS CT features, the area under the curve (AUC) of the model predicting ILs increased from 0.953 to 0.986 with a sensitivity of 96.03% and a specificity of 94.03% (P=0.0027). Conclusions: The HyS is more common in ILs than in MLs. A single, regular, and well-defined HyS with a ΔCT value of <9.5 HU on CECT is highly suggestive of ILs. Combining the HyS with other morphological features could improve the diagnosis accuracy of pulmonary mass-like lesions.

Liver cirrhosis prediction for patients with Wilson disease based on machine learning: a case-control study from southwest China.

OBJECTIVES: Wilson disease (WD) is a rare autosomal recessive disease caused by an ATP7B gene mutation. Liver cirrhosis is an important issue that affects the clinical management and prognosis of WD patients. Blood routine examination is a potential biomarker for predicting the occurrence of liver cirrhosis in WD. We aim to construct a predictive model for the occurrence of liver cirrhosis using general clinical information, blood routine examination, urine copper, and serum ceruloplasmin through a machine learning approach. METHODS: Case-control study of WD patients admitted to West China Fourth Hospital between 2005 and 2020. Patients with a score of at least four in scoring system of WD were enrolled. A machine learning model was constructed by EmpowerStats software according to the general clinical data, blood routine examination, 24 h urinary copper, and serum ceruloplasmin. RESULTS: This study analyzed 346 WD patients, of which 246 were without liver cirrhosis. And we found platelet large cell count (P-LCC), red cell distribution width CV (RDW-CV), serum ceruloplasmin, age at diagnosis, and mean corpuscular volume (MCV) were the top five important predictors. Moreover, the model was of high accuracy, with an area under the receiver operating characteristic curve of 0.9998 in the training set and 0.7873 in the testing set. CONCLUSIONS: In conclusion, the predictive model for predicting liver cirrhosis in WD, constructed by machine learning, had a higher accuracy. And the most important indices in the predictive model were P-LCC, RDW-CV, serum ceruloplasmin, age at diagnosis, and MCV.

RNA-Seq Reveals the Role of miR-29c in Regulating Inflammation and Oxidative Stress of Bovine Mammary Epithelial Cells.

Healthy mammary gland is essential for milk performance in dairy cows. MicroRNAs (miRNAs) are the key molecules to regulate the steady state of mammary gland in dairy cows. This study investigated the potential role of miR-29c in bovine mammary epithelial cells (bMECs). RNA sequencing (RNA-seq) was used to measure the transcriptome profile of bovine mammary epithelial cells line (MAC-T) transfected with miR-29c inhibitor or negative control (NC) inhibitor, and then differentially expressed genes (DEGs) were screened. The results showed that a total of 42 up-regulated and 27 down-regulated genes were found in the miR-29c inhibitor group compared with the NC inhibitor group. The functional enrichment of the above DEGs indicates that miR-29c is a potential regulator of oxidative stress and inflammatory response in bMECs through multiple genes, such as forkhead box O1 (FOXO1), tumor necrosis factor-alpha (TNF-α), and major histocompatibility complex, class II, DQ alpha 5 (BoLA-DQA5) in the various biological process and signaling pathways of stress-activated mitogen-activated protein kinase (MAPK) cascade, Epstein-Barr virus infection, inflammatory bowel disease, etc. The results imply that miR-29c plays an important role in a steady state of bMECs or cow mammary gland and may be a potential therapeutic target for mastitis in dairy cows.

Differential expression of circRNAs related to lipopolysaccharide-induced inflammation in bovine mammary epithelial cells.

Circular RNAs (circRNAs) are widely involved in inflammatory responses, but their specific regulatory roles in cow mastitis remain controversial. In this study, RNA-seq was used to generate a circRNA expression profile, which identified 71 differentially expressed circRNAs (DEcircRNAs) in lipopolysaccharide (LPS)-stimulated MAC-T bovine mammary epithelial cells (bMECs) at different stages of inflammation. Functional analyses revealed that these DEcircRNAs may be involved in cellular proliferation, apoptosis, migration, and the inflammatory responses through regulation of numerous related signaling pathways. In addition, these data suggest that 2 novel circRNAs, named novel_circ_0004830 and novel_circ_0003097, may act as the key competing endogenous RNAs (ceRNAs) in the regulation of bovine mastitis through binding to inflammation-related microRNAs (miRNAs). These results provide a new angle for the study of the molecular regulatory mechanisms in dairy cow mastitis.

Differential Expression Profiles of lncRNA Following LPS-Induced Inflammation in Bovine Mammary Epithelial Cells.

Bovine mastitis is an inflammatory response of mammary glands caused by pathogenic microorganisms such as Escherichia coli (E. coli). As a key virulence factor of E. coli, lipopolysaccharide (LPS) triggers innate immune responses via activation of the toll-like-receptor 4 (TLR4) signaling pathway. However, the molecular regulatory network of LPS-induced bovine mastitis has yet to be fully mapped. In this study, bovine mammary epithelial cell lines MAC-T were exposed to LPS for 0, 6 and 12 h to assess the expression profiles of long non-coding RNAs (lncRNAs) using RNA-seq. Differentially expressed lncRNAs (DElncRNAs) were filtered out of the raw data for subsequent analyses. A total of 2,257 lncRNAs, including 210 annotated and 2047 novel lncRNAs were detected in all samples. A large proportion of lncRNAs were present in a high abundance, and 112 DElncRNAs were screened out at different time points. Compared with 0 h, there were 22 up- and 25 down-regulated lncRNAs in the 6 h of post-infection (hpi) group, and 27 up- and 22 down-regulated lncRNAs in the 12 hpi group. Compared with the 6 hpi group, 32 lncRNAs were up-regulated and 25 lncRNAs were down-regulated in the 12 hpi group. These DElncRNAs are involved in the regulation of a variety of immune-related processes including inflammatory responses bMECs exposed to LPS. Furthermore, lncRNA TCONS_00039271 and TCONS_00139850 were respectively significance down- and up-regulated, and their target genes involve in regulating inflammation-related signaling pathways (i.e.,Notch, NF-κB, MAPK, PI3K-Akt and mTOR signaling pathway), thereby regulating the occurrence and development of E. coli mastitis. This study provides a resource for lncRNA research on the molecular regulation of bovine mastitis.

MiR-125b regulates inflammation in bovine mammary epithelial cells by targeting the NKIRAS2 gene.

Mastitis is a complex inflammatory disease caused by pathogenic infection of mammary tissue in dairy cows. The molecular mechanism behind its occurrence, development, and regulation consists of a multi-gene network including microRNA (miRNA). Until now, there is no report on the role of miR-125b in regulating mastitis in dairy cows. This study found that miR-125b expression is significantly decreased in lipopolysaccharide (LPS)-induced MAC-T bovine mammary epithelial cells. Also, its expression is negatively correlated with the expression of NF-κB inhibitor interacting Ras-like 2 (NKIRAS2) gene. MiR-125b target genes were identified using a double luciferase reporter gene assay, which showed that miR-125b can bind to the 3' untranslated region (3' UTR) of the NKIRAS2, but not the 3'UTR of the TNF-α induced protein 3 (TNFAIP3). In addition, miR-125b overexpression and silencing were used to investigate the role of miR-125b on inflammation in LPS-induced MAC-T. The results demonstrate that a reduction in miR-125b expression in LPS-induced MAC-T cells increases NKIRAS2 expression, which then reduces NF-κB activity, leading to low expression of the inflammatory factors IL-6 and TNF-α. Ultimately, this reduces the inflammatory response in MAC-T cells. These results indicate that miR-125b is a pro-inflammatory regulator and that its silencing can alleviate bovine mastitis. These findings lay a foundation for elucidating the molecular regulation mechanism of cow mastitis.

Expression Profiling of microRNA From Peripheral Blood of Dairy Cows in Response to Staphylococcus aureus-Infected Mastitis.

As the main pathogen causing dairy cow mastitis, Staphylococcus aureus can cause subclinical mastitis, which is difficult to be diagnosed. It seriously affects milk quality and the economic benefits of the dairy industry. Therefore, it is very necessary to find biomarkers for early diagnosis of S. aureus-infected mastitis in peripheral blood of dairy cows. In this study, S. aureus was used to infect the mammary gland tissues of dairy cows, and a mastitis model was successfully constructed. The RNAseq technology was used to determine the expression profiles of microRNA (miRNA) from peripheral blood of dairy cows infected with S. aureus at 0, 1, 3, 5, and 7 days. A total of 288 differentially expressed miRNAs (DIE-miRNAs) were found, of which 108 were known miRNAs and 180 were novel predicted miRNAs. Bioinformatics analysis results showed that the above DIE-miRNAs might be involved in 10 immune system-related signaling pathways (i.e., chemokine signaling pathway, leukocyte transendothelial migration, natural killer cell-mediated cytotoxicity, toll-like receptor signaling pathway, Jak-STAT signaling pathway, MAPK signaling pathway, Wnt signaling pathway, cell adhesion molecules, cytokine-cytokine receptor interaction, and ECM-receptor interaction), thus regulating the process of S. aureus mastitis. It was also found that the expression variation of up-regulated expression of miR-320a, miR-19a, and miR-19b as well as down-regulated expression of miR-143, miR-205, and miR-24 reached a significant level on the 5th and 7th day of infection, suggesting that they might play an important biological role in mastitis and provide a direction for the research and development of molecular therapy technology for mastitis. However, at different times after S. aureus infection, miR-1301 was significantly up-regulated in peripheral blood. miR-2284r was significantly down-regulated, suggesting that these two miRNAs might be the new blood biomarkers for S. aureus-infected dairy cow mastitis. The above results laid a new foundation for the research and development of molecular diagnosis and biological therapy technology for S. aureus-infected mastitis in dairy cow.

miR-223: An Effective Regulator of Immune Cell Differentiation and Inflammation.

MicroRNAs (miRNAs) play a critical role in regulating various biological processes, such as cell differentiation and immune modulation by binding to their target genes. miR-223 is a miRNA with important functions and has been widely investigated in recent years. Under certain physiological conditions, miR-223 is regulated by different transcription factors, including sirtuin1 (Sirt1), PU.1 and Mef2c, and its biological functions are mediated through changes in its cellular or tissue expression. This review paper summarizes miR-223 biosynthesis and its regulatory role in the differentiation of granulocytes, dendritic cells (DCs) and lymphocytes, macrophage polarization, and endothelial and epithelial inflammation. In addition, it describes the molecular mechanisms of miR-223 in regulating lung inflammation, rheumatoid arthritis, enteritis, neuroinflammation and mastitis to provide insights into the existing molecular regulatory networks and therapies for inflammatory diseases in humans and animals.

Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety.

BACKGROUND: World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP). METHODS: AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort. RESULTS: By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1-2) and 33.1% as serious (Grade 3-5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75-169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually. CONCLUSIONS: Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.

Factors Affecting the Risk of Postpartum Hemorrhage in Pregnant Women in Tibet Health Facilities.

BACKGROUND Postpartum hemorrhage (PPH), the leading cause of maternal death, is defined as a blood loss >500 mL within 24 h after vaginal delivery or >1000 mL within 24 h after cesarean section. This study aimed to investigate the incidence of PPH and assess its risk factors in pregnant women in Tibet to provide a reference for clinicians in this region. MATERIAL AND METHODS A total of 4796 pregnant women with gestational age ≥28 weeks who were admitted to hospitals in Tibet between December 2010 and December 2016 were involved in this study. Patient sociological and clinical data and pregnancy outcomes were collected. The related risk factors of PPH were analyzed by univariate and multivariable logistic regression. The area under the curve of the receiver operating characteristic curves was used to evaluate the effect of the PPH prediction model. RESULTS PPH occurred in 95 women, with an incidence of 1.98%. The following factors were associated with higher risk for PPH: maternal age ≥35 (odds ratio [OR]=1.96; 95% confidence interval [CI], 1.18-3.27; P=0.010), history of preterm birth (OR=2.66; 95% CI, 1.60-4.42; P<0.001), cesarean section (OR=6.69; 95% CI, 4.30-10.40; P<0.001), neonatal weight >4 kg (OR=3.92; 95% CI, 1.75-8.81; P<0.001) and occurrence of neonatal asphyxia (OR=5.52; 95% CI, 2.22-13.74; P<0.001). CONCLUSIONS Maternal age ≥35, history of preterm birth, cesarean section, newborn weight >4 kg, and neonatal asphyxia were risk factors of PPH, which can help evaluate PPH in Tibet.