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Leptomeningeal metastasis (LM) is associated with poor prognosis and represents a terminal event of non-small cell lung cancers (NSCLC). In previous studies, most of LM-patients have detected epidermal growth factor receptor (EGFR) mutation and responded to the third generation of EGFR-tyrosine kinase inhibitor (TKI). This study aimed to report a case of ERBB2 (HER2) exon 20 insertion mutations in the cerebrospinal fluid (CSF) of LM-patient which response to poziotinib. At the beginning, postoperative pathology showed a primary invasive adenocarcinoma with no mutations in EGFR and ROS-1. Pemetrexed plus carboplatin combined with bevacizumab was administered as the first-line followed by bevacizumab alone for continuation maintenance therapy. Targeted therapy and immunotherapy were given after the disease progressed in two months. Subsequently, the patient developed mental symptoms and adenocarcinoma cells were found in the CSF. Next-generation sequencing (NGS) results showed HER2 exon 20 insertion mutations in the primary tissue, CSF and plasma samples. Then, poziotinib was administered and the symptoms improved significantly after 3 days and the progress free survival was nearly 2 months. Therefore, we speculate that the CSF concentration and penetration rate of poziotinib may significantly higher than of other TKIs so that it achieves a higher CSF concentration than standard dosing, and successfully controlled LM. It may provide a new therapeutic option for LM-patient and may be especially who are lung adenocarcinoma with HER2 exon 20 insertion.

The study aimed to compare the performance of human papillomavirus (HPV)-based strategies to cytology for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in routine program in China. The study included 50,434 women ages 30–64 years from January 2015 to December 2019, to assess four strategies: cytology with HPV triage (strategy 1), primary HPV testing with reflex cytology (strategy 2), primary HPV testing with HPV-16/18 genotyping and reflex cytology for non-16–18 high-risk HPV genotypes (strategy 3), and co-testing (strategy 4). The main outcomes were sensitivity for CIN3+ and colposcopy referral rate. Overall, the rates of HPV positivity and cytologic abnormality were 7.0% [95% confidential interval (CI), 6.8–7.2] and 3.5% (95% CI, 3.3–3.6], respectively. The sensitivity for CIN3+ were 88.5% for strategy 4, 83.2% for strategy 3, 64.6% for strategy 1, and 60.1% for strategy 2. The relative sensitivity of strategy 4 and strategy 3 compared with strategy 1 for detecting CIN3+ were 1.38 (95% CI, 1.24–1.54) and 1.29 (95% CI, 1.14–1.46), respectively. The colposcopy referral rates of strategies 4 and 3 were significantly higher than that of strategy 1 (2.4% and 2.2% vs. 1.4%, P < 0.001). In conclusion, co-testing and primary HPV testing with HPV-16/18 genotyping and reflex cytology improved the sensitivity for CIN3+ compared with cytology but increased the colposcopy referral rate. Long-term negative predicted value for HPV-negative women should be studied to determine the screening interval. Our study provides further evidence to the introduction of HPV-based strategies in China. Prevention Relevance: Both co-testing and primary HPV testing with HPV-16/18 genotyping and reflex cytology triage provided higher sensitivity for detecting CIN3+; however, the number of colposcopy referrals also increased compared with cytology in a routine program. It has great public health implications for the introduction of HPV-based screening strategies in China.

OBJECTIVE To investigate the effect of therapeutic plasma exchange (TPE) on lowering triglyceride (TG) levels in patients with hypertriglyceridemic pancreatitis (HLAP). METHODS The TG-lowering in patients with HLAP was compared between the TPE group and conservative treatment group (non-TPE). The primary outcome was TG reduction to less than 500 mg/dL within 48 hours. RESULTS The primary outcome was significantly correlated with TPE (univariate analysis odds ratio [OR] 2.74; 95% confidence interval [CI] 1.30-5.79, P = .008; multivariate analysis OR 3.03; 95% CI 1.28-7.19, P = .012). At 24 and 48 hours, conservative treatment resulted in a 48.24% and 70.44% reduction in TG, while TPE resulted in a 70.91% and 76.39% reduction in TG, respectively. A more rapid decrease of in TGs in a short period was clearly associated with TPE (P

Background: Vaccine hesitancy has been recognized as an urgent public health issue. We aimed to explore the acceptance of a COVID-19 vaccine and related factors among pregnant women, a vulnerable population for vaccine-preventable diseases. Methods: A multi-center cross-sectional study among pregnant women was conducted in five provinces of mainland China from November 13 to 27, 2020. We collected sociodemographic characteristics, attitude, knowledge, and health beliefs on COVID-19 vaccination. Locally weighted scatterplot smoothing regression analysis was used to assess the trends of vaccination acceptance. Multivariable logistic regression was performed to identify factors related to vaccination acceptance. Results: Among the 1392 pregnant women, the acceptance rate of a COVID-19 vaccine were 77.4% (95%CI 75.1–79.5%). In the multivariable regression model, the acceptance rate was associated with young age (aOR = 1.87, 95% CI: 1.20–2.93), western region (aOR = 2.73, 95% CI: 1.72–4.32), low level of education (aOR = 2.49, 95% CI: 1.13–5.51), late pregnancy (aOR = 1.49, 95% CI: 1.03–2.16), high knowledge score on COVID-19 (aOR = 1.05, 95% CI: 1.01–1.10), high level of perceived susceptibility (aOR = 2.18, 95% CI: 1.36–3.49), low level of perceived barriers (aOR = 4.76, 95% CI: 2.23–10.18), high level of perceived benefit (aOR = 2.18, 95% CI: 1.36–3.49), and high level of perceived cues to action (aOR = 15.70, 95% CI: 8.28–29.80). Conclusions: About one quarters of pregnant women have vaccine hesitancy. Our findings highlight that targeted and multipronged efforts are needed to build vaccine literacy and confidence to increase the acceptance of a COVID-19 vaccine during the COVID-19 pandemic, especially for vulnerable populations.

A hypertrophic scar is a common dermal fibroproliferative lesion usually treated with topical silicone. Verapamil, a type of calcium channel blocker, is considered a candidate drug for the treatment of hypertrophic scars. Here, we report that the addition of verapamil to topical silicone gel enhances treatment outcomes of hypertrophic scars. Upon creation of hypertrophic scars with the rabbit ear model, varying concentrations of verapamil‐added silicone gel (0.1, 1, and 10 mg/g) were applied daily for 28 days. After the animals were euthanised, microscopic measurement was performed for (a) scar elevation index (SEI), (b) fibroblast count, and (c) capillary count. On gross analysis, features of hypertrophic scars were significantly alleviated in the verapamil‐added groups. On histologic examination, verapamil‐added groups showed (a) reduced SEI (1.93 (1.79‐2.67) for control vs 1.34 (1.21‐1.51) for silicone only and 1.13 (1.01‐1.65) for verapamil‐added silicone), (b) fibroblast count 700.5 (599.5‐838.5) for control, 613.25 (461‐762.5) for silicone only, and 347.33 (182.5‐527) for verapamil‐added silicone), and (c) capillary formation (52 (35.5‐96.5) for control, 46 (28‐64.5) for silicone only, and 39.83(24‐70) for verapamil‐added silicone) (Kruskal‐Wallis test, P

Objectives We aimed to assess the prevalence of poor sleep quality during early pregnancy and its risk factors, and to explore the association between sleep quality and adverse pregnancy outcomes. Methods This was a prospective birth cohort study that included 4352 pregnant women. Sleep quality were assessed using the Pittsburgh Sleep Quality Index (PSQI). The risk factors for poor sleep quality were analyzed by a logistic regression model. Log-binomial regression models were used to analyze the association between sleep quality and pregnancy outcomes. Results The prevalence of maternal poor sleep quality during early pregnancy was 34.14%. The multivariate logistic model showed that stillbirth history (OR = 2.45; 95% CI: 1.34, 4.47), history of induced abortion (OR = 1.26; 95% CI: 1.07, 1.49), general health-related quality of life (OR = 3.98; 95% CI: 2.97, 5.34), insufficient physical activity (OR = 1.18; 95% CI: 1.03, 1.36), smoking (OR = 1.59; 95% CI: 1.18, 2.15), and vegetarian (OR = 2.18; 95% CI: 1.54, 3.08) were risk factors for poor sleep quality, while taking folic acid consistently before pregnancy (OR = 0.83; 95% CI: 0.72,0.97) was the protective factor. After controlling for all the confounders, poor sleep quality during early pregnancy increased the risk of premature rupture of membranes by 12% (95% CI: 1.00, 1.25). Conclusion Pregnant women with a history of stillbirth and induced abortion, general health-related quality of life, insufficient physical activity, smoking, and a vegetarian diet tended to have poor sleep quality. More attention should be paid to healthy lifestyle of pregnant women to improve sleep quality and better pregnancy outcomes.

Abnormal ion channel currents caused by myocardial electrical remodeling is one of the main causes of malignant arrhythmias. Glycogen synthase kinase 3β (GSK-3β) is the main therapeutic target following ischemia as it regulates nerve cell channels. However, few studies have investigated its role in myocardial electrical remodeling. The present study aimed to investigate the role of GSK-3β in a rat myocardial infarction (MI)–induced electrical remodeling and potential effects on cardiac ionic channels including KCNJ2/Kir2.1/IK1. Ligation of the left anterior descending artery in rats was performed to establish a MI model. The rats were randomly divided into three groups, the sham, MI, and MI + SB group. The animals in the latter group were administered SB216763 (GSK-3β inhibitor) at a dose of 0.6 mg·kg−1·day−1. The ventricular function was assessed by echocardiography, electrocardiography, and histological analysis 7 days post-surgery. Serum was collected to measure lactate dehydrogenase and cardiac troponin I levels, and the mRNA and protein levels of the KCNJ2/Kir2.1/IK1 channel in the heart tissues were assessed. H9c2 cells were cultured to examine the effects of SB216763 on the protein expression of Kir2.1 channel under hypoxic conditions. The results revealed that SB216763 ameliorated acute cardiac injury and improved myocardial dysfunction. Moreover, SB216763 increased the mRNA and protein expression of Kir2.1 during MI. Furthermore, SB216763 treatment abrogated the decreased expression of Kir2.1 in H9c2 cells under hypoxic conditions. GSK-3β inhibition upregulates Kir2.1 expression in a rat model of MI.

Background and aims Optimal candidates for early transjugular intrahepatic portosystemic shunt (TIPS) in patients with Child-Pugh B cirrhosis and acute variceal bleeding (AVB) remain unclear. This study aimed to test the hypothesis that risk stratification using the Chronic Liver Failure Consortium Acute Decompensation score (CLIF-C ADs) may be useful to identify a subgroup at high risk of mortality or further bleeding that may benefit from early TIPS in patients with Child-Pugh B cirrhosis and AVB. Approach and results We analyzed the pooled individual data from two previous studies of 608 patients with Child-Pugh B cirrhosis and AVB who received standard treatment between 2010 and 2017 in China. The concordance index values of CLIF-C ADs for 6-week and 1-year mortality (0.715 and 0.708) were significantly better than those of active bleeding at endoscopy (0.633 [P 56), with a 5.6%, 16.8%, and 25.4% risk of 6-week death, respectively. Nevertheless, the performance of CLIF-C ADs for predicting a composite endpoint of 6-week death or further bleeding was not satisfactory (area under the receiver operating characteristics curve [AUC], 0.588). A nomogram incorporating components of CLIF-C ADs and albumin, platelet, active bleeding, and ascites significantly improved the prediction accuracy (AUC, 0.725). Conclusions In patients with Child-Pugh B cirrhosis and AVB, risk stratification using CLIF-C ADs identifies a subgroup with high risk of death that may derive survival benefit from early TIPS. With improved prediction accuracy for 6-week death or further bleeding, the data-driven nomogram may help to stratify patients in randomized trials. Future external validation of these findings in patients with different etiologies is required.

BackgroundWhat kind of patients with hypertriglyceridemic acute pancreatitis (HLAP) might benefit from plasmapheresis (PP) remains unknown. The objective of this study is to determine the predict function of total cholesterol (TC) on the Triglyceride (TG)-lowing effect in patients on either non-PP or PP therapy.MethodsPatients were categorized into high total cholesterol (HTC)/low total cholesterol (LTC) groups based on TC level of 12.4 mmol/L. The primary outcome was TG reduction to below 500 mg/dL within 48 h. Linear mixed-effect model and logistic regression analyses were used to assess the association of TC level and TG-lowing efficacy in different therapy groups.ResultsCompared with LTC group, patients with HTC showed more severe imaging manifestations (p p = 0.036). Deaths occurred only in HTC groups. Significant interaction of time sequence with the 2 TGs-lowing therapy groups on TG level was only found in HTC group (p p = 0.002). Furthermore, in patients with lower TC level, no significant difference was found in primary outcome between PP group and non-PP group (81.25% versus 62.30%, adjusted OR 2.05; 95% CI 0.45–9.40;p = 0.353).ConclusionsTC could be a potential biomarker to predict the effects of TG-lowing therapy in patients with HLAP.

We report a massive outbreak of human Q fever cases, which occurred at totally 11 humans. The occurrence was related to a goat farm where Coxiella burnetii infection was diagnosed from goat tissues and environmental specimens. From January of 2018, continuous abortions from 6 goats occurred. Laboratory tests from 77 goat specimens for C. burnetii showed that 54 (70.1%) and 63 (81.8%) goats were positive by polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The infection was also confirmed from the farmer, his wife and 9 persons from all 16 veterinary officials who had visited the farm for protective measures and preparing goat specimens for laboratory tests. The farm was found to be extensively contaminated with C. burnetii from the examination to the environmental specimens and epidemiological inspections, which might be the main source of C. burnetii infection to humans. The extensive contamination to the farm was derived from the uncareful handling of postpartum animal tissues or discharges by the farm owner. This report will contribute to the establishment of educational system on the biosecurity to novice farmers.

Objectives Small-molecule polypeptide neutrophil peptide 1 (NP-1) was reported to promote the regeneration of the sciatic nerve after denervation, but the mechanisms underlying this effect of NP-1 ...

Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by insulin resistance, and patients with GDM have a higher risk of cardiovascular disease. Multiple microRNAs (miRNAs) are reported to be involved in the regulation of myocardial injury. Moreover, miR-873 was predicted to target insulin-like growth factor binding protein 2 (IGFBP2) through bioinformatic analysis, which was further confirmed using a luciferase assay. Thus, our objective was to assess whether microRNA-873 (miR-873) affects insulin resistance and myocardial injury in an established GDM rat model. The GDM rats were treated with miR-875 mimic or inhibitor or IGFBP2 siRNA. The effects of miR-875 and IGFBP2 on the cardiac function, insulin resistance, and myocardial injury were evaluated by hemodynamic measurements, determination of biochemical indices of myocardium and serum, and insulin homeostatic model assessment. The results indicated that downregulation of miR-873 upregulated the expression of IGFBP2 and promoted the activation of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. With downregulation of miR-873 in GDM rats, the cardiac function was improved and the myocardial apoptosis was inhibited, coupled with elevated activity of superoxide dismutase, carbon monoxide synthase, and the nitric oxide content. In addition, the inhibition of miR-873 in GDM rats modulated the insulin resistance and reduced myocardial apoptosis. Overall, the data showed that inhibition of miR-873 by targeting IGFBP2 may regulate the insulin resistance and curtail myocardial injury in GDM rats through activating the PI3K/AKT/mTOR axis, thus providing a potential means of impeding the progression of GDM.

The most severe sequelae after rehabilitation from SARS are femoral head necrosis and pulmonary fibrosis. We performed a 15-year follow-up on the lung and bone conditions of SARS patients. We evaluated the recovery from lung damage and femoral head necrosis in an observational cohort study of SARS patients using pulmonary CT scans, hip joint MRI examinations, pulmonary function tests and hip joint function questionnaires. Eighty medical staff contracted SARS in 2003. Two patients died of SARS, and 78 were enrolled in this study from August 2003 to March 2018. Seventy-one patients completed the 15-year follow-up. The percentage of pulmonary lesions on CT scans diminished from 2003 (9.40 ± 7.83)% to 2004 (3.20 ± 4.78)% (P 1/FVC%, t = 2.21, P = 0.04) and mid-flow of maximum expiration (FEF25%–75%, t = 2.76, P = 0.01). The volume of femoral head necrosis decreased significantly from 2003 (38.83 ± 21.01)% to 2005 (30.38 ± 20.23)% (P = 0.000 2), then declined slowly from 2005 to 2013 (28.99 ± 20.59)% and plateaued until 2018 (25.52 ± 15.51)%. Pulmonary interstitial damage and functional decline caused by SARS mostly recovered, with a greater extent of recovery within 2 years after rehabilitation. Femoral head necrosis induced by large doses of steroid pulse therapy in SARS patients was not progressive and was partially reversible.

Trastuzumab is commonly used in the treatment of human epidermal growth factor receptor-2 positive (HER-2+) breast cancer, but its efficacy is often limited by the emergence of chemoresistance. Recent studies indicate that exosomes act as vehicles for exchange of genetic cargo between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development and progression. However, the specific contribution of breast cancer-derived exosomes is poorly understood. In this study, publicly available expression profiling data from breast cancer and bioinformatics analyses were used to screen potential miRNAs in trastuzumab resistance. A series of gain- or loss-functional assays were performed to define the function of miR-567 and ATG5 in trastuzumab resistance and autophagy, both in vitro and in vivo. Our results showed that miR-567 was significantly decreased in trastuzumab-resistant patients compared with responding patients. Moreover, miR-567 was also downregulated in trastuzumab-resistant cells compared with parental cells. Overexpression of miR-567 reversed chemoresistance, whereas silence of miR-567 induced trastuzumab resistance, both in vitro and in vivo. In addition, enhanced miR-567 could be packaged into exosomes, incorporated into receipt cells, suppressing autophagy and reversed chemoresistance by targeting ATG5. To conclude, exosomal miR-567 plays a key role in reversing trastuzumab resistance via regulating autophagy, indicating it may be a promising therapeutic target and prognostic indicator for breast cancer patients.

Neutrophil peptide 1 belongs to a family of peptides involved in innate immunity. Continuous intramuscular injection of neutrophil peptide 1 can promote the regeneration of peripheral nerves, but clinical application in this manner is not convenient. To this end, the effects of a single intraoperative administration of neutrophil peptide 1 on peripheral nerve regeneration were experimentally observed. A rat model of sciatic nerve crush injury was established using the clamp method. After model establishment, a normal saline group and a neutrophil peptide 1 group were injected with a single dose of normal saline or 10 μg/mL neutrophil peptide 1, respectively. A sham group, without sciatic nerve crush was also prepared as a control. Sciatic nerve function tests, neuroelectrophysiological tests, and hematoxylin-eosin staining showed that the nerve conduction velocity, sciatic functional index, and tibialis anterior muscle fiber cross-sectional area were better in the neutrophil peptide 1 group than in the normal saline group at 4 weeks after surgery. At 4 and 8 weeks after surgery, there were no differences in the wet weight of the tibialis anterior muscle between the neutrophil peptide 1 and saline groups. Histological staining of the sciatic nerve showed no significant differences in the number of myelinated nerve fibers or the axon cross-sectional area between the neutrophil peptide 1 and normal saline groups. The above data confirmed that a single dose of neutrophil peptide 1 during surgery can promote the recovery of neurological function 4 weeks after sciatic nerve injury. All the experiments were approved by the Medical Ethics Committee of Peking University People's Hospital, China (approval No. 2015-50) on December 9, 2015.

Dysfunction of natural killer (NK) cells is associated with poor prognosis in hepatocellular carcinoma (HCC). We explored the phenotypic and functional characteristics of peripheral blood NK cells in HCC patients following sorafenib treatment.Peripheral blood samples were collected from 60 HCC patients in a single centre (2015~2017) and 45 healthy donors. The percentage and cytoplasmic granule production of NK cells were analysed. Subset proportions were evaluated for their associations with the modified Response Evaluation Criteria in Solid Tumors (mRECIST), time to progression, and median overall survival (OS).Compared with baseline, the percentages of total and CD56dimCD16+ NK cells increased after two months of treatment, while the percentage of CD56brightCD16- NK cells decreased, leading to a dramatically reduced ratio of CD56bright and CD56dim NK cells (ratiobri/dim). Patients with low ratiobri/dim exhibited better mRECIST responses and longer median OS than those with high ratiobri/dim. The expression levels of granzyme B and perforin in total NK cells and in both subsets of cells were increased after treatment.This study showed that sorafenib could affect the proportions and functions of peripheral CD56brightCD16- and CD56dimCD16+ NK cells, which was associated with the outcomes including OS of HCC patients.

An abdominal aortic aneurysm is a life-threatening cardiovascular disorder caused by dissection and rupture. No effective medicine is currently available for the > 90% of patients whose aneurysms are below the surgical threshold. The present study investigated the impact of rosmarinic acid, salvianolic acid C, or salvianolic acid B on experimental abdominal aortic aneurysms. Abdominal aortic aneurysms were induced in apolipoprotein E-deficient mice via infusion of angiotensin II for 4 wks. Rosmarinic acid, salvianolic acid C, salvianolic acid B, or doxycycline as a positive control was provided daily through intraperitoneal injection. Administration of rosmarinic acid was found to decrease the thickness of the aortic wall, as determined by histopathological assay. Rosmarinic acid also exhibited protection against elastin fragmentation in aortic media and down-regulated cell apoptosis and proliferation in the aortic adventitia. Infiltration of macrophages, T lymphocytes, and neutrophils in aortic aneurysms was found, especially at the aortic adventitia. Rosmarinic acid, salvianolic acid C, or salvianolic acid B inhibited the infiltration on macrophages specifically, but these compounds did not influence T lymphocytes and neutrophils. Expression of matrix metalloproteinase 9 and macrophage migration inhibitory factor significantly increased in aortic aneurysms. Rosmarinic acid and salvianolic acid C decreased the expression of matrix metalloproteinase-9 in media, and rosmarinic acid also tended to reduce migration inhibitory factor expression. Further then, partial least squares-discriminate analysis was used to classify metabolic changes among different treatments. Rosmarinic acid affected most of the metabolites in the biosynthesis of the citrate cycle, fatty acid pathway significantly. Our present study on mice demonstrated that rosmarinic acid inhibited multiple pathological processes, which were the key features important in abdominal aortic aneurysm formation. Further study on rosmarinic acid, the novel candidate for aneurysmal therapy, should be undertaken to determine its potential for clinical use.

Background Persistent infection with high-risk human papillomavirus (HR-HPV) is the main leading cause of cervical precancerous lesions and cervical cancer. This study aims to explore the epidemiological characteristics of HR-HPV genotypes and their correlation with the ThinPrep cytological test (TCT) results among women in Chongqing, in China. Methods In this retrospective study, cervical exfoliations of 14,548 women who visited Chongqing university cancer hospital were collected for detecting HR-HPV genotypes and TCT. Results Overall, the rate of HR-HPV infection was 14.26%. The three most common HR-HPV genotypes are HPV52 (4.39%), HPV58 (2.21%), and HPV16 (1.94%). In this study, the positive rate of cervical TCT was 4.54%. Atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells that could not exclude high-grade squamous intraepithelial lesion (ASU-H), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and atypical glandular cells of undetermined significance (AGC) were 2.99%, 0.20%, 0.92%, 0.29%, and 0.14%, respectively. Among the several types of cytological lesions, the HR-HPV infection rates of ASC-US, ASC-H, LSIL, HSIL, and (AGC) were 24.82%, 41.38%, 64.18%, 95.24%, and 23.81%, respectively. Conclusions HPV52, HPV 58, and HPV16 are the most common infection subtypes in Chongqing. When implementing HPV vaccine programs in Chongqing, HPV58 and HPV52 should be attached importance as HPV16 and HPV18.

Background: To investigate the drug resistance and clinical characteristics of hospitalized children with drug-resistant Mycoplasma pneumoniae pneumonia (MRMP).Methods: Sixty patients with MPP admitted to the Second Pediatric Respiratory Ward of Shengjing Hospital, Affiliated to China Medical University from November 2016 to February 2017 were enrolled in the study.Results: Of these 53/60 (88.3%) patients had Mycoplasma pneumoniae nucleic acid identified by throat swab. 23S rRNA V region gene sequencing was performed, 47/49 (95.9%) had mutation sites, including 46 cases of A2063G, one case of A2064G, two cases of no mutation, and a final drug resistance rate of 95.9%. The summary characteristics of the 47 cases of drug-resistant MPP were based on 22 male and 25 female patients. The onset age was 6.9 ± 2.5 years and the total fever duration was 9.8 ± 3.7 days. The leukocyte count during the acute phase was (8,300 ± 4,200) cells/mm3, C-reactive Protein (CRP) was 18.2 (8.2–32.5) mg/L, neutrophil/lymphocyte ratio (NLR) was 2.1 (1.5–3.3), There was no significant difference between the acute phase and the convalescent phase for leukocyte count, P = 0.336. The NLR and CRP levels were significantly higher during the acute phase compared to the recovery period (P < 0.05). The level of lactate dehydrogenase (LDH) increased in 65.7% of patients, with a median of 248.5 (200.0–299.7) U/L. D-dimer levels were elevated in 59.4% of patients, with a median of 301.0 (188.5–545.0) mg/L. A total of 23/47 (48.9%) patients were diagnosed with severe MPP. The incidence of extra-pulmonary complications was 38.2%. Conclusions: In summary, MRMP patients had a fever of long duration, higher inflammatory index, higher LDH and D-dimer levels, and an increased incidence of extra-pulmonary complications.

The aim of this study was to investigate the effects of the GSK-3β/NF-κB pathway on integrin-associated protein (CD47) expression after myocardial infarction (MI) in rats. An MI Sprague Dawley rat model was established by ligating the left anterior descending coronary artery. The rats were divided into three groups: Sham, MI, and SB + MI (SB216763) groups. Immunohistochemistry was used to observe the changes in cardiac morphology. A significant reduction in the sizes of fibrotic scars was observed in the SB + MI group compared to that in the MI group. SB216763 decreased the mRNA and protein expression of CD47 and NF-κB during MI. Primary rat cardiomyocytes (RCMs) and the H9c2 cell line were used to establish in vitro hypoxia models. Quantitative real-time PCR and western blotting analyses were conducted to detect mRNA and protein expression levels of CD47 and NF-κB and apoptosis-related proteins, respectively. Apoptosis of hypoxic cells was assessed using flow cytometry. SB216763 reduced the protein expression of CD47 and NF-κB in RCMs and H9c2 cells under hypoxic conditions for 12 h, and alleviated hypoxia-induced apoptosis. SN50 (an NF-κB inhibitor) also decreased CD47 protein expression in RCMs and H9c2 cells under hypoxic conditions for 12 h and protected cells from apoptosis. GSK-3β upregulates CD47 expression in cardiac tissues after MI by activating NF-κB, which in turn leads to myocardial cell damage and apoptosis.

Li Ma,1 Hong Li,1,2 Huijun Zhuang,1 Qiao Zhang,1 Nianchun Peng,1 Ying Hu,1 Na Han,1 Yuxing Yang,1 Lixin Shi1 1Department of Endocrinology and Metabolism, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 2School Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Hong LiDepartment of Endocrinology and Metabolism, Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Road, Guiyang, Guizhou, 550001, People’s Republic of ChinaTel +8618685136016Fax +86-851-86770523Email lee-helen@sjtu.edu.cnPurpose: The study was conducted to investigate metabolic syndrome (MS) incidence within the normal blood pressure (BP) range in a population over 40 years old in an urban area of Guiyang, Guizhou Province, China, and to identify a valid BP cutoff value for predicting MS.Materials and Methods: Data from this study are based on the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. In total, 2935 subjects in the normal BP range and without MS (795 males, 2140 females) aged 40– 80 years were included in this study. Follow-up subjects were classified by baseline BP and grouped by age. After the 3-year follow-up, the MS incidence and valid BP cutoff value for predicting MS were calculated for subjects within the normal BP range.Results: After the 3-year follow-up study, the crude and standardized MS incidences in the cohort were 19.83% and 16.89% for follow-up subjects, respectively, with incidences of 10.94% and 10.50% for males and 23.13% and 20.66% for females. The incidence of MS in normotensive subjects (15.53%) was lower than that in subjects with high-normal BP (29.08%). After adjusting for age, sex, BMI, smoking, and drinking, the risk of having MS in the high-normal BP group was 1.823-fold [HR 1.823 95% CI (1.538– 2.162)] higher than that in the normotensive group. The ROC curve showed that the BP cutoff values were more than 117/74 mmHg in males and 112/74 mmHg in females.Conclusion: When BP was within the normal range, the incidence of MS in participants was very high. The MS incidence was higher among high-normal BP subjects than among normotensive subjects, as was the risk of having MS. The valid BP cutoff value for predicting MS in the population was 117/74 mmHg in males and 112/74 mmHg in females. Currently, epidemiological investigations are needed to determine whether a lower BP cutoff value is needed in diagnosing MS.Keywords: metabolic syndrome, high-normal blood pressure, normotensive, incidence, cutoff value

To explore trajectories of gestational weight gain (GWG) before diagnosis and its association with risk of gestational diabetes mellitus (GDM).A population-based retrospective cohort study including 37,060 women with live singleton was conducted between 2013 and 2019 in China. Latent class trajectory model (LCTM) was used to identify GWG trajectories, and Poisson regression with robust error estimates was used to estimate risk ratio (RR) of GDM.Among total 37,060 participants, 25.47% of women were developed with GDM. Two trajectories of GWG were identified as non-excessive weight gain (94.31%) and excessive weight gain (5.69%) before diagnosis of GDM. Women with excessive GWG trajectory before diagnosis had significantly 32.8% (aRR = 1.328, 95 %CI: 1.252 ∼ 1.409, P 0.001) increased risk of developing GDM compared with non-excessive GWG trajectory. Women with excessive GWG trajectory also had higher risk of macrosomia (aRR = 1.476, 95 %CI: 1.307 ∼ 1.666, P 0.001) and cesarean delivery (aRR = 1.126, 95 %CI: 1.081 ∼ 1.174, P 0.001). The impact of excessive GWG trajectory on GDM was greater among pre-pregnancy normal weight women compared with overweight/obese or underweight women.Women with excessive GWG trajectory before diagnosis had significantly higher risk of GDM and GDM-related adverse outcomes, and pre-pregnancy normal weight women with excessive GWG trajectory should also be concerned.

The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH. NEW & NOTEWORTHY This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.

Breast cancer is one of the commonest malignancies in women, especially in middle-aged and elderly women. Abnormal activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKt/mTOR) pathway has been found to be involved in breast cancer proliferation. Pictilisib (GDC-0941) is a potent inhibitor of PI3K with high affinity and is undergoing phase 2 clinical trials. In this study, we aimed to develop a noninvasive PI3K radiotracer to help determine the mechanism of the PI3K/AKt/mTOR pathway to aid in diagnosis. We designed a new 18F-radiolabeled radiotracer based on the structure of pictilisib, to evaluate noninvasively abnormal activation of the PI3K/AKT/mTOR pathway. To increase the water solubility, and to decrease hepatobiliary and gastrointestinal uptake of the tracer, pictilisib was modified with triethylene glycol di(p-toluenesulfonate) (TsO-PEG3-OTs) to obtain TsO-PEG3-GDC-0941 as the precursor for 18F labeling. A nonradiolabeled reference compound [19F]-PEG3-GDC-0941 was also prepared. Breast cancer cell lines, MCF-7 and MDA-MB-231, were used as high- and low-expression PI3K models, respectively. PET imaging and ex vivo biodistribution assays of [18F]-PEG3-GDC-0941 in MCF-7 and MDA-MB-231 xenografts were also performed, and the results were compared. The precursor compound and reference standard compound were successfully synthesized and identified using NMR and mass spectroscopy. The 18F radiolabeling was achieved with a high yield (61 ± 1%) at a high molar activity (2100 ± 100 MBq/mg). MicroPET images and biodistribution studies showed a higher uptake of the radiotracer in MCF-7 tumors than in MDA-MB-231 tumors (7.56 ± 1.01%ID/g vs 4.07 ± 0.68%ID/g, 1 h postinjection). Additionally, the MCF-7 tumor uptake was significantly decreased when a blocking dose of GDC-0941 was coinjected, indicating high specificity. The liver was found to be the major excretory organ with 5.82 ± 0.88%ID/g at 30 min postinjection for MCF-7 mice. This radiotracer holds great potential for patient screening, diagnosis, and therapy prediction of PI3K-related diseases.

BackgroundSmall-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies.MethodsEligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate.ResultsForty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand–foot syndrome, increased L-gamma-glutamyltransferase.ConclusionsApatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted.Trial registrationNCT02945852.

Summary Background Angioplasty recanalisation is recommended as the first-line interventional procedure for Budd-Chiari syndrome, but subsequent restenosis is common. We aimed to test whether use of routine, non-selective stenting in angioplasty could improve patency and treatment efficacy with adequate safety in Budd-Chiari syndrome. Methods We did a randomised controlled trial, for which patients aged 18–75 years with Budd-Chiari syndrome with membranous obstruction or short-length stenosis (≤4 cm), and a Child-Pugh score of less than 13 were considered eligible. Patients were excluded if they had obstruction not amenable to angioplasty, were recommended to be treated with transjugular intrahepatic portosystemic shunt or liver transplantation, or had contraindications for angioplasty. Eligible patients were randomly assigned (1:1) to an angioplasty-only group or an angioplasty plus routine stenting group, with use of a web-based allocation system (Pocock and Simon's minimisation method, stratified by obstruction features and Child-Pugh score). Recanalisation procedures were done within 24 h of randomisation. The statistician and investigators responsible for data collection data and endpoint assessment were masked to group allocation. The primary outcome was the proportion of patients free of restenosis, analysed in the intention-to-treat population. The study is registered on ClinicalTrials.gov ( NCT02201485 ) and is completed. Findings Between July 28, 2014, and Sept 29, 2017, 88 (59%) of 150 screened patients were enrolled and assigned either the angioplasty-only group (n=45) or the angioplasty plus routine stenting group (n=43). During a median follow-up period of 27 months (IQR 19–41), the angioplasty plus routine stenting group had significantly higher proportion of patients free of restenosis (42 [98%] of 43 patients) than did the angioplasty-only group (27 [60%] of 45 patients; p Interpretation Routine stenting with angioplasty is superior to angioplasty alone for preventing restenosis in patients with Budd-Chiari syndrome with short-length stenosis and is safe to use as part of first-line invasive treatment. Further validation is needed in similar settings and other regions in which different characteristics of Budd-Chiari syndrome are more prevalent. Funding National Natural Science Foundation of China, National Key Technology R&D Programme, Optimised Overall Project of Shaanxi Province, Boost Programme of Xijing Hospital.

Background Bladder cancer (BC) is one of the most prevalent malignancies of the genitourinary system, yet the underlying mechanism of BC progression still remains unclear. Growth arrest and DNA damage-inducible 45 alpha (GADD45a) is a repressive gene implicated in cell cycle regulation, as well as in human cancers development. However, its role in BC remains to be determined. Methods First, quantitative real-time polymerase chain reaction (PCR) and Western blot assays were used to detect GADD45a expression in BC tissues and adjacent non-tumor tissues, as well as in bladder cancer cell lines, respectively. Then, cell counting kit-8 (CCK-8) assays, colony formation assays, and flow cytometry assays were used to measure the ability of cell growth, proliferation and cell cycle distribution. Lentiviral infection technology was used to increase gene expression, while siRNA interfering technology was used to knockdown gene expression. Finally, nude mice were used to construct tumor-burdened models in vivo by injecting tumor cells subcutaneously. Results PCR results showed that the level of GADD45a mRNA and protein levels were lower in BC tissues than in adjacent normal tissues. After increasing GADD45a expression, both the ability of growth and proliferation of BC cells were seriously impaired. Additionally, the upregulation of GADD45a expression resulted in BC cell cycle in G2/M and S phases in a p53-regulated pathway. Conclusion GADD45a-mediated cell cycle inhibition is regulated by p53 in bladder cancer cells.

Summary Background The survival benefit of early placement of transjugular intrahepatic portosystemic shunts (TIPS) in patients with cirrhosis and acute variceal bleeding is controversial. We aimed to assess whether early TIPS improves survival in patients with advanced cirrhosis and acute variceal bleeding. Methods We did an investigator-initiated, open-label, randomised controlled trial at an academic hospital in China. Consecutive patients with advanced cirrhosis (Child-Pugh class B or C) and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy were randomly assigned (2:1) to receive either early TIPS (done within 72 h after initial endoscopy [early TIPS group]) or standard treatment (vasoactive drugs continued to day 5, followed by propranolol plus endoscopic band ligation for the prevention of rebleeding, with TIPS as rescue therapy when needed [control group]). Randomisation was done by web-based randomisation system using a Pocock and Simon's minimisation method with Child-Pugh class (B vs C) and presence or absence of active bleeding as adjustment factors. The primary outcome was transplantation-free survival, analysed in the intention-to-treat population, excluding individuals subsequently found to be ineligible for enrolment. This study is registered with ClinicalTrials.gov , number NCT01370161 , and is completed. Findings From June 26, 2011, to Sept 30, 2017, 373 patients were screened and 132 patients were randomly assigned to the early TIPS group (n=86) or to the control group (n=46). After exclusion of three individuals subsequently found to be ineligible for enrolment (two patients in the early TIPS group with non-cirrhotic portal hypertension or hepatocellular carcinoma, and one patient in the control group due to non-cirrhotic portal hypertension), 84 patients in the early TIPS group and 45 patients in the control group were included in the intention-to-treat population. 15 (18%) patients in the early TIPS group and 15 (33%) in the control group died; two (2%) patients in the early TIPS group and one (2%) in the control group underwent liver transplantation. Transplantation-free survival was higher in the early TIPS group than in the control group (hazard ratio 0·50, 95% CI 0·25–0·98; p=0·04). Transplantation-free survival at 6 weeks was 99% (95% CI 97–100) in the early TIPS group compared with 84% (75–96; absolute risk difference 15% [95% CI 5–48]; p=0·02) and at 1 year was 86% (79–94) in the early TIPS group versus 73% (62–88) in the control group (absolute risk difference 13% [95% CI 2–28]; p=0·046). There were no significant differences between the two groups in the incidence of hepatic hydrothorax (two [2%] of 84 patients in the early TIPS group vs one [2%] of 45 in the control group; p=0·96), spontaneous bacterial peritonitis (one [1%] vs three [7%]; p=0·12), hepatic encephalopathy (29 [35%] vs 16 [36%]; p=1·00), hepatorenal syndrome (four [5%] vs six [13%]; p=0·10), and hepatocellular carcinoma (four [5%] vs one [2%]; p=0·68). There was no significant difference in the number of patients who experienced other serious adverse events (ten [12%] vs 11 [24%]; p=0·07) or non-serious adverse events (21 [25%] vs 19 [42%]; p=0·05) between groups. Interpretation Early TIPS with covered stents improved transplantation-free survival in selected patients with advanced cirrhosis and acute variceal bleeding and should therefore be preferred to the current standard of care. Funding National Natural Science Foundation of China, National Key Technology R&D Program, Optimized Overall Project of Shaanxi Province, Boost Program of Xijing Hospital.

During peripheral nerve transposition repair, if the diameter difference between transposed nerves is large or multiple distal nerves must be repaired at the same time, traditional epineurial neurorrhaphy has the problem of high tension at the suture site, which may even lead to the failure of nerve suture. We investigated whether a small gap bio-sleeve suture with different inner diameters at both ends can be used to repair a 2-mm tibial nerve defect by proximal transposition of the common peroneal nerve in rats and compared the results with the repair seen after epineurial neurorrhaphy. Three months after surgery, neurological function, nerve regeneration, and recovery of nerve innervation muscle were assessed using the tibial nerve function index, neuroelectrophysiological testing, muscle biomechanics and wet weight measurement, osmic acid staining, and hematoxylin-eosin staining. There was no obvious inflammatory reaction and neuroma formation in the tibial nerve after repair by the small gap bio-sleeve suture with different inner diameters at both ends. The conduction velocity, muscle strength, wet muscle weight, cross-sectional area of muscle fibers, and the number of new myelinated nerve fibers in the bio-sleeve suture group were similar to those in the epineurial neurorrhaphy group. Our findings indicate that small gap bio-sleeve suture with different inner diameters at both ends can achieve surgical suture between nerves of different diameters and promote regeneration and functional recovery of injured peripheral nerves.

Purpose: The Myc family, especially C-MYC and MYCL1, has been found involved in small-cell lung carcinoma (SCLC). Identification of the frequency of C-MYC and MYCL1 expression among SCLC patients may help to identify potential targets for therapeutic intervention. Our aim was to detect MYCL1 amplification, L-Myc and c-Myc expression, and investigate clinicopathological characteristics and survival status in patients with surgically resected SCLC.Methods:MYCL1 amplification was detected using fluorescence in situ hybridization (FISH), while L-Myc and c-Myc protein expressions were determined using immunohistochemistry (IHC) in the primary tumors of 46 resected SCLC patients.Results: Among the 46 evaluated specimens, MYCL1 amplification was identified in 3/46 cases (6.5%). One of the positive cases was MYCL1 gene amplification combined with fusion. 3/46 (6.5%) was positive for L-myc protein expression, and 4/46 (8.7%) was positive for c-Myc protein expression.Conclusion: Our study firstly multidimensional explored the expression of MYCL1 amplification, L-Myc and c-Myc protein and investigated clinicopathological characteristics and survival status in patients with surgically resected SCLC, which makes a contribution to subsequent research and therapeutic strategies.

ObjectivesThe secondary impacts of the COVID-19 pandemic on adverse maternal and neonatal outcomes remain unclear. In this study, we aimed to evaluate the association between the COVID-19 pandemic and the risk for adverse pregnancy outcomes.DesignWe conduced retrospective analyses on two cohorts comprising 7699 pregnant women in Beijing, China, and compared pregnancy outcomes between the pre-COVID-2019 cohort (women who delivered from 20 May 2019 to 30 November 2019) and the COVID-2019 cohort (women who delivered from 20 January 2020 to 31 July 2020). The secondary impacts of the COVID-2019 pandemic on pregnancy outcomes were assessed by using multivariate log-binomial regression models, and we used interrupted time-series (ITS) regression analysis to further control the effects of time-trends.SettingOne tertiary-level centre in Beijing, ChinaParticipants7699 pregnant women.ResultsCompared with women in the pre-COVID-19 pandemic group, pregnant women during the COVID-2019 pandemic were more likely to be of advanced age, exhibit insufficient or excessive gestational weight gain and show a family history of chronic disease (all p<0.05). After controlling for other confounding factors, the risk of premature rupture of membranes and foetal distress was increased by 11% (95% CI, 1.04 to 1.18; p0.05).ConclusionsDuring the COVID-19 pandemic, more women manifested either insufficient or excessive gestational weight gain; and the risk of premature rupture of membranes and foetal distress was also higher during the pandemic.

Objective. The study is aimed at examining the effects of fatty acid-binding protein 4 (FABP4) on insulin resistance and gestational diabetes mellitus (GDM). Methods. Based on a prospective birth cohort in Beijing, China, we conducted a nested case-control study and analyzed 135 GDM case-control pairs matched by age and the gestational week when they took the oral glucose tolerance test. We performed linear regression to analyze the association of plasma FABP4 concentrations with insulin resistance. We used logistic regression to estimate odds ratios (ORs) of FABP4 for GDM, controlling for potential confounders, including dietary intake and physical activity. Results. Plasma FABP4 levels in the first and second trimesters were positively associated with fasting insulin and homeostasis model assessment for insulin resistance (HOMA-IR) in the second trimester (both P < 0.001 ). Compared with those in the lowest FABP4 tertile, women in the highest tertile of FABP4 levels in the first and second trimesters had 1.053 times ( OR = 2.053 , 95% CI 1.091 to 3.863) and 1.447 times ( OR = 2.447 , 95% CI 1.305 to 4.588) higher risk of developing GDM. Conclusions. Elevated FABP4 levels in the first and second trimesters were associated with a higher level of insulin resistance and greater GDM risk, indicating FABP4 might predict women with high risk of developing GDM.

Under the ongoing COVID-19 prevention and control measures in China, increasing the laboratory severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid testing capacity has become the top priority. Since the COVID-19 outbreak in Xinfadi market in Beijing in June 2020, large-scale screening of key populations has been carried out, challenging the nucleic acid testing capabilities of hospital laboratories. Therefore, within 48 hours, Peking University People’s Hospital (PKUPH) transformed a non-nucleic acid testing laboratory into a SARS-CoV-2 nucleic acid testing laboratory. Based on the original structure of the building, we adapted measures to local conditions, sorted out a new testing process, and quickly started testing for COVID-19. The nucleic acid testing process has been optimized, including quality control, personal operating specifications, and the timeliness of the release of LIS results to form closed-loop management. This high-throughput COVID-19 testing optimization process provides a reference model for other countries that are fighting the epidemic.

Background The COVID-19 pandemic has resulted in changes to normal life and disrupted social and economic function worldwide. However, little is known about the impact of social media use, unhealthy lifestyles, and the risk of miscarriage among pregnant women during the COVID-19 pandemic. Objective This study aims to assess the association between social media use, unhealthy lifestyles, and the risk of miscarriage among pregnant women in the early stage of the COVID-19 pandemic in China. Methods In this prospective cohort study, 456 singleton pregnant women in mainland China were recruited during January and February 2020. Sociodemographic characteristics, history of previous health, social media use, and current lifestyles were collected at baseline, and we followed up about the occurrence of miscarriage. Log-binomial regression models were used to estimate the risk ratios (RRs) of miscarriage for women with different exposures to COVID-19–specific information. Results Among all the 456 pregnant women, there were 82 (18.0%) who did no physical activities, 82 (18.0%) with inadequate dietary diversity, 174 (38.2%) with poor sleep quality, and 54 (11.8%) spending >3 hours on reading COVID-19 news per day. Women with excessive media use (>3 hours) were more likely to be previously pregnant (P=.03), have no physical activity (P=.003), have inadequate dietary diversity (P=.03), and have poor sleep quality (P3 hours (17/54, 31.5%) was higher (P3 hours of media use daily (adjusted RR 2.56, 95% CI 1.43-4.59; P=.002) were associated with miscarriage. In the sensitivity analysis, results were still stable. Conclusions Pregnant women with excessive media use were more likely to have no physical activity, inadequate dietary diversity, and poor sleep quality. Excessive media use and poor sleep quality were associated with a higher risk of miscarriage. Our findings highlight the importance of healthy lifestyles during the COVID-19 pandemic.

Fat-soluble vitamins during pregnancy are important for fetal growth and development. The present study aimed at exploring the association between vitamin A, E and D status during pregnancy and birth weight. A total of 19 640 women with singleton deliveries from a retrospective study were included. Data were collected by the hospital electronic information system. Maternal serum vitamin A, E and D concentrations were measured during pregnancy. Logistic regression was performed to estimate the association between the vitamin status and low birth weight (LBW) or macrosomia. Women with excessive vitamin E were more likely to have macrosomia (OR 1·30, 95 % CI 1·07, 1·59) compared with adequate concentration. When focusing on Z scores, there was a positive association between vitamin E and macrosomia in the first (OR 1·07, 95 % CI 1·00, 1·14), second (OR 1·27, 95 % CI 1·11, 1·46) and third (OR 1·28, 95 % CI 1·06, 1·54) trimesters; vitamin A was positively associated with LBW in the first (OR 1·14, 95 % CI 1·01, 1·29), second (OR 1·31, 95 % CI 1·05, 1·63) and third (OR 2·00, 95 % CI 1·45, 2·74) trimesters and negatively associated with macrosomia in the second (OR 0·79, 95 % CI 0·70, 0·89) and third (OR 0·77, 95 % CI 0·62, 0·95) trimesters. The study identified that high concentrations of vitamin E are associated with macrosomia. Maintaining a moderate concentration of vitamin A during pregnancy might be beneficial to achieve optimal birth weight. Further studies to explore the mechanism of above associations are warranted.

Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system. It is mainly expressed by oligodendrocytes. Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition, neuronal homeostasis, precursor migration, plasticity, and neurodegeneration, its functions in the process of oxidative injury are largely uncharacterized. In this study, oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats. We used hydrogen peroxide (H2O2) to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes. After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes, Nogo-A expression was increased, and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death. Furthermore, knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2. Intervention with a Nogo-66 antibody, a LINGO1 blocker, or Y27632, an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway, did not affect the death of oligodendrocytes. Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes. In conclusion, Nogo-A aggravated reactive oxygen species damage in oligodendrocytes, and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process. This study was approved by the Ethics Committee of Peking University People’s Hospital, China (approval No. 2018PHC081) on December 18, 2018.

Introduction Current guidelines recommend anticoagulation as the mainstay of portal vein thrombosis (PVT) treatment in cirrhosis. However, because of the heterogeneity of PVT, anticoagulation alone does not always achieve satisfactory results. This study aimed to prospectively evaluate an individualized management algorithm using a wait-and-see strategy (i.e., no treatment), anticoagulation, and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT in cirrhosis. Methods Between February 2014 and June 2018, 396 consecutive patients with cirrhosis with nonmalignant PVT were prospectively included in a tertiary care center, of which 48 patients (12.1%) were untreated, 63 patients (15.9%) underwent anticoagulation, 88 patients (22.2%) underwent TIPS, and 197 patients (49.8%) received TIPS plus post-TIPS anticoagulation. The decision of treatment option mainly depends on the stage of liver disease (symptomatic portal hypertension or not) and degree and extension of thrombus. Results During a median 31.7 months of follow-up period, 312 patients (81.3%) achieved partial (n = 25) or complete (n = 287) recanalization, with 9 (3.1%) having rethrombosis, 64 patients (16.2%) developed major bleeding (anticoagulation-related bleeding in 7 [1.8%]), 88 patients (22.2%) developed overt hepatic encephalopathy, and 100 patients (25.3%) died. In multivariate competing risk regression models, TIPS and anticoagulation were associated with a higher probability of recanalization. Long-term anticoagulation using enoxaparin or rivaroxaban rather than warfarin was associated with a decreased risk of rethrombosis and an improved survival, without increasing the risk of bleeding. However, the presence of complete superior mesenteric vein thrombosis was associated with a lower recanalization rate, increased risk of major bleeding, and poor prognosis. Discussion In patients with cirrhosis with PVT, the individualized treatment algorithm achieves a high-probability recanalization, with low rates of portal hypertensive complications and adverse events.

Aplastic anemia (AA) is a bone marrow failure disease. It is difficult to treat AA, and in addition, relapses are common because of its complex disease pathogenesis. Allogeneic bone marrow-derived mesenchymal stem cells (BMSCs) infusion is an effective and safe treatment option for the AA patients. However, it found that BMSCs infusion in AA patients is less than 30% effective. Therefore, the key to improve the efficacy of BMSCs treatment in these patients is to enhance their homing efficiency to the target sites. Studies have shown that stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays an important role in promoting BMSCs homing. In this study, human BMSCs were transduced with lentivirus stably expressing CXCR4-BMSCs. Transduced BMSCs resemble normal BMSCs in many ways. Migration ability of CXCR4-BMSCs toward SDF-1 was increased because of the overexpression of CXCR4. In the mice with bone marrow failure, the migration and colonization ability of CXCR4-BMSCs to the bone marrow was significantly improved as seen by IVIS imaging and FACS. The SDF-1 level in the bone marrow failure mice was significantly higher than in the normal mice. Thus, from our study, it is clear that after CXCR4-BMSCs were infused into mice with bone marrow failure, SDF-1 interacted with CXCR4 receptor, leading cells to migrate and colonize to bone marrow. Because of the high SDF-1 expression in mouse bone marrow and CXCR4 receptor expression in cells, BMSCs homing was increased.

Background The clinical efficacy of plasmapheresis (PP) in patients with hypertriglyceridemic acute pancreatitis (HLAP) might affected by total cholesterol (TC). The objective of this study is to determine the relationship of TC and the Triglyceride (TG)-lowing effect in patients on either non-PP or PP therapy.MethodsPatients were categorized into high total cholesterol (HTC) /low total cholesterol (LTC) groups based on TC level of 12.4 mmol/l. The primary outcome was TG reduction to below 500mg/dl within 48 hours. Linear mixed-effect model and logistic regression analyses were used to assess the association of TC and different therapy groups on TG-lowing efficacy.ResultsCompared with LTC group, patients with HTC showed more severe imaging manifestations(pConclusions: TC could be a potential biomarker to predict the effects of TG-lowing therapy in patients with HLAP.

ObjectiveTo examine the effects of dynamic change in fetuin-A levels before the diagnosis of gestational diabetes mellitus (GDM) on insulin resistance and GDM.Research design and methodsA total of 135 women with GDM and 135 normal glucose tolerance (NGT) women with matched age (±2 years old) and gestational age at taking the oral glucose tolerance test (OGTT) were included in this nested case–control study. Fasting venous blood samples were collected at the prenatal visit of the first trimester and during OGTT of the second trimester. Plasma concentration of fetuin-A and insulin was determined.ResultsThe plasma fetuin-A concentration in women with GDM was significantly higher than NGT controls in both the first trimester (medians: 403.0 pg/mL vs 273.4 pg/mL; pConclusionsThe dynamic change in fetuin-A levels was associated with the changes in insulin resistance and β-cell function from the first to the second trimester, and was associated with an increased risk of the development of GDM, indicating that fetuin-A could be a biomarker to predict the risk of GDM.Trial registration numberNCT03814395.

Objective. Few studies have examined whether maternal 25(OH)D deficiency and gestational diabetes mellitus (GDM) jointly affect fetal growth. We aimed to examine the separate and combined effects of maternal 25(OH)D deficiency and GDM on trajectories of fetal growth. Methods. We established a birth cohort (2016-2017) with 10,913 singleton pregnancies in Tongzhou Maternal and Child Health Hospital of Beijing, China. Maternal 25(OH)D deficiency (serum 25OHD concentration<20.0 ng/mL) was detected, and GDM was diagnosed at 24~28 gestational weeks. Fetal growth was assessed by longitudinal ultrasound measurements of estimated fetal weight (EFW) and abdominal circumference (AC) from 28 gestational weeks to delivery, both of which were standardized as gestational-age-adjusted Z-score. A k-means algorithm was used to cluster the longitudinal measurements (trajectories) of fetal growth. Logistic regression models were used for estimating exposure-outcome associations and additive interactions. Results. We identified two distinct trajectories of fetal growth, and the faster one resembling the 90th centile curve in the reference population was classified as excessive fetal growth. Maternal 25(OH)D deficiency and GDM were independently associated with an increased risk of excessive fetal growth. The combination of maternal 25(OH)D deficiency and GDM was associated with an increased risk of excessive fetal growth assessed by EFW Z-score (odds ratio (OR): 1.36; 95% confidence interval (CI): 1.15~1.62) and AC Z-score (OR (95% CI): 1.32 (1.11~1.56)), but the relative excess risks attributable to interaction were nonsignificant (P>0.05). Conclusion. Maternal 25(OH)D deficiency and GDM may jointly increase the risk of excessive fetal growth. Interventions for pregnancies with GDM may be more beneficial for those with 25(OH)D deficiency than those without regarding risk of excessive fetal growth, if confirmed in a large sample.

Background To assess the association between plasma retinol-binding protein 4 (RBP4) levels both in the first trimester and second trimester and risk of gestational diabetes mellitus (GDM). Methods Plasma RBP4 levels and insulin were measured among 135 GDM cases and 135 controls nested within the Peking University Birth Cohort in Tongzhou. Multivariable linear regression analysis was conducted to assess the influence of RBP4 levels on insulin resistance. Conditional logistic regression models were used to compute the odds ratio (OR) and 95% confidence interval (CI) between RBP4 levels and risk of GDM. Results The GDM cases had significantly higher levels of RBP4 in the first trimester than controls (medians: 18.0 μg/L vs 14.4 μg/L; P P Conclusions Plasma RBP4 levels both in the first trimester and second trimester were dose-dependently associated with increased risk of GDM.

Background: Although studies have examined the association between residential greenness and birth weight, there is no evidence regarding the association between residential greenness and fetal growth in utero. We aimed to investigate the associations of residential greenness with both fetal growth in utero and birth weight. Methods: A birth cohort (2014–2017) with 18,665 singleton pregnancies was established in Tongzhou Maternal and Child hospital of Beijing, China. Residential greenness was matched with maternal residential address and estimated from remote satellite data using normalized difference vegetation index with 200 m and 500 m buffers (NDVI-200 and NDVI-500). Fetal parameters including estimated fetal weight (EFW), abdominal circumference (AC), head circumference (HC) and femur length (FL) were assessed by ultrasound measurements during pregnancy. Fetal parameters were standardized as gestational-age- and gender-adjusted Z-score and undergrowth was defined as Z-score

Ambinine, the major alkaloid of the tuber of Corydalis ambigua var. amurensis, has protective effects on H9C2 myocardial cells. In the present paper, we observed that ambinine demonstrates activities of both anticoagulation and thrombolysis in vitro by significantly degrading the blood clot and delaying the plasma recalcification time (PRT) in a dose-dependent manner (0.5–2 mg/mL). We further studied its safety profile of acute and subacute toxicity by repeated-dose intravenous injection. The median lethal dosage (LD50) of mice given by oral and intravenous administration of ambinine were approximate 800, 41.60 mg/kg, respectively. The acute toxicity research results suggested that compared with an intravenous administration, the oral route is safer to administer ambinine as the promising lead compound for thrombosis. In subacute toxicity research, when mice were given ambinine at doses of 1.40 and 2.10 mg/kg for 7 days by injection, significant alteration of the relative kidney weight, the relative liver weight and serum biochemistry parameters and marked histopathological changes of them were found.

Background Small cell lung cancer (SCLC) is an aggressive and deadly neuroendocrine tumor derived from bronchial epithelial cells. Although it results in a 95% mortality rate, the development of targeted therapies for SCLCs has lagged behind. The aim of this study is to better research mutation characteristics of SCLC and identify potential biomarkers for target therapy. Methods We utilized high-resolution melting analysis to identify the mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatase and tensin homolog (PTEN), and phosphatidylinositol-3-kinase catalytic (PIK3CA) from the blood. A cohort of 99 SCLC patients including 44 limited-stage disease patients and 55 extensive-stage disease patients were prospectively collected. Results EGFR 18 (G719X) mutation was found in 5 patients, EGFR 19 (del) mutation in 2, EGFR 20 (T790M) in 3, EGFR 21 (L858R) in 2, KRAS 2 (G13D) in 5, BRAF 15 (V600E) in 1, PIK3CA 9 (E542K) in 1, and no mutations in PTEN 5 (R130G), PTEN 6 (R173C), PTEN 8 (T319fs*1), and PIK3CA 20 (H1047R) were identified. Among these patients, two harbored EGFR double mutation, one patient with EGFR double mutation and KRAS 2 (G13D) mutation. Conclusion The mutation form of EGFR may differ from lung adenocarcinoma, and mutations of KRAS, BRAF, and PIK3CA were rare in SCLC. These results aided us in comprehensively analyzing genetic features and laid the foundation for exploring the possibility of target therapy.

Tumor targeting delivery system has been suggested as an attractive strategy against tumor progression. Combination chemotherapy is essential and effective in preventing ovarian cancer. Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) is a lipophilic anthraquinone. Emerging evidence indicates that rhein has many pharmacological effects, such as nephroprotective, hepatoprotective, anti-inflammatory, antioxidant, and anticancer activities. In our study, doxorubicin (DOX) and rhein (RHE) co-loaded polymeric micelle (nano-DOX/RHE) were prepared to attenuate drug resistance in ovarian cancer cells while promoting the therapeutic efficiency of DOX. The morphology, particle size (about 25 nm), zeta potential, release profile in vitro, cell proliferation and cytotoxicity effects were calculated. The results suggested that DOX and RHE could be efficiently loaded into micelle nanoparticles, and in vitro study indicated that they could be released from the nanoparticles in an extended period into DOX-resistant SKOV3 cells (SKOV3/DOX). Nano-DOX/RHE exerted an enhanced cytotoxicity and high apoptosis-inducing activities in SKOV3/DOX cells. Importantly, nano-DOX/RHE exhibited better cancer targeting ability, enhancing the anti-tumor efficacy with little toxicity. In conclusion, nano-DOX/RHE promoted the drug target on tumor site with preferable anti-tumor effects, which could be a promising therapeutic strategy against human ovarian cancer.

Interferon-γ (IFN-γ) is a cytokine that plays an important role in the host defense of infectious diseases and in immune surveillance during tumor development; however, it has adverse effects in the pathogenesis of autoimmune diseases and in immunosuppressive microenvironments, promoting the immunoevasion of cancer cells. In this study, we identified lac water extract (Lac) as a candidate that can suppress IFN-γ signaling amongst 112 types of natural products, using PD-L1 promoter as a readout for the IFN-γ signaling. Moreover, we determined that Lac inhibits IFN-γ-induced PD-L1 and MHC class I expression on the cell surface in melanoma cells, both of which have been identified as the downstream molecules of IFN-γ signaling. We also determined that Lac inhibited the JAK2-STAT1-IRF1 pathway. Finally, we identified laccaic acids, encompassing laccaic acid A, B, C, and E, as the active components in Lac that inhibit IFN-γ signaling. Collectively, the laccaic acids are lead compounds for a novel inhibitor that targets the JAK2-STAT1-IRF1 pathway for diseases caused by the aberrant activation of IFN-γ signaling.

Aims As cohort studies of the impact of sleep duration during early pregnancy on gestational diabetes mellitus (GDM) are lacking, our study aimed to explore the association between sleep duration in the first trimester and GDM in one region of mainland China. Methods For this prospective cohort study, sleep duration data were collected from 3692 pregnant women at the first prenatal care appointment before 14 weeks of gestation. Multivariable log-binomial regression models were used to analyze the association of sleep duration with GDM after adjusting for demographic characteristics, health status (such as family history of diabetes, history of GDM, prepregnancy body mass index, gestational weight gain) and lifestyle habits (such as physical activity, dietary intakes). Results Our cohort included 166 (4.5%) short sleepers and 505 (14%) long sleepers. Shorter sleep duration was more likely to be observed in women aged ≥35 years who were multiparous, and had previous pregnancy, insufficient gestational weight gain, engaged in more vigorous physical activity, drank alcohol, were vegan and/or never took folic-acid supplements. Compared with normal sleepers (29%), the prevalence of GDM was significantly higher in short sleepers (38%; P = 0.01), but not in long sleepers (31%; P = 0.224). In the multivariable model, women with short sleep durations during early pregnancy had a 32% greater risk of GDM [adjusted risk ratio (aRR): 1.32, 95% CI: 1.06–1.63], whereas long sleepers did not (aRR: 1.09, 95% CI: 0.94–1.26). Conclusion Short sleep duration during early pregnancy is associated with an increased risk of GDM. This suggests that more attention should be paid to controlling the development of GDM in pregnant women with insufficient sleep.

We aimed to explore the mediating role of plasma retinol-binding protein 4 (RBP4) in the relationship between sleep quality and insulin resistance (IR) among pregnant women.We conducted a cross-sectional study including 263 pregnant women in the first trimester. Sleep quality was evaluated by Pittsburgh Sleep Quality Index (PSQI). The ELISA and homeostasis model assessment (HOMA) was used to analyze plasma RBP4 and estimate IR. The mediating model was used to analyze the mediating role of RBP4 in the relationship between PSQI score and IR.In the multivariable linear regression model, the three terms were positively related with each other, PSQI score was positively associated with IR levels (β = 0.55, p0.05). In the mediating model, RBP4 levels mediated completely the relationship between PSQI scores and IR levels (β = 0.29, p0.0001). The indirect effect of RBP4 in the relation between sleep quality and IR explained 89.10% of total effect.RPB4 may play a complete mediating role in the relation between sleep quality and insulin resistance in early pregnancy. Improvements in sleep quality in the first trimester may provide a pathway to reduce plasma RBP4, which is beneficial for less IR and GDM prevention.