Structure-based development of potent and selective type-II kinase inhibitors of RIPK1

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Effect of opioid-sparing analgesia on incidence of sepsis in severely burned patients: a retrospective cohort study / 中华麻醉学杂志

Objective:To evaluate the effects of opioid-sparing analgesia on the incidence of sepsis in severely burned patients in the retrospective cohort study.Methods:The clinical data from patients with severe burns admitted to three teaching hospitals in Guangdong from 2011 to 2020 were retrospectively extracted and analyzed. The patients were divided into 2 groups based on the analgesic regimen within 30 days after injury: continuous opioids analgesia group (continuous opioid infusion at a relative constant rate for more than 72 h) and opioid-sparing analgesia group (patient-controlled intravenous analgesia/intermittent administration/opioid-free analgesia). Patient′s age, severity of burn, inhalation injury and basal pain score at rest were matched by the propensity score at a 1∶1 ratio. The primary outcome measure was the occurrence of sepsis within 90 days of admission. Secondary outcome measures included 30-day and 90-day all-cause mortality, clinical diagnosis of multiple organ dysfunction syndrome, and prevalence of burn wound infection. The amount of opioid used was also recorded.Results:A total of 328 severely burned patients were finally enrolled, with 145 patients in continuous opioid analgesia group and 183 patients in opioid-sparing analgesia group, and 110 pairs of patients (220 cases) were finally matched by the propensity score.Compared with continuous opioid analgesia group, the total consumption of opioid, daily consumption per analgesia, and consumption per burn area were significantly decreased, and the incidence of sepsis and wound infection was decreased( P<0.05), and no significant change was found in the incidence of multiple organ dysfunction syndrome, 30-day and 90-day all-cause mortality in opioid-sparing analgesia group( P>0.05). Conclusions:Compared with the continuous opioid analgesia regimen, opioid-sparing analgesia can reduce the risk of sepsis in severely burned patients.

Metformin use and risk of ischemic stroke in patients with type 2 diabetes: A cohort study / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between the use of metformin and the risk of ischemic stroke in patients with type 2 diabetes.@*METHODS@#A prospective cohort study was designed from the Fangshan family cohort in Beijing. According to metformin use at baseline, 2 625 patients with type 2 diabetes in Fangshan, Beijing were divided into metformin group or non-metformin group and the incidence of ischemic stroke between the different groups during follow-up was estimated and compared by Cox proportional hazard regression model. The participants with metformin were first compared with all the parti-cipants who did not use metformin, and then were further compared with those who did not use hypoglycemic agents and those who used other hypoglycemic agents.@*RESULTS@#The patients with type 2 diabetes were with an average age of (59.5±8.7) years, and 41.9% of them were male. The median follow-up time was 4.5 years. A total of 84 patients developed ischemic stroke during follow-up, with a crude incidence of 6.4 (95%CI: 5.0-7.7) per 1 000 person-years. Among all the participants, 1 149 (43.8%) took metformin, 1 476 (56.2%) were metformin non-users, including 593 (22.6%) used other hypoglycemic agents, and 883 (33.6%) did not use any hypoglycemic agents. Compared with metformin non-users, the Hazard ratio (HR) for ischemic stroke in metformin users was 0.58 (95%CI: 0.36-0.93; P = 0.024). Compared with other hypoglycemic agents, HR was 0.48 (95%CI: 0.28-0.84; P < 0.01); Compared with the group without hypoglycemic agents, HR was 0.65 (95%CI: 0.37-1.13; P=0.13). The association between metformin and ischemic stroke was statistically significant in the patients ≥ 60 years old compared with all the metformin non-users and those who used other hypoglycemic agents (HR: 0.48, 95%CI: 0.25-0.92; P < 0.05). Metformin use was associated with a lower incidence of ischemic stroke in the patients with good glycemic control (0.32, 95%CI: 0.13-0.77; P < 0.05). In the patients with poor glycemic control, and the association was not statistically significant (HR: 0.97, 95%CI: 0.53-1.79; P>0.05). There was an interaction between glycemic control and metformin use on incidence of ischemic stroke (Pinteraction < 0.05). The results of the sensitivity analysis were consistent with the results in the main analysis.@*CONCLUSION@#Among patients with type 2 diabetic in rural areas of northern China, metformin use was associated with lower incidence of ischemic stroke, especially in patients older than 60 years. There was an interaction between glycemic control and metformin use in the incidence of ischemic stroke.

Genotype-environment interaction on arterial stiffness: A pedigree-based study / 北京大学学报(医学版)

OBJECTIVE@#To utilized the baseline data of the Beijing Fangshan Family Cohort Study, and to estimate whether the association between a healthy lifestyle and arterial stiffness might be modified by genetic effects.@*METHODS@#Probands and their relatives from 9 rural areas in Fangshan district, Beijing were included in this study. We developed a healthy lifestyle score based on five lifestyle behaviors: smoking, alcohol consumption, body mass index (BMI), dietary pattern, and physical activity. The measurements of arterial stiffness were brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI). A variance component model was used to determine the heritability of arterial stiffness. Genotype-environment interaction effects were performed by the maximum likelihood methods. Subsequently, 45 candidate single nucleotide polymorphisms (SNPs) located in the glycolipid metabolism pathway were selected, and generalized estimated equations were used to assess the gene-environment interaction effects between particular genetic loci and healthy lifestyles.@*RESULTS@#A total of 6 302 study subjects across 3 225 pedigrees were enrolled in this study, with a mean age of 56.9 years and 45.1% male. Heritability of baPWV and ABI was 0.360 (95%CI: 0.302-0.418) and 0.243 (95%CI: 0.175-0.311), respectively. Significant genotype-healthy diet interaction on baPWV and genotype-BMI interaction on ABI were observed. Following the findings of genotype-environment interaction analysis, we further identified two SNPs located in ADAMTS9-AS2 and CDH13 might modify the association between healthy dietary pattern and arterial stiffness, indicating that adherence to a healthy dietary pattern might attenuate the genetic risk on arterial stiffness. Three SNPs in CDKAL1, ATP8B2 and SLC30A8 were shown to interact with BMI, implying that maintaining BMI within a healthy range might decrease the genetic risk of arterial stiffness.@*CONCLUSION@#The current study discovered that genotype-healthy dietary pattern and genotype-BMI interactions might affect the risk of arterial stiffness. Furthermore, we identified five genetic loci that might modify the relationship between healthy dietary pattern and BMI with arterial stiffness. Our findings suggested that a healthy lifestyle may reduce the genetic risk of arterial stiffness. This study has laid the groundwork for future research exploring mechanisms of arterial stiffness.

Latent period and incubation period with associated factors of COVID-19 caused by Omicron variant / 中华预防医学杂志

Objective: To estimate the latent period and incubation period of Omicron variant infections and analyze associated factors. Methods: From January 1 to June 30, 2022, 467 infected persons and 335 confirmed cases in five local Omicron variant outbreaks in China were selected as the study subjects. The latent period and incubation period were estimated by using log-normal distribution and gamma distribution models, and the associated factors were analyzed by using the accelerated failure time model (AFT). Results: The median (Q1, Q3) age of 467 Omicron infections including 253 males (54.18%) was 26 (20, 39) years old. There were 132 asymptomatic infections (28.27%) and 335 (71.73%) symptomatic infections. The mean latent period of 467 Omicron infections was 2.65 (95%CI: 2.53-2.78) days, and 98% of infections were positive for nucleic acid detection within 6.37 (95%CI: 5.86-6.82) days after infection. The mean incubation period of 335 symptomatic infections was 3.40 (95%CI: 3.25-3.57) days, and 97% of them developed clinical symptoms within 6.80 (95%CI: 6.34-7.22) days after infection. The results of the AFT model analysis showed that compared with the group aged 18~49 years old, the latent period [exp(β)=1.36 (95%CI: 1.16-1.60), P<0.001] and incubation period [exp(β)=1.24 (95%CI: 1.07-1.45), P=0.006] of infections aged 0~17 year old were also prolonged. The latent period [exp(β)=1.38 (95%CI: 1.17-1.63), P<0.001] and the incubation period [exp(β)=1.26 (95%CI: 1.06-1.48), P=0.007] of infections aged 50 years old and above were also prolonged. Conclusion: The latent period and incubation period of most Omicron infections are within 7 days, and age may be the influencing factor of the latent period and incubation period.

Thirteen new peptaibols with antimicrobial activities from Trichoderma sp / 中国天然药物

From the fungus Trichoderma sp., we isolated seven novel 18-residue peptaibols, neoatroviridins E-K (1-7), and six new 14-residue peptaibols, harzianins NPDG J-O (8-13). Additionally, four previously characterized 18-residue peptaibols neoatroviridins A-D (14-17) were also identified. The structural configurations of the newly identified peptaibols (1-13) were determined by comprehensive nuclear magnetic resonance (NMR) and high-resolution electrospray ionization tandem mass spectrometry (HR-ESI-MS/MS) data. Their absolute configurations were further determined using Marfey's method. Notably, compounds 12 and 13 represent the first 14-residue peptaibols containing an acidic amino acid residue. In antimicrobial assessments, all 18-residue peptaibols (1-7, 14-17) exhibited moderate inhibitory activities against Staphylococcus aureus 209P, with minimum inhibitory concentration (MIC) values ranging from 8-32 μg·mL-1. Moreover, compound 9 exhibited moderate inhibitory effect on Candida albicans FIM709, with a MIC value of 16 μg·mL-1.

Preparation, properties and antibacterial applications of medical nano-metals and their oxides: a review / 生物工程学报

Antibiotics are playing an increasingly important role in clinical antibacterial applications. However, their abuse has also brought toxic and side effects, drug-resistant pathogens, decreased immunity and other problems. New antibacterial schemes in clinic are urgently needed. In recent years, nano-metals and their oxides have attracted wide attention due to their broad-spectrum antibacterial activity. Nano-silver, nano-copper, nano-zinc and their oxides are gradually applied in biomedical field. In this study, the classification and basic properties of nano-metallic materials such as conductivity, superplasticity, catalysis, and antibacterial activities were firstly introduced. Secondly, the common preparation techniques, including physical, chemical and biological methods, were summarized. Subsequently, four main antibacterial mechanisms, such as cell membrane, oxidative stress, DNA destruction and cell respiration reduction, were summarized. Finally, the effect of size, shape, concentration and surface chemical characteristics of nano-metals and their oxides on antibacterial effectiveness and the research status of biological safety such as cytotoxicity, genotoxicity and reproductive toxicity were reviewed. At present, although nano-metals and their oxides have been applied in medical antibacterial, cancer treatment and other clinical fields, some issues such as the development of green preparation technology, the understanding of antibacterial mechanism, the improvement of biosafety, and the expansion of application fields, require further exploration.

Progress in research of influenza vaccination in pregnant women / 中华流行病学杂志

Influenza is an acute respiratory infectious disease caused by influenza virus. Pregnancy is associated with physiologic and immunological changes that may increase the risk for influenza virus infection and influenza-related complications. Influenza vaccination is the most effective way to prevent influenza virus infection. WHO and many countries have classified pregnant women as a priority population for influenza vaccination, however, there are still many challenges for promoting influenza vaccination in pregnant women in China, influenza vaccination coverage in pregnant women remains low and some influenza vaccine package inserts list pregnancy as an absolute contraindication. In this paper, we summarize the research progress in the effects of influenza infection and influenza vaccination during pregnancy both at home and abroad, then discuss the strategies to promote influenza vaccination in pregnancy for the purpose of providing reference for the related research and policy development in China.

Performance of screening of contacts of COVID-19 cases in same flight / 中华流行病学杂志

Objective: To understand the performance of 2019-nCoV nucleic acid detection in screening of contacts of COVID-19 cases in same flights and provide evidence for the effective screening of persons at high risk for the infection in domestic flights. Methods: The information of passengers who took same domestic flights with COVID-19 cases in China from April 1, 2020 to April 30, 2022 were retrospectively collected,and χ2 test was used to analyze positive nucleic acid detection rates in the passengers in different times before the onsets of the index cases, in different seat rows and in epidemic periods of different 2019-nCoV variants. Results: During the study period, a total of 433 index cases were identified among 23 548 passengers in 370 flights. Subsequently, 72 positive cases of 2019-nCoV nucleic acid were detected in the passengers, in whom 57 were accompanying persons of the index cases. Further analysis of the another 15 passengers who tested positive for the nucleic acid showed that 86.67% of them had onsets or positive detections within 3 days after the diagnosis of the index cases, and the boarding times were all within 4 days before the onsets of the index cases. The positive detection rate in the passengers who seated in first three rows before and after the index cases was 0.15% (95%CI: 0.08%-0.27%), significantly higher than in the passengers in other rows (0.04%, 95%CI: 0.02%-0.10%, P=0.007),and there was no significant difference in the positive detection rate among the passengers in each of the 3 rows before and after the index cases (P=0.577). No significant differences were found in the positive detection rate in the passengers, except the accompanying persons, among the epidemics caused by different 2019-nCoV variants (P=0.565). During the Omicron epidemic period, all the positive detections in the passengers, except the accompanying persons, were within 3 days before the onset of the index cases. Conclusions: The screening test of 2019-nCoV nucleic acid can be conducted in the passengers took the same flights within 4 days before the onsets of the index cases on board. Passengers who seated within 3 rows from the index cases can considered as the close contacts at high risk for 2019-nCoV, for whom screening should be conducted first and special managements are needed. The passengers in other rows can be classified as general risk persons for screening and management.

Latent period and incubation period with associated factors of COVID-19 caused by Omicron variant / 中华预防医学杂志

Objective: To estimate the latent period and incubation period of Omicron variant infections and analyze associated factors. Methods: From January 1 to June 30, 2022, 467 infections and 335 symptomatic infections in five local Omicron variant outbreaks in China were selected as the study subjects. The latent period and incubation period were estimated by using log-normal distribution and gamma distribution models, and the associated factors were analyzed by using the accelerated failure time model (AFT). Results: The median (Q1, Q3) age of 467 Omicron infections including 253 males (54.18%) was 26 (20, 39) years old. There were 132 asymptomatic infections (28.27%) and 335 (71.73%) symptomatic infections. The mean latent period of 467 Omicron infections was 2.65 (95%CI: 2.53-2.78) days, and 98% of infections were positive for nucleic acid test within 6.37 (95%CI: 5.86-6.82) days after infection. The mean incubation period of 335 symptomatic infections was 3.40 (95%CI: 3.25-3.57) days, and 97% of them developed clinical symptoms within 6.80 (95%CI: 6.34-7.22) days after infection. The results of the AFT model analysis showed that compared with the group aged 18-49 years old, the latent period [exp(β)=1.36 (95%CI: 1.16-1.60), P<0.001] and incubation period [exp(β)=1.24 (95%CI: 1.07-1.45), P=0.006] of infections aged 0-17 years old were prolonged. The latent period [exp(β)=1.38 (95%CI: 1.17-1.63), P<0.001] and the incubation period [exp(β)=1.26 (95%CI: 1.06-1.48), P=0.007] of infections aged 50 years old and above were also prolonged. Conclusion: The latent period and incubation period of most Omicron infections are within 7 days, and age may be a influencing factor of the latent period and incubation period.

Effect of Huatan Tongluo Prescription on Vulnerability of Carotid Atherosclerotic Plaque in Hypertension / 中国实验方剂学杂志

ObjectiveTo evaluate the effect of Huatan Tongluo prescription on the vulnerability of atherosclerotic plaques in the carotid arteries of patients with hypertension of phlegm-stasis combination syndrome. MethodA total of 132 eligible patients were randomly divided into an observation group （66 cases） and a control group （66 cases）. The control group received oral atorvastatin calcium tablets and enteric-coated aspirin tablets， while the observation group received Huatan Tongluo prescription in addition to the treatment received by the control group. The treatment duration was 6 months. A carotid artery ultrasound examination was performed to record the number of plaques， the maximum plaque area， the maximum plaque cross-sectional thickness， and the intima-media thickness （IMT） of the carotid artery. Crouse score， plaque vulnerability score， and phlegm-stasis combination syndrome score were assessed. Blood lipid levels ［total cholesterol （TC）， triglyceride （TG）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C）］， inflammatory markers ［neutrophil-to-lymphocyte ratio （NLR）， monocyte-to-lymphocyte ratio （MLR）， interleukin-6 （IL-6）， and high-sensitivity C-reactive protein （hs-CRP）］， vascular endothelial function ［endothelin-1 （ET-1）， von Willebrand factor （vWF）， and nitric oxide （NO）］， and relevant proteins ［pentraxin 3 （PTX3） and galectin-3 （Gal-3）］ levels were measured. Safety evaluation was conducted， and comparisons were made in terms of carotid artery stenosis rate， plaque regression efficacy， and traditional Chinese medicine （TCM） syndrome efficacy. ResultCompared with the results before treatment， both groups showed significant reductions in IMT， plaque number， maximum plaque area， and maximum plaque cross-sectional thickness （P<0.05）. After treatment， the observation group exhibited more significant reductions in the above indicators compared with the control group （P<0.05）. After treatment， Crouse scores， plaque vulnerability scores， and phlegm-stasis combination syndrome scores in both groups were lower than those before treatment （P<0.05）. After treatment， the observation group had lower scores in these indicators than the control group （P<0.05）. In terms of blood lipid levels， both groups showed decreases in TC， TG， and LDL-C levels， and an increase in HDL-C levels after treatment compared to those before treatment （P<0.05）. The observation group exhibited greater improvements in these lipid parameters than the control group （P<0.05）. Inflammatory markers NLR， MLR， IL-6， and hs-CRP significantly decreased in both groups after treatment compared with those before treatment （P<0.05）. The observation group showed more significant reductions in these markers than the control group after treatment （P<0.05）. After treatment， both groups demonstrated decreases in levels of ET-1， vWF， PTX3， and Gal-3， along with an increase in NO levels compared with those before treatment （P<0.05）. The observation group showed more significant improvements in these markers than the control group after treatment （P<0.05）. After treatment， the observation group had a lower carotid artery stenosis rate than the control group （P<0.05）. The plaque regression efficacy rate was 51.72% （30/58） in the observation group， and the total effective rate of TCM syndrome was 84.48% （49/58）， both of which were higher than 18.64% （11/59） and 52.54% （31/59） in the control group （χ²=10.061， 13.799， P<0.05）. No adverse reactions related to the Huatan Tongluo prescription were observed during the treatment period. ConclusionIn addition to statin therapy， Huatan Tongluo prescription can effectively reverse carotid artery atherosclerotic plaques in patients with hypertension and carotid artery stenosis， reduce plaque vulnerability， exhibit lipid-lowering and anti-inflammatory effects， and improve vascular endothelial function. The treatment demonstrates favorable clinical efficacy and safety. Therefore， it is very worthy of clinical promotion and application.

Optimization of molding process of Jinpuju Qingrelishi Granules by Response Surface Methodology / 国际中医中药杂志

Objective:To optimize the best molding process of Jinpuju Qingrelishi Granules.Methods:Based on the single factor test, the relative density of clear ointment and the amount of diluent (dextrin∶lactose=2∶1) are used as investigating factors, and the overall evaluation of the molding rate and angle of repose overall desirability (OD) is used as the evaluation index. The effect surface method is used to optimize the best molding process of Jinpuju Qingrelishi Granules.Results:The best molding process conditions: the relative density of the clear paste is 1.20 (60 ℃) and the amount of diluent is 3 times that of the clear paste. After mixing the clear paste and diluent, make soft material, pass through a 14-mesh sieve to granulate, dry in an oven (55 ℃) for 1 hour, and sizing to obtain. The molding rates of the three batches of verification test granules were 93.73%, 93.03%, 95.59%, respectively, the predicted OD value was 0.928, the verification value was 0.936, and the deviation from the predicted value was -0.86%.Conclusion:The molding process of this experiment is stable and reliable, with good repeatability, which can provide a reference for the follow-up research of Jinpuju Qingrelishi Granules.

Time distribution of positive nucleic acid detection in imported cases infected with SARS-CoV-2 in China / 中华流行病学杂志

Objective: To analyze the time distribution of the first positive nucleic acid detection in imported cases infected with SARS-CoV-2 reported nationwide in China and provide references for further improvement of the prevention and control of COVID-19 in international travelers. Methods: The data of imported cases infected with SARS-CoV-2 reported by provinces from 24 July 2020 and 23 July 2021 were collected for the analysis on the time distribution of the first positive nucleic acid detection after entering China. Results: A total of 7 199 imported cases infected with SARS-CoV-2 were reported in 28 provinces during 24 July 2020 to 23 July 2021. The median interval (Q1, Q3) from the entry to the first positive nucleic acid detection of SARS-CoV-2 was 1 (0, 5) day. The imported cases who had the first positive nucleic acid detections within 14 days and 14 days later after the entry accounted for 95.15% (6 850/7 199) and 4.85% (349/7 199) respectively. Among these cases, 3.65% (263/7 199), 0.88% (63/7 199) and 0.32% (23/7 199) had the first positive nucleic acid detections within 15-21 days, 22-28 days and 28 days later after the entry respectively. The proportion of asymptomatic infections were 47.24% (3 236/6 850) and 63.61% (222/349) among the cases who had the first positive nucleic acid detections within 14 days and 14 days later after the entry respectively. A total of 39.54% (138/349) of cases infected with SARS-CoV-2 with the first positive nucleic acid detections 14 days later after the entry had inter-provincial travel after the discharge of entry point isolation. Conclusions: About 5% of the imported cases infected with SARS-CoV-2 were first positive 14 days later after the entry. In order to effectively reduce the risk of domestic COVID-19 secondary outbreaks caused by imported cases, it is suggested to add a nucleic acid test on 8th -13th day after the entry.

The role of p75 neurotrophin receptor in neurodegenerative diseases / 中国药理学通报

Recently p75 neurotrophin receptor (p75NTR) has been found to play a critical role in the pathology of neurodegen¬erative! diseases including Alzheimer's disease (AD) , Parkin¬son' s disease ( PI)), Huntington's disease ( HI)) , amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS).This arti¬cle reviews the research progress of p75NTR in regulating neuron apoptosis, axon degeneration and cognitive impairment, explo¬ring the application of p75NTR as a potential therapeutic target for the treatment of neurodegenerative diseases.

Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design.@*METHODS@#Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database.@*RESULTS@#A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes.@*CONCLUSION@#Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.

Network Meta-analysis of efficacy and safety of Chinese patent medicines in treatment of ankylosing spondylitis / 中国中药杂志

To evaluate the efficacy and safety of Chinese patent medicines in the treatment of ankylosing spondylitis(AS) by frequency network Meta-analysis. Randomized controlled trials(RCTs)of Chinese patent medicines for AS were retrieved from CNKI, Wanfang, VIP, CBM, PubMed, EMbase and Cochrane Library databases from the time of database establishment to January 2021. The quality of the included RCTs was evaluated according to the Cochrane bias risk standard, and the data was analyzed by RevMan 5.3 and Stata/MP 15.1. A total of 12 kinds of Chinese patent medicines in 55 RCTs were included. According to Meta-analysis, in term of the effectiveness, the top three optimal medication regimens were Biqi Capsules, Yishen Juanbi Pills and Yaobitong Capsules combined with western medicine. The top three interventions to reduce the erythrocyte sedimentation rate(ESR)were Yishen Juanbi Pills, Xianling Gubao Capsules and Fufang Xuanju Capsules combined with western medicine. The top three interventions to reduce the C-reactive protein(CRP)were Biqi Capsules, Xianling Gubao Capsules and Fufang Xuanju Capsules combined with western medicine. In terms of the safety, top three optimal medication regimens were Total Glucosides of Paeony Capsules, Yishen Juanbi Pills, and Wangbi Tablets combined with western medicine. This network Meta-analysis suggests that Chinese patent medicines combined with conventional western medicine can effectively improve the joint pain symptoms of AS patients and reduce the acute inflammatory indicators, with high safety. However, the literature included in this study is generally of low methodological quality, and the conclusion needs to be verified by high-quality research.

The clinical phenotype and gene analysis of syndromic deafness with PTPN11 gene mutation / 中华耳鼻咽喉头颈外科杂志

Objective: To analyze the clinical phenotype and screen the genetic mutations of hereditary deafness in three deaf families to clarify their molecular biology etiology. Methods: From January 2019 to January 2020, three deaf children and family members were collected for medical history, physical examination, audiology evaluation, electrocardiogram and cardiac color Doppler ultrasound, temporal bone CT examination, and peripheral blood DNA was obtained for high-throughput sequencing of deafness genes. Sanger sequencing was performed to verify the variant sites among family members. The pathogenicity of the variants was evaluated according to the American College of Medical Genetics and Genomics. Results: The probands in the three families had deafness phenotypes. In family 1, proband had multiple lentigines, special facial features, growth retardation, pectus carinatum, abnormal skin elasticity, cryptorchidism and other manifestations. In family 2, proband had special facial features, growth retardation and abnormal heart, and the proband in family 3 had growth retardation and abnormal electrocardiogram. Genetic testing of three families detected three heterozygous mutations in the PTPN11 gene: c.1391G>C (p.Gly464Ala), c.1510A>G (p.Met504Val), c.1502G>A (p.Arg501Lys). All three sites were missense mutations, and the mutation sites were highly conserved among multiple homologous species. Based on clinical manifestations and genetic test results, proband 1 was diagnosed with multiple lentigines Noonan syndrome, and probands 2 and 3 were diagnosed with Noonan syndrome. Conclusion: Missense mutations in the PTPN11 gene may be the cause of the disease in the three deaf families. This study enriches the clinical phenotype and mutation spectrum of the PTPN11 gene in the Chinese population.

Incidence and risk factors of ischemic stroke in patients with type 2 diabetes among urban workers in Beijing, China / 北京大学学报(医学版)

OBJECTIVE@#To explore the incidence of ischemic stroke after the onset of type 2 diabetes, and further analyze the risk factors, so as to provide a basis for further research.@*METHODS@#The data were obtained from the database of the Beijing Urban Employee Basic Medical Insurance Database. The study used a prospective design to describe the incidence of ischemic stroke in patients with type 2 diabetes. In our study, these patients were followed up for seven years. Multivariate Logistic regression models were used to analyze the risk factors of ischemic stroke in patients with type 2 diabetes.@*RESULTS@#A total of 185 813 newly diagnosed type 2 diabetes patients were enrolled, with an average age of (58.5±13.2) years, and 49.0% of them were males. A total of 10 393 patients with newly diagnosed ischemic stroke occurred in 7 years, with a cumulative incidence of 5.6% and an incidence density of 8.1/1 000 person-years. Ischemic stroke occurred in all age groups in patients with type 2 diabetes. The cumulative incidence was 1.5% (95%CI: 1.3%-1.6%) in group ≤44 years old, 3.6% (95%CI: 3.4%-3.7%) in group 45-54 years old, 5.4% (95%CI: 5.2%-5.5%) in group 55-64 years old, and 9.2% (95%CI: 9.0%-9.4%) in group ≥65 years old, and the cumulative incidence increased with age (P < 0.05). Cumulative incidence rate of the males (6.8%, 95%CI: 6.7%-7.0%) was higher than the females (4.4%, 95%CI: 4.3%-4.6%). Among the patients < 80 years old, the cumulative incidence rate of the males was higher than that of the females in all the age groups. In the patients ≥80 years of age, the cumulative incidence was higher in the females (9.2%) than in the males (7.9%). Further analysis revealed that complications, such as coronary heart disease (OR=3.18, 95%CI: 2.72-3.72), heart failure (OR=1.53, 95%CI: 1.32-1.79) and kidney failure (OR=1.45, 95%CI: 1.20-1.75) were associated with ischemic stroke in the patients with type 2 diabetes.@*CONCLUSION@#The incidence level of ischemic stroke in patients with type 2 diabetes is high. It is necessary to strengthen the management of risk factors in elderly patients, screen the complications of type 2 diabetes as early as possible, and take active preventive and control measures.

Efficacy and safety of naborphine versus dizocine in painless visual anesthetics induced abortion / 中国基层医药

Objective:To investigate the efficacy and safety of naborphine versus dezocine in painless visual anesthetics induced abortion. Methods:A total of 120 patients who underwent painless visual anesthetics induced abortion in Zhongshan City People's Hospital and Zhongshan Shaxi Longdu Hospital, China during January to September in 2020. They were randomly assigned to receive intravenous naborphine hydrochloride injection (0.15 mg/kg, naborphine group) or dezocine injection (5 mg, dezocine group), followed by intravenous propofol (2 mg/kg). When the eyelash reflex disappeared, surgery was initiated. If there were body movements, 30-50 mg propofol was added as appropriate. Systolic blood pressure, diastolic blood pressure, blood oxygen saturation, and heart rate before anesthesia (T 0), at 3 minutes after the beginning of surgery (T 1), and during recovery (T 2) were compared between the two groups. The time to regain consciousness, postoperative visual analogue pain score, propofol dose, operative time, and adverse reactions were determined in each group. Results:There were slight, but not significant, differences in systolic blood pressure and heart rate between the two groups at T 0, T 1 and T2 (all P > 0.05). There were no significant differences in time to regain consciousness, postoperative visual analogue pain score, propofol dose and operative time between the two groups (all P > 0.05). The incidence of nausea and vertigo in the naborphine group was 8.3% (5/60) and 11.6% (7/60), respectively, which was significantly lower than that in the dezocine group [30.0% (18/60), 31.6% (19/60), χ2 = 9.09, 7.07, both P < 0.05). Conclusion:Naborphine combined with propofol for painless visual anesthetics induced abortion exhibits good anesthetic effects and safety, with fewer intraoperative and postoperative adverse reactions than dezocine combined with propofol.

Distribution and infectious characteristics of re-positive cases infected with SARS-CoV-2 / 中华流行病学杂志

Domestic and foreign literatures related to the persistence of SARS-CoV-2 and the re-positive cases infected with SARS-CoV-2 were reviewed, and the characteristics and infectivity of the re-positive cases were analyzed to provide scientific evidence for the improvement of case management and the development of measures to stop the spread of SARS-CoV-2. Existing studies have shown that re-positive rate of SARS-CoV-2 ranged from 2.4% to 19.8%, the median of interval between re-positive detection and discharge was 4-15 days. Following the second course of the disease, the anti-SARS-CoV-2 IgM, IgG and IgA positive rates of the cases were 11.11%-86.08%, 52.00%-100.00% and 61.54%-100.00% respectively, the total antibody and neutralizing antibody positive rates were 98.72% and 88.46%. The viral load of the re-positive cases was lower than that in the initial infection. At least 3 380 re-positive cases have been reported globally. SARS-CoV-2 strains were isolated from the samples of 3 re-positive cases (1 immunodeficiency case and 2 cases with abnormal pulmonary imaging). There were close contacts that were infected by an asymptomatic case taking immunosuppressive agents. In conclusion, the infectivity of re-positive cases infected with SARS-CoV-2 is generally very low. Rare re-positive cases infected with SARS-CoV-2 might cause further transmission. The management approach for the re-positive cases can be based on the assessment of the individual transmission risk according to the pathogen detection results.