Co-Immobilization of ADH and GDH on Metal-Organic-Framework: An Effective Biocatalyst for Asymmetric Reduction of Ketones.

Chiral alcohols are not only important building blocks of various bioactive natural compounds and pharmaceuticals, but can serve as synthetic precursors for other valuable organic chemicals, thus the synthesis of these products is of great importance. Bio-catalysis represents one effective way to obtain these molecules, however, the weak stability and high cost of enzymes often hinder its broad application. In this work, we designed a biological nanoreactor by embedding alcohol dehydrogenase (ADH) and glucose dehydrogenase (GDH) in metal-organic-framework ZIF-8. The biocatalyst ADH&GDH@ZIF-8 could be applied to the asymmetric reduction of a series of ketones to give chiral alcohols in high yields (up to 99 %) and with excellent enantioselectivities (>99 %). In addition, the heterogeneous biocatalyst could be recycled and reused at least four times with slight activity decline. Moreover, E. coli containing ADH and GDH was immobilized by ZIF-8 to form biocatalyst E. coli@ZIF-8, which also exhibits good catalytic behaviours. Finally, the chiral alcohols are further converted to marketed drugs (R)-Fendiline, (S)-Rivastigmine and NPS R-568 respectively.

Directed Evolution and Immobilization of Lactobacillus brevis Alcohol Dehydrogenase for Chemo-Enzymatic Synthesis of Rivastigmine.

Rivastigmine is one of the several pharmaceuticals widely prescribed for the treatment of Alzheimer's disease. However, its practical synthesis still faces many issues, such as the involvement of toxic metals and harsh reaction conditions. Herein, we report a chemo-enzymatic synthesis of Rivastigmine. The key chiral intermediate was synthesized by an engineered alcohol dehydrogenase from Lactobacillus brevis (LbADH). A semi-rational approach was employed to improve its catalytic activity and thermal stability. Several LbADH variants were obtained with a remarkable increase in activity and melting temperature. Exploration of the substrate scope of these variants demonstrated improved activities toward various ketones, especially acetophenone analogs. To further recycle and reuse the biocatalyst, one LbADH variant and glucose dehydrogenase were co-immobilized on nanoparticles. By integrating enzymatic and chemical steps, Rivastigmine was successfully synthesized with an overall yield of 66 %. This study offers an efficient chemo-enzymatic route for Rivastigmine and provides several efficient LbADH variants with a broad range of potential applications.

A Novel KIF4A-Related Model for Predicting Immunotherapy Response and Prognosis in Kidney Renal Clear Cell Carcinoma.

BACKGROUND: The efficacy of chemotherapy in treating Kidney Renal Clear Cell Carcinoma (KIRC) is limited, whereas immunotherapy has shown some promising clinical outcomes. In this context, KIF4A is considered a potential therapeutic target for various cancers. Therefore, identifying the mechanism of KIF4A that can predict the prognosis and immunotherapy response of KIRC would be of significant importance. METHODS: Based on the TCGA Pan-Cancer dataset, the prognostic significance of the KIF4A expression across 33 cancer types was analyzed by univariate Cox algorithm. Furthermore, overlapping differentially expressed genes (DEGs1) between the KIF4A high- and lowexpression groups and DEGs2 between the KIRC and normal groups were also analyzed. Machine learning and Cox regression algorithms were performed to obtain biomarkers and construct a prognostic model. Finally, the role of KIF4A in KIRC was analyzed using quantitative real-time PCR, transwell assay, and EdU experiment. RESULTS: Our analysis revealed that KIF4A was significant for the prognosis of 13 cancer types. The highest correlation with KIF4A was found for KICH among the tumour mutation burden (TMB) indicators. Subsequently, a prognostic model developed with UBE2C, OTX1, PPP2R2C, and RFLNA was obtained and verified with the Renal Cell Cancer-EU/FR dataset. There was a positive correlation between risk score and immunotherapy. Furthermore, the experiment results indicated that KIF4A expression was considerably increased in the KIRC group. Besides, the proliferation, migration, and invasion abilities of KIRC tumor cells were significantly weakened after KIF4A was knocked out. CONCLUSION: We identified four KIF4A-related biomarkers that hold potential for prognostic assessment in KIRC. Specifically, early implementation of immunotherapy targeting these biomarkers may yield improved outcomes for patients with KIRC.

Covalent Organic Frameworks Based Photoenzymatic Nano-reactor for Asymmetric Dynamic Kinetic Resolution of Secondary Amines.

Bio-catalysis represents a highly efficient and stereoselective method for the synthesis of valuable chiral compounds, however, the poor stability and limited reaction types of free enzymes restrict their wide application in industrial production. In this work, to overcome these problems, a multifunctional photoenzymatic nanoreactor CALB@COF-Ir was developed through the encapsulation of Candida antarctica lipase B (CALB) in a photosensitive covalent organic framework COF-Ir. This bio-nanocluster serves as efficient catalysts in asymmetric dynamic kinetic resolution (DKR) of secondary amines to give a series of chiral amines in high yields (up to 99 %) and enantioselectivities (up to 99 % ee). The well-designed COF-Ir not only acts as safety cover to prevent CALB from deactivation but promotes racemization of secondary amines via photo-induced hydrogen atom transfer (HAT) process. Photoelectric characterization and TDDFT calculation revealed that (ppy)2Ir units in COF-Ir play crucial role in this photocatalytic system which enhance its photo-redox properties through facilitating the separation between photoelectrons (e-) and holes (h+). Furthermore, the heterogeneous photoenzymatic nanoreactor could be recycled for five rounds with slight decline of catalytic reactivity.

Prediction of Foodborne Norovirus Outbreaks in Coastal Areas in China in 2008-2018.

Foodborne norovirus outbreak usually poses high risks in coastal areas in China. Owing to the influence of multiple climatic factors, it demonstrates typical seasonality and the hotspots gradually expanded northwards from 2008 to 2018. However, the complex mechanism of the onset of outbreaks makes accurate prediction difficult. Thus, it is in necessity to construct a predictive model for foodborne norovirus outbreaks in coastal areas based on environmental and geographical variables. A novel predictive nonlinear autoregressive model with exogenous inputs model was developed using 11 years of environmental and foodborne norovirus outbreak data collected from coastal areas in China. Five input variables (temperature, precipitation, elevation, latitude, and longitude) were screened through stepwise regression analysis. The predicted model developed in this study was able to reproduce 88.53% of outbreaks reported to the National Public Health Emergency Event Surveillance System (PHEESS) in the model development and 100% of outbreaks reported in the independent cross-validation since the system was first launched in China. In particular, foodborne norovirus outbreaks might occur when the probability is >0.6. The findings of this study suggest that foodborne norovirus outbreaks could be accurately predicted in coastal areas in China using the developed predictive model on a daily basis. The model output is most sensitive to temperature, followed by precipitation, and locations. The application of this predictive model is promising to improve local hygiene management levels, prevent foodborne norovirus outbreaks, and reduce the disease and economic costs in coastal areas in China.

Epidemiological Characteristics and Spatiotemporal Distribution Patterns of Human Norovirus Outbreaks in China, 2012-2018.

Objective: To clarify the epidemiological characteristics and spatial distribution patterns of human norovirus outbreaks in China, identify high-risk areas, and provide guidance for epidemic prevention and control. Methods: This study analyzed 964 human norovirus outbreaks involving 50,548 cases in 26 provinces reported from 2012 to 2018. Epidemiological analysis and spatiotemporal scanning analysis were conducted to analyze the distribution of norovirus outbreaks in China. Results: The outbreaks showed typical seasonality, with more outbreaks in winter and fewer in summer, and the total number of infected cases increased over time. Schools, especially middle schools and primary schools, are the most common settings of norovirus outbreaks, with the major transmission route being life contact. More outbreaks occurred in southeast coastal areas in China and showed significant spatial aggregation. The highly clustered areas of norovirus outbreaks have expanded northeast over time. Conclusion: By identifying the epidemiological characteristics and high-risk areas of norovirus outbreaks, this study provides important scientific support for the development of preventive and control measures for norovirus outbreaks, which is conducive to the administrative management of high-risk settings and reduction of disease burden in susceptible areas.

Integration of history of medicine in the education and reform exploration of standardized residency training in endocrinology department — taking hundred years of history of insulin development as an example / 中华医学教育探索杂志

Objective:To study the methods of hormone-related teaching in standardized residency training of endocrinology.Methods:From February 2022 to June 2022, 25 residents in the Department of Endocrinology, Peking University Third Hospital were given a standardized residency training. The teaching mode combined with a hundred years of insulin development was adopted to practice insulin teaching, and questionnaires were evaluated before and after the teaching. Chi-square test was performed by SPSS 20.0.Results:A total of 31 physicians participated in the training, and 25 residents who were included in the first-stage standardized training were analyzed. Before the training, only 3 people (12%) knew the development history of insulin, and 10 people (40%) answered all the questions about clinical use of insulin correctly. After the training, 23 residents (92%) said they knew or were familiar with the history of insulin development, and 20 residents (80%) answered the questions about the clinical use of insulin correctly, all of which were higher than those before the training, and the difference was statistically significant.Conclusion:The integration of medical history in standardized residency training in endocrinology department can effectively improve the teaching effect, and enhance the humanity quality of young doctors, which can become an effective vehicle in standardized residency training.

Synthesis of bioactive fluoropyrrolidines via copper(i)-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides.

Chiral pyrrolidinyl units are important building blocks in biologically active natural products and drugs, and the development of efficient methods for the synthesis of diverse structured pyrrolidine derivatives is of great importance. Meanwhile, incorporating fluorine containing groups into small molecules often changes their activities to a great extent due to the special physicochemical properties of fluorine atoms. Herein, we report an efficient route to obtain enantioenriched 3,3-difluoro- and 3,3,4-trifluoropyrrolidinyl derivatives by Cu(i)-catalysed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active 1,1-difluoro- and 1,1,2-trifluorostyrenes. A series of new fluorinated pyrrolidines have been prepared in high yields (up to 96%) and with excellent stereoselectivities (up to >20 : 1 dr and 97% ee), and these unique structural blocks could be readily introduced into some natural compounds and pharmaceuticals. Additionally, antifungal activity investigation against four common plant fungi showed that some products possess general and high biological activities; comparison with the low antifungal activities of corresponding nonfluorinated compounds revealed that the fluorine atoms at the pyrrolidinyl rings play a crucial role in the antifungal activity.

Bilateral adrenal hemorrhage caused by anticoagulant therapy after joint replacement surgery: One case report and literature review / 中华内分泌代谢杂志

Bilateral adrenal hemorrhage is a rare cause of primary adrenal insufficiency, and bilateral adrenal hemorrhage due to anticoagulant use is even rarer. We describe the case of a 62-year-old woman receiving post total knee arthroplasty anticoagulant therapy who presented fever, vomitting, stomachache, and severe fatigue on the 8th day. It was until 4 months later that the patient was finally diagnosed with adrenal insufficiency resuting from bilateral adrenal hemorrhage, her symptoms were relieved by glucocorticoid replacement therapy. In order to promote the awareness, diagnosis, and mangement of post-surgery anticoagulants induced bilateral adrenal hemorrhage, the clinical characteristics of the reported cases were summarized and analyzed.

Prognosis factors for death within 90 days of discharge in patients with acute kidney injury requiring continuous renal replacement therapy after surgery for Stanford type A acute aortic dissection / 中华外科杂志

Objective: To investigate the prognosis factors for death within 90 days after discharge in patients with acute kidney injury(AKI) treated requiring continuous renal replacement therapy(CRRT) undergoing surgery for acute Standford type A aortic dissection. Methods: The clinic data of 126 patients undergoing CRRT for postoperative AKI after acute type A aortic dissection surgery in the Center for Cardiac Intensive Care, Beijing Anzhen Hospital from July 2016 to February 2019 were analyzed retrospectively. There were 83 males and 43 females, aging (52.9±11.2) years(range: 25 to 70 years). The patients' demographic characteristics, disease-related information, perioperative data, laboratory indexes during CRRT, complications, and survival information within 90 days after discharge were recorded. Independent prognosis factors for death within 90 days of discharge were determined by Kaplan-Meier survival analysis, univariate and multifactorial Cox regression analysis. Results: Totally 57 of 126 patients(45.2%) died over the first 90 days after discharge. Kaplan-Meier survival analysis and univariate Cox regression analysis showed that there were significant differences between the non-survival and survival group including ≥65 years old, high lactate values 12 hours after CRRT, pulmonary infection, liver dysfunction, presence of permanent neurological complications, and postoperative ejection fraction(EF)<45%. Multifactorial Cox regression analysis revealed that ≥65 years old(HR=2.14, 95%CI: 1.09 to 4.21, P=0.03), high lactate values 12 hours after CRRT(HR=1.13, 95%CI: 1.06 to 1.20, P=0.01) and postoperative EF<45%(HR=2.21, 95%CI: 1.09 to 4.51, P=0.03) were independent prognosis factors for patients' death within 90 days after hospital discharge. Conclusions: ≥65 years old, high lactate values 12 hours after CRRT and postoperative EF<45% are independent prognosis factors for death within 90 days after discharge in patients undergoing CRRT for AKI after acute type A aortic dissection surgery. Proper identification and management of prognosis factors could be beneficial to improve patients' outcomes.

Strengthening the Reporting of Pharmacogenetic Studies (STROPS) guideline / 中华流行病学杂志

Pharmacogenetic studies are designed to investigate the associations between genetic variation and treatment response for a particular drug in terms of both efficacy and adverse events and have high sample size requirements. To improve the quality of pharmacogenetic studies and facilitate the Meta-analyses to investigate statistically significant associations, Strengthening the Reporting of Pharmacogenetic Studies (STROPS) guideline was developed in 2020 based on the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. The objective of this article is to present a brief introduction to the STROPS guideline and an interpretation of the key points in some items with examples for the better understanding and application.

Assessing Asymptomatic, Presymptomatic, and Symptomatic Transmission Risk of Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: The relative contributions of asymptomatic, presymptomatic, and symptomatic transmission of severe acute respiratory syndrome coronavirus 2 have not been clearly measured, although control measures may differ in response to the risk of spread posed by different types of cases. METHODS: We collected detailed information on transmission events and symptom status based on laboratory-confirmed patient data and contact tracing data from 4 provinces and 1 municipality in China. We estimated the variation in risk of transmission over time and the severity of secondary infections by symptomatic status of the infector. RESULTS: There were 393 symptomatic index cases with 3136 close contacts and 185 asymptomatic index cases with 1078 close contacts included in the study. The secondary attack rates among close contacts of symptomatic and asymptomatic index cases were 4.1% (128 of 3136) and 1.1% (12 of 1078), respectively, corresponding to a higher transmission risk from symptomatic cases than from asymptomatic cases (odds ratio, 3.79; 95% confidence interval, 2.06-6.95). Approximately 25% (32 of 128) and 50% (6 of 12) of the infected close contacts were asymptomatic from symptomatic and asymptomatic index cases, respectively, while more than one third (38%) of the infections in the close contacts of symptomatic cases were attributable to exposure to the index cases before symptom onset. CONCLUSIONS: Asymptomatic and presymptomatic transmissions play an important role in spreading infection, although asymptomatic cases pose a lower risk of transmission than symptomatic cases. Early case detection and effective test-and-trace measures are important to reduce transmission.

Epidemiological characteristics of brucellosis in Yunnan Province from 2008 to 2018 and prediction of grey GM (1, 1) model / 中华地方病学杂志

Objective:To discover the epidemic characteristics of brucellosis in Yunnan Province, and establish a grey GM (1, 1) model to predict brucellosis in Yunnan Province.Methods:The epidemic data of incidence rate of brucellosis and population data in Yunnan Province from 2008 to 2018 were collected from China Disease Prevention and Control Information System and Yunnan Provincial Bureau of Statistics. Epidemiological characteristics (including time, area and population distributions) were analyzed, and grey GM (1, 1) model was used to predict the incidence of brucellosis in Yunnan Province in 2019 and 2020.Results:A total of 1 216 brucellosis cases were reported in Yunnan Province from 2008 to 2018, with an average annual incidence rate of 0.237 4/100 000, showing an increasing trend year by year (χ 2trend = 843.34, P<0.01). Case reports were mainly from March to September, accounted for 69.41% (844/1 216) of the total number of cases. The top five regions with case reports were Honghe (289 cases), Qujing (264 cases), Kunming (258 cases), Dali (160 cases), and Yuxi (134 cases), accounting for 90.87% (1 105/1 216). The occupation was mainly farmers, accounting for 79.03% (961/1 216). A grey GM (1, 1) model was established to predict the incidence of brucellosis in Yunnan Province in 2019 and 2020, which was 0.487 6/100 000 and 0.481 7/100 000, respectively. Conclusion:The incidence of brucellosis in Yunnan Province has increased compared with that of the past, and targeted prevention and control should be carried out in key areas and key populations, and the prediction results should be prospectively evaluated to gradually improve the establishment of brucellosis prediction model in Yunnan Province.

Expert consensus on Antiviral Oral Liquid in treatment of influenza in clinical practice / 中国中药杂志

Antiviral Oral Liquid is modified on the basis of Baihu Decoction in Treatise on Febrility Diseases by ZHANG Zhongjing and Qingwen Baidu Yin in Qing Dynasty, with effects in clearing toxic heat, repelling dampness and cooling blood. It is widely used in clinical treatment of common colds, influenza and upper respiratory tract infection, mumps, viral conjunctivitis and hand-foot-mouth disease, with a good clinical efficacy and safety. Based on a questionnaire survey of clinicians and a systematic review of study literatures on Antiviral Oral Liquid, the international clinical practice guidelines development method was adopted to analyze the optimal available evidences and expert experiences in the "evidence-based, consensus-based and experience-based" principles. The consensus was jointly reached by more than 30 multidisciplinary experts nationwide, including clinical experts of traditional Chinese and Western medicine in the field of respiratory diseases and infectious diseases, and methodological experts. In the study, literatures were retrieved based on clinical problems in the clinical survey as well as PICO clinical problems. The GRADE system was used for the classification and evaluation of evidence, and fully combined with clinical expert experience, so as to reach expert consensus by the nominal grouping method. This expert consensus recommended or suggested indications, usage and dosage, course of treatment, intervention time for treatment, and the safety and precautions of Antiviral Oral Liquid for treatment of influenza, and can provide reference for the rational use of this drug in clinical practice.

Author Correction: Directed self-assembly of herbal small molecules into sustained release hydrogels for treating neural inflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Neutrophil to high-density lipoprotein ratio has a superior prognostic value in elderly patients with acute myocardial infarction: a comparison study.

BACKGROUND: The importance of the lipid-related biomarkers has been implicated in the pathological process and prognosis of acute myocardial infarction (AMI). Our work was conducted to discuss and compare the predictive ability of the neutrophil to high-density lipoprotein cholesterol (HDL-C) ratio (NHR) with other existing prognostic indices, for instance, the monocyte to HDL-C ratio (MHR) and the low-density lipoprotein cholesterol (LDL-C) to HDL-C ratio (LDL-C/HDL-C) in elderly patients with AMI. METHODS: Our population was 528 consecutive elderly AMI patients (65-85 years) who were enrolled from Tongji Hospital and grouped according to the cutoff points which were depicted by the receiver operating characteristic (ROC). The Kaplan-Meier curves were plotted with the survival data from the follow-up to investigate the difference between cutoff point-determined groups. Moreover, we assessed the impact of NHR, MHR, LDL-C/HDL-C on the long-term mortality and recurrent myocardial infarction (RMI) with Cox proportional hazard models. RESULTS: Mean duration of follow-up was 673.85 ± 14.32 days (median 679.50 days). According to ROC curve analysis, NHR ≥ 5.74, MHR ≥ 0.67, LDL-C/HDL-C ≥ 3.57 were regarded as high-risk groups. Kaplan-Meier analysis resulted that the high-NHR, high-MHR and high-LDL-C/HDL-C groups presented higher mortality and RMI rate than the corresponding low-risk groups in predicting the long-term clinical outcomes (log-rank test: all P < 0.050). In multivariate analysis, compared with MHR and LDL-C/HDL-C, only NHR was still recognized as a latent predictor for long-term mortality (harzard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.02 to 3.75, P = 0.044) and long-term RMI (HR: 2.23, 95% CI: 1.04 to 4.79, P = 0.040). Furthermore, the positive correlation between NHR and Gensini score (r = 0.15, P < 0.001) indicated that NHR was relevant to the severity of coronary artery to some extent. CONCLUSIONS: NHR, a novel laboratory marker, might be a predictor of the long-term clinical outcomes of elderly patients with AMI, which was superior to MHR and LDL-C/HDL-C.

Pathogen Spectrum of Hand, Foot, and Mouth Disease Based on Laboratory Surveillance - China, 2018.

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?: Enterovirus 71 (EV-A71) is the main causative pathogen for severe and fatal patients with Hand, Foot, and Mouth Disease (HFMD) in mainland China from 2008 to 2017. Non-EV-A71 and non-CV-A16 (other enterovirus) serotypes were the major causative-serotypes for mild HFMD in years of 2013, 2015, and 2017. WHAT IS ADDED BY THIS REPORT?: In 2018, other enterovirus serotypes replaced EV-A71 for the first time as the major cause of severe HFMD with a proportion of 70.7%. However, at the national level, only a small proportion of the other enterovirus serotypes were further identified as CV-A6 and CV-A10. WHAT ARE THE LIMITATIONS FOR PUBLIC HEALTH PRACTICE?: Further identification of other enterovirus serotypes is highly recommended for provincial CDCs, especially for severe HFMD. Studies contributing to a multivalent vaccine for HFMD should be prioritized.

Could platelet-to-lymphocyte ratio be a predictor for contrast-induced nephropathy in patients with acute coronary syndrome?: A systematic review and meta-analysis.

BACKGROUND: Contrast-induced nephropathy (CIN) is acute renal failure observed after administration of iodinated contrast media during angiographic or other medical procedures. In recent years, many studies have focused on biomarkers that recognize CIN and/or predict its development in advance. One of the many biomarkers studied is the platelet-to-lymphocyte ratio (PLR). We performed a systematic review and meta-analysis to evaluate the correlation between PLR level and CIN. METHODS: Relevant studies were searched in PUBMED, EMBASE, and Web of Science until September 15, 2018. Case-control studies reporting admission PLR levels in CIN and non-CIN group in patients with acute coronary syndrome (ACS) were included. The pooled weighted mean difference (WMD) and 95% confidence intervals (95%CI) were calculated to assess the association between PLR level and CIN using a random-effect model. RESULTS: Six relevant studies involving a total of 10452 ACS patients (9720 non-CIN controls and 732 CIN patients) met our inclusion criteria. A meta-analysis of 6 case-control studies showed that PLR levels were significantly higher in CIN group than those in non-CIN group (WMD = 33.343, 95%CI = 18.863 to 47.823, P < .001, I = 88.0%). CONCLUSION: For patients with ACS after contrast administration, our meta-analysis shows that on-admission PLR levels in CIN group are significantly higher than those of non-CIN group. However, large and matched cohort studies are needed to validate these findings and assess whether there is a real connection or just an association.