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.

Objective:To establish a predictive scoring model for bladder neck contracture(BNC)after laparoscopic enuclea-tion of the prostate with preservation of the urethra(Madigan surgery)and explore the preventive measures against this postoperative complication.Methods:We included 362 cases of BPH treated by laparoscopic Madigan surgery from January 2019 to March 2022(45 with and 317 without postoperative BNC)in the training group and another 120 cases treated the same way in the verification group,collected the clinical data on the patients and evaluated the results of surgery.Using the least absolute shrinkage and selection operator(LASSO)and multivariate logistic regression,we analyzed the risk factors for postoperative BNC and constructed a predictive scoring model for evaluation of the factors.Results:Compared with the baseline,the IPSS,quality of life(QOL)score and postvoid residual urine volume(PVR)were significantly decreased(P＜0.05)while the maximum urinary flow rate(Qmax)remarkably in-creased(P＜0.05)in the BPH patients at 3 months after surgery.Eight non-zero characteristic predictors were identified by LASSO regression analysis.Multivariate logistic regression analysis showed that short clinical experience of the surgeon,concurrent prostatitis,bladder rinse solution temperature＜34℃,catheter blockage,urethral balloon injection volume＞40 ml and postoperative constipation were independent risk factors for postoperative BNC(P＜0.05).The best cut-off value was 2.36 points in both the training and the verification groups.The results of evaluation exhibited a high discriminability of the predictive scoring model.Conclusion:Laparo-scopic Madigan surgery is a safe and effective method for the treatment of BPH.Short clinical experience of the surgeon,concurrent prostatitis,bladder rinse solution temperature＜34℃,catheter blockage,water injected into the urethral balloon＞40 ml and postop-erative constipation were independent risk factors for postoperative BNC.The predictive scoring model constructed in this study has a good discriminability and is simple and feasible,contributive to the prediction of postoperative BNC in BPH patients undergoing laparo-scopic Madigan surgery.

Objective:To study the risk factors of patients with hepatocellular carcinoma (HCC) to transcatheter arterial chemoembolization(TACE) refractoriness.Methods:The clinical data of 106 HCC patients who underwent TACE at the Affiliated Hospital of Xuzhou Medical University from January 2020 to December 2021 were retrospectively studied. There were 90 males and 16 females, with the age of (59.9±9.3) years. These patients were divided into the TACE-refractory group ( n=47) and the control group ( n=59) based on whether TACE refratoriness occurred after surgery. Serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVIKA-II), maximum diameter of tumor, number of tumor and tumor vascularization patterns between the two groups were compared. Multivariate logistic regression analysis was performed to analyse the risk factors of TACE refractoriness in patients with HCC after TACE. Results:The proportion of patients with AFP >400 μg/L, PIVIKA-II >40 AU/L, number of tumor and tumor vascularization patterns Ⅲ+ Ⅳ (uneven enhancement) were significantly higher in the TACE-refractory group than the control group (all P<0.05). The maximum diameter of tumor for patients in the TACE-refractory group was significantly larger than that in the control group ( Z=-2.41, P=0.016). Multivariate logistic regression analysis showed that patients with serum AFP >400 μg/L( OR=2.707, 95% CI: 1.008-7.271), multiple tumors ( OR=6.069, 95% CI: 2.115-17.415) and tumor vascularization patterns Ⅲ+ Ⅳ (uneven enhancement)( OR=7.813, 95% CI: 2.246-27.176) before the first TACE were at increased risks of TACE refractoriness (all P<0.05). Conclusion:Preoperative AFP >400 μg/L, multiple tumors and tumor vascularization patterns Ⅲ+ Ⅳ were independent risk factors for TACE refractoriness in patients with HCC.

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34⁺⁰ weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.
Infant ; Infant, Newborn ; Humans ; Birth Weight ; Intensive Care Units, Neonatal ; Retrospective Studies ; Tertiary Care Centers ; Infant, Extremely Low Birth Weight ; Gestational Age ; Infant, Extremely Premature ; Sepsis/epidemiology* ; Retinopathy of Prematurity/epidemiology* ; Bronchopulmonary Dysplasia/epidemiology*

Objective: To investigate the incidence and trend of short-term outcomes among preterm infants born <34 weeks' gestation. Methods: A secondary analysis of data from the standardized database established by a multicenter cluster-randomized controlled study "reduction of infection in neonatal intensive care units (NICU) using the evidence-based practice for improving quality (REIN-EPIQ) study". This study was conducted in 25 tertiary NICU. A total of 27 192 infants with gestational age <34 weeks at birth and admitted to NICU within the first 7 days of life from May 2015 to April 2018 were enrolled. Infants with severe congenital malformation were excluded. Descriptive analyses were used to describe the mortality and major morbidities of preterm infants by gestational age groups and different admission year groups. Cochran-Armitage test and Jonckheere-Terpstra test were used to analyze the trend of incidences of mortality and morbidities in 3 study-years. Multiple Logistic regression model was constructed to analyze the differences of outcomes in 3 study-years adjusting for confounders. Results: A total of 27 192 preterm infants were enrolled with gestational age of (31.3±2.0) weeks at birth and weight of (1 617±415) g at birth. Overall, 9.5% (2 594/27 192) of infants were discharged against medical advice, and the overall mortality rate was 10.7% (2 907/27 192). Mortality for infants who received complete care was 4.7% (1 147/24 598), and mortality or any major morbidity was 26.2% (6 452/24 598). The incidences of moderate to severe bronchopulmonary dysplasia, sepsis, severe intraventricular hemorrhage or periventricular leukomalacia, proven necrotizing enterocolitis, and severe retinopathy of prematurity were 16.0% (4 342/27 192), 11.9% (3 225/27 192), 6.8% (1 641/24 206), 3.6% (939/25 762) and 1.5% (214/13 868), respectively. There was a decreasing of the overall mortality (P<0.001) during the 3 years. Also, the incidences for sepsis and severe retinopathy of prematurity both decreased (both P<0.001). However, there were no significant differences in the major morbidity in preterm infants who received complete care during the 3-year study period (P=0.230). After adjusting for confounders, infants admitted during the third study year showed significantly lower risk of overall mortality (adjust OR=0.62, 95%CI 0.55-0.69, P<0.001), mortality or major morbidity, moderate to severe bronchopulmonary dysplasia, sepsis and severe retinopathy of prematurity, compared to those admitted in the first study year (all P<0.05). Conclusions: From 2015 to 2018, the mortality and major morbidities among preterm infants in Chinese NICU decreased, but there is still space for further efforts. Further targeted quality improvement is needed to improve the overall outcome of preterm infants.
Bronchopulmonary Dysplasia/epidemiology* ; Gestational Age ; Humans ; Infant ; Infant Mortality/trends* ; Infant, Newborn ; Infant, Premature ; Infant, Premature, Diseases/epidemiology* ; Patient Discharge ; Retinopathy of Prematurity/epidemiology* ; Sepsis/epidemiology*

Objective To improve the early diagnosis of congenital heart disease (CHD), investigate the awareness, screening knowledge and screening ability of CHD among health care providers in the rural areas of Yunnan province and discover an effective way to improve the related knowledge and skills of CHD screening. Methods From 2015 September to 2017 April, we set up charity mobile schools and chose eight areas as the investigating and training sites. We designed two questionnaires, and adopted the theoretical training as the main method combined with the training of clinical skills. We investigated and trained a total of 1022 medical staff. The training content include the awareness of CHD,the knowledge and skills of CHD screening. We also evaluated the outcomes of the training. Results A total of 2044 questionnaires were collected. After training, the number of objects which would screen CHD in future increased, and the cognition of the incidence and common clinical manifestations of CHD, Eisenmanger's syndrome,cardiac auscultation, pulse oximetry and the related knowledge of CHD were also improved; 563 took the test on practical skills of CHD detection. The correct rate of auscultation, period of murmurs and characteristics of murmurs was 98.22%(553),30.55%(172) and 28.60%(161). The correct rate of murmurs in ventricular septal defect,atrial septal defect and patent ductus arteriosus was 45.47%(256), 39.79 (224) and 50.80%(286) respectively. Online training was advised by 244 trainees. Increasing investment in congenital heart disease screening was suggested by 652 trainees. Conclusions The awareness of CHD screening in grassroots medical workers of Yunnan province is insufficient. It is an effective way to establish charity mobile school and to train the grassroots medical staff with the theory and practical knowledge to improve the awareness,screening knowledge and screening skills of CHD. The next step suggests that we can improve the early diagnosis of congenital heart disease (CHD).

Objective To investigate the effect of urate-lowering therapy on renal function in chronic kidney disease (CKD) stages 2-5 patients with hyperuricemia (HUA).Methods A total of 132 patients of CKD stages 2-5 with HUA between July 2016 and December 2017 in Department of Nephrology of the Second Affiliated Hospital of Anhui Medical University were prospectively and self-controlled analyzed.Serum uric acid (SUA),estimated glomerular filtration rate (eGFR) and other clinical parameters were measured at baseline and after 1-6 months treatment.The patients were divided into group A (CKD stages 2-3a) and group B (CKD stages 3b-5) on the baseline value of eGFR.The changes of SUA and eGFR before and after treatment were compared.According to the level of SUA after 6 months treatment,patients were divided into attainment group (SUA ＜ 360 μmol/L) and nonattainment group (SUA ≥ 360 μmol/L).The difference of renal function in pre-treatment and post-treatment was compared.Multiple stepwise linear regression was used to analyze the relationship among the change of eGFR after receiving 6 months' treatment (deGFR) and SUA level,baseline eGFR and other indexes.Results After 1,3,6 months treatment,the average levels of SUA,Scr and urea nitrogen of all patients were decreased significantly while eGFR value was increased significantly (all P ＜ 0.050) than those in pre-treatment period.After six-month-therapy,proteinuria and hematuria were improved significantly in all patients (P ＜ 0.001,P=0.001).Compared with pre-treatment period,both the SUA levels of group A and group B were declined significantly while eGFR had a significant rise after treatment (P ＜ 0.001).The change of eGFR post-treatment in group A was significantly higher than that of group B [(13.64±15.35) vs (8.97±9.79) ml· min-1· (1.73 m2)-1,P=0.044].At 6 months after treatment,the eGFR value increased markedly in both attainment group and nonattainment group compared with pre-treatment period (P ＜ 0.001).After six-month-therapy,the eGFR value in attainment group was increased more obviously than that of nonattainment group [(13.96 ± 14.64) vs (8.03±9.69) ml· min-1· (1.73 m2)-1,P=0.021].Multiple stepwise linear regression analysis showed that the baseline eGFR value was an influencing factor of deGFR (b=0.161,P=0.020).Conclusions The renal function of CKD stages 2-5 patients with HUA can be significantly improved by urate-lowering therapy,which can effectively reduce proteinuria and hematuria.

Objective: To explore the peri-operative application of GLP-1 analogue and insulin on myocardial perfusion and clinical prognosis in patients of acute ST segment elevation myocardial infarction (STEMI) with stress-induced hyperglycemia. Methods: Our research was a prospective single center randomized control study. A total of 114 consecutive STEMI patients received percutaneous coronary intervention (PCI) within 12h of onset were enrolled, the patients had no diabetes while blood glucose ≥11.1mmol/L at immediate admission. Based on random number table, the patients were divided into 2 groups: Observation group, the patients received GLP-1 analogue, n=59 and Control group, the patients received insulin, n=55. The post-operative myocardial perfusion, indicators of myocardial damage and cardiac function, myocardial infarct area (MIA) and myocardial salvage index (MSI) were compared between 2 groups. The patients were followed-up for 6 months to record the incidence of major adverse cardiovascular events (MACE). Results: At peri-operative period, compared with Control group, Observation group had decreased peak values of creatine kinase isoenzyme (CK-MB) and troponin T (cTnT), P<0.05. At 6 months post-operation, compared with Control group, Observation group showed increased myocardial perfusion and left ventricular ejection fraction (LVEF), P<0.05, reduced MIA (15±12) g vs (20±14) g, P<0.05 and 12% elevated MSI as (0.64±0.13) vs (0.56±0.12), P<0.001. The MACE incidence was similar between 2 groups, P=0.217. Conclusion: In STEMI patients with stress-induced hyperglycemia, peri-operative application of GLP-1 analogue may safely regulate blood glucose, improve cardiac perfusion and function, reduce MIA; while it had no influence on myocardial perfusion at peri-operative period and no impact on MACE occurrence at 6 months post-operation.

OBJECTIVETo investigate the effect of intermittent fasting on metabolize and gut microbiota in obese presenium rats fed with high-fat-sugar-diet.

METHODSWe fed the Wistar rats with high-fat and high-sugar diet to induce adiposity, and the rats for intermittent fasting were selected base on their body weight. The rats were subjected to fasting for 72 h every 2 weeks for 18 weeks. OGTT test was performed and fasting blood samples and fecal samples were collected for measurement of TC, TG, HDL-C and LDL-C and sequence analysis of fecal 16S rRNA V4 tags using Illumina. Gut microbial community structure was analyzed with QIIME and LEfSe.

RESULTSAfter the intervention, the body weight of the fasting rats was significantly lower than that in high-fat diet group (P<0.01). OGTT results suggested impairment of sugar tolerance in the fasting group, which showed a significantly larger AUC than compared with the high-fat diet group (P<0.05). Intermittent fasting significantly reduced blood HDL-C and LDL-C levels (P<0.05) and partially restored liver steatosis, and improved the gut microbiota by increasing the abundance of YS2, RF32 and Helicobacteraceae and reducing Lactobacillus, Roseburia, Erysipelotrichaceae and Ralstonia. Bradyrhizobiaceae was found to be positively correlated with CHOL and HDL-C, and RF39 was inversely correlated with the weight of the rats.

CONCLUSIONIntermittent fasting can decrease the body weight and blood lipid levels and restore normal gut microbiota but can cause impairment of glucose metabolism in obese presenium rats.

Animals ; Body Weight ; Diet, High-Fat ; Fasting ; Fatty Liver ; microbiology ; physiopathology ; Gastrointestinal Microbiome ; Lipids ; blood ; Obesity ; microbiology ; physiopathology ; RNA, Ribosomal, 16S ; Rats ; Rats, Wistar