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 study the expression of thyroid hormone receptor binding protein 4(TRIP4)and DNA damage inducing transcription factor 4(DDIT4)in glioma tissue and their relationship with clinical pathological characteristics and prognosis.Methods 94 glioma patients admitted to the First Hospital of Hebei Medical University from February 2018 to February 2019 were selected as the research subjects.The expression of TRIP4,DDIT4 proteins in tissues were detected by immunohistochemistry.The relationship between the expression of TRIP4,DDIT4 proteins in glioma tissues and clinical pathological characteristics were compared.The differences in survival prognosis of glioma patients with different levels of TRIP4,DDIT4 protein expression were analyzed by Kaplan-Meier survival curve.Univariate and multivariate COX regression analysis was conducted to analyze the factors affecting the survival prognosis of glioma patients.Results The positive rates of TRIP4(68.09%),DDIT4(65.96%)proteins in glioma tissues were higher than those in adjacent tissues(13.83%,10.64%),with statistically significant differences(χ2=57.212,60.866,all P<0.05).There was a significant positive correlation between TRIP4 and DDIT4 protein expression in glioma tissues(r=0.722,P<0.05).The positive rates of TRIP4(83.64%vs 46.15%,80.00%vs 51.28%)and DDIT4(80.00%vs 46.15%,76.36%vs 51.28%)proteins in glioma tissues with tumor diameter≥3cm,WHO grade Ⅲ were significantly higher than those in tissues with tumor diameter＜3cm,WHO grade Ⅰ～Ⅱ(χ2=6.393～14.754,P<0.05).The 3-year overall survival rates of the TRIP4 positive and negative expression groups were 37.50%(24/64)and 66.67%(20/30),respectively.The 3-year cumulative survival of the TRIP4 positive expression group was significantly lower than that in the TRIP4 negative expression group(Log-rank χ2=5.949,P=0.015).The 3-year overall survival rate of DDIT4 positive and negative expression group was 37.10%(23/62)and 70.00%(21/30),respectively.The 3-year cumulative survival of the DDIT4 positive expression group was significantly lower than that in the DDIT4 negative expression group(Log-rank χ2=7.642,P=0.006).Tumor diameter≥3cm(HR=1.614,P=0.000),WHO grade Ⅲ(HR=1.790,P=0.000),positive TRIP4(HR=1.665,P=0.000)and positive DDIT4(HR=1.476,P=0.000)were independent risk factors affecting the survival prognosis of glioma patients.Conclusion The expression of TRIP4 and DDIT4 protein in glioma tissue was increased.Both of them were related to tumor diameter and WHO grade,and are potential tumor markers for survival prognosis of glioma.

Objective:To explore the classification and influencing factors of family resilience and post-traumatic growth in patients with spinal tumor.Methods:A cross-sectional investigation was conducted among 219 inpatients with spinal tumor admitted from July 2021 to July 2022. The General Demographic Information questionnaire, Chinese-Family Resilience Assessment Scale, Posttraumatic Growth Inventory, Family Crisis-Oriented Personal Evaluation Scales (F-COPES), and Social Support Rating Scale (SSRS) were used in the study. The ordinal and multivariate logistic regression analyses was applied to identify the factors associated with the classification of family resilience and post-traumatic growth.Results:Of the 219 patients, there were 62 cases of primary spinal tumors (28.3%). According to the results of latent profile analysis, the respondents were classified into three categories by family resilience and post-traumatic growth, namely family difficulty-resistant type ( n=38, 17.4%), general resilience-struggle type ( n=99, 45.2%) and family adaptation-growth type ( n=82, 37.4%). There were significant differences in occupational status, commitment to housework, family atmosphere( χ2=10.75, P=0.025; χ2=6.95, P=0.031; χ2=11.37, P=0.017), and total score of F-COPES and SSRS ( F=25.95, P<0.001; F=19.06, P<0.001)among three groups. Ordinal and multivariate logisitc regression analyses showed that retirement ( OR=2.928, 95% CI:1.098-7.808, P<0.05), family coping ( OR=1.113, 95% CI:1.063-1.165, P<0.05), and social support ( OR=1.226, 95% CI:1.103-1.362, P<0.05) were independently associated with family resilience and post-traumatic growth in patients with spinal tumor. Conclusion:Patients with spinal tumor have significant differences in characteristics by family resilience and post-traumatic growth. As a result, more targeted interventions should be provided for different categories of spinal tumor patients in the future.

OBJECTIVE To evaluate the quality and existing problems of Compound Paracetamol and Chlorphenamine Tablets for Infant. METHODS Using legal standards to inspect sampled samples, and several analytical methods were subsequently established or improved for the exploratory research on related substances, assay, dissolution, subdivision characteristics of scored tablets, and genotoxic impurities. RESULTS All samples met the regulatory specification, and the pass rate was 100%. However, the control for related substances was lacking, and the method for assay and content uniformity was defective. The exploratory studies showed that the assay and content uniformity met the requirements, and the risk of related substances and genotoxic impurities was acceptable. As a divisible tablet, the subdivision characteristics could not meet the requirements of the scored tablet, and the dissolution performance of some enterprise samples could not meet the requirements of similar products in foreign pharmacopoeias. CONCLUSION The overall quality of this product is adequate. However, due to the early time on the market, some quality attributes no longer meet the requirements of current regulations or relevant guidelines. The manufacturers should further optimize the prescription and production process, referring to foreign similar products. The current specification needs to be revised and improved.

Objective:To construct a risk prediction model for the inter-hospital transfer of critically ill children using machine learning methods, identify key medical features affecting transfer outcomes, and improve the success rate of transfers.Methods:A prospective study was conducted on critically ill children admitted to the pediatric transfer center of Hunan Children's Hospital from January 2020 to January 2021. Medical data on critical care features and relevant data from the Pediatric Risk of Mortality (PRISMⅢ) scoring system were collected and processed. Three machine learning models, including logistic regression, decision tree, and Relief algorithm, were used to construct the risk prediction model. A back propagation neural network was employed to build a referral outcome prediction model to verify and analyze the selected medical features from the risk prediction model, exploring the key medical features influencing inter-hospital transfer risk.Results:Among the 549 transferred children included in the study, 222 were neonates (40.44%) and 327 were non-neonates (59.56%). There were 50 children in-hospital deaths, resulting in a mortality rate of 9.11%. After processing 151 critical care medical feature data points, each model selected the top 15 important features influencing transfer outcomes, with a total of 34 selected features. The decision tree model had an overlap of 72.7% with PRISMⅢ indicators, higher than logistic regression (36.4%) and Relief algorithm (27.3%). The training prediction accuracy of the decision tree model was 0.94, higher than the accuracy of 0.90 when including all features, indicating its clinical utility. Among the top 15 important features selected by the decision tree model, the impact on transfer outcomes was ranked as follows based on quantitative feature violin plots: base excess, total bilirubin, ionized calcium, total time, arterial oxygen pressure, blood parameters (including white blood cells, platelets, prothrombin time/activated partial thromboplastin time), carbon dioxide pressure, blood glucose, systolic blood pressure, heart rate, organ failure, lactate, capillary refill time, temperature, and cyanosis. Eight of these important features overlapped with PRISMⅢ indicators, including systolic blood pressure, heart rate, temperature, pupillary reflex, consciousness, acidosis, arterial oxygen pressure, carbon dioxide pressure, blood parameters, and blood glucose. The decision tree was used to select the top 15 medical features with high impact on the neonatal and non-neonatal datasets, respectively. A total of 19 features were selected, among which there were 8 differences and 11 overlap terms between the important features of the neonatal and non-neonatal.Conclusions:Machine learning models could serve as reliable tools for predicting the risk of inter-hospital transfer of critically ill children. The decision tree model exhibits superior performance and helps identify key medical features affecting inter-hospital transfer risk, thereby improving the success rate of inter-hospital transfers for critically ill children.

Objective:To investigate the clinical characteristics and prognosis of cytomegalovirus-sepsis-like syndrome (CMV-SLS) in premature infants, and to provide the evidence for early clinical identification and treatment.Methods:Premature infants with CMV-SLS admitted to Children′s Hospital Affiliated of Zhengzhou University from January 1, 2019 to December 31, 2022 were selected as the research subjects, and their clinical characteristics, treatment, and prognosis were retrospectively analyzed.Results:A total of seven cases of CMV-SLS were included, with a gestational age of (26.8±1.2) weeks and a birth weight of (890±121) g. The age of disease onset was 55(45, 60) days, and the age of diagnosis was 67(56, 71) days. All the seven cases were exclusively breast feeding after birth, and cytomegalovirus (CMV) DNA was detected positive in their breast milk when diagnosed with CMV-SLS. The common clinical features were fever, abdominal distension, liver function damage, decreased neutrophil and platelet counts. Pneumonia, neonatal necrotizing enterocolitis, hearing loss, and chorioretinitis were common. After the diagnosis was confirmed, all the seven cases were given intravenous treatment of ganciclovir and followed by oral formulations, with a course of treatment ranging from five to seven weeks. Two cases were treated with intravitreal injection of ganciclovir for chorioretinitis. All the seven cases survived. During the follow-up with a corrected gestational age of 12 months, one case had delayed intellectual and motor development, two cases had delayed motor development, and the remaining cases had normal development.Conclusions:CMV-SLS in premature infants mainly occurs in extremely low birth weight infants, with atypical clinical manifestations and may be misdiagnosed easily. If extremely low birth weight infants who receive CMV DNA positive breast feeding show sepsis-like symptoms, the possibility of CMV infection should be considered, and early diagnosis and treatment should be carried out to prevent adverse outcomes.

Objective:To investigate the effects of different feeding formulas on the feeding and growth and metabolism of premature infants in the early postnatal period.Methods:Eligible premature infants with the gestational age of ≤ 34 weeks hospitalized from March 2023 to March 2024 were selected as per inclusion criteria, excluding those with congenital metabolic diseases, severe congenital heart disease and developmental malformations of digestive tract. According to the feeding formulas within 2 weeks after birth, premature infants were divided into three groups, namely donor human milk (DHM) group, preterm formula (PF) group and extensively hydrolyzed formula (eHF) group. The characteristics of premature infants, perinatal condition, feeding formulas, milk intake on the 7th and 14th day, the time to the daily milk intake of 120ml/kg and 150ml/kg respectively, the time on parenteral nutrition, the length of hospitalization, feeding intolerance, cholestasis, extrauterine growth retardation and biochemical metabolic indexes at 7 days, 14 days and discharge were collected. The differences of feeding and biochemical metabolic parameters were compared across the three groups.Results:A total of 108 cases were enrolled ,of whom 39 were in DHM group, 37 in PF group and 32 in eHF group. There was no significant difference in gestational age, birth weight, head circumference and maternal complications across the three groups. The milk intake in the DHM group was (50.7±29.1) ml/(kg·d) on the 7th day, compared with (34.2±27.3) ml/(kg·d) in PF group ( P=0.031), and (103.1±36.7) ml/(kg·d) on the 14th day, compared with (73.9±39.2) ml/(kg·d) in the PF group. Compared with the PF group, the DHM group reached the daily milk intake of 120 ml/(kg·d) earlier [(18.5±10.4) days vs. (24.1±10.3) days, P=0.020], had shorter duration of parenteral nutrition [(17.9±10.9) days vs. (23.2±11.2) days, P=0.042], and lower incidence of feeding intolerance (28.2% vs. 48.6%). The length of hospitalization in DHM group was shorter than that in PF group [(33.8±15.5) days vs. (37.8±17.6) days], but there was no significant difference ( P>0.05). There was no significant difference between the DHM group and the eHF group in terms of the milk intake on the 7th and 14th day, the time to the daily milk intake of 120 ml/(kg·d), the time on parenteral nutrition, the length of hospitalization and feeding intolerance. At 1 and 2 weeks after birth, alkaline phosphatase in DHM group was higher than that in PF group and eHF group ( P<0.05), but there was no significant difference in biochemical nutritional metabolism parameters (hemoglobin, urea nitrogen, albumin, prealbumin, alkaline phosphatase and total bile acid) across the three groups at discharge( P>0.05). Conclusion:Early use of DHM in premature infants is better tolerated than PF and can help achieve complete enteral nutrition earlier and shorten the use of parenteral nutrition, while not affecting the growth and development of premature infants.

Objective:To observe the efficacy and safety of the M receptor antagonist Bencycloquidium bromide nasal spray in treatment of seasonal allergic rhinitis with runny nose as the main symptom. Methods:From August 2021 to September 2021, 134 patients with seasonal allergic rhinitis were enrolled in the otolaryngology Outpatient Department of Peking University Third Hospital, First Affiliated Hospital of Harbin Medical University and China-Japanese Friendship Hospital of Jilin University, including 71 males and 63 females, with a median age of 38 years. TNSS score and visual analogue scale（VAS） of total nasal symptoms were observed during 2 weeks of treatment with Bencycloquidium bromide nasal spray. Results:TNSS score decreased from （8.89±3.31） on day 0 to （3.71±2.51） on day 14（P<0.001）, VAS score of nasal symptoms decreased from （24.86±7.40） on day 0 to （6.84±5.94） on day 14（P<0.001）, VAS score of rhinorrhoea decreased from （6.88±2.06） on day 0 to （1.91±1.81） on day 14（P<0.001）. Rhinoconjunctivitis quality of life questionnaire（RQLQ） score decreased from （94.63±33.35） on day 0 to （44.95±32.28） on day 14（P<0.001）. The incidence of adverse reaction was low and no serious adverse events occurred during the whole experiment. Conclusion:Bencycloquidium bromide nasal spray has significant efficacy and good safety in the treatment of seasonal allergic rhinitis.
Male ; Female ; Humans ; Adult ; Rhinitis, Allergic, Seasonal/drug therapy* ; Nasal Sprays ; Quality of Life ; Administration, Intranasal ; Rhinorrhea ; Double-Blind Method ; Treatment Outcome ; Rhinitis, Allergic/drug therapy*

This article reported a male patient with neonatal onset mental retardation autosomal dominant 35 (MRD35). The boy presented with repeated convulsions, hypotonia, enlarged head circumference, congenital muscular torticollis and feeding difficulties in the neonatal period. Dynamic electroencephalogram showed paroxysmal epileptic discharges in the left central-temporal region. High-throughput whole-exome sequencing revealed a heterozygous mutation of c.139G>A (p.Glu47Lys) in the PPP2R5D gene, which was a de novo mutation not inherited from his parents. The child had significant developmental delay at the age of one year. MRD35 lacks typical clinical manifestations and requires whole-exome sequencing for definitive diagnosis. Currently, there is no specific treatment for MRD35 and symptomatic treatments, including rehabilitation training, language training and seizure control, are mostly adopted.

Objective The aim of this study was to collect diagnosis,treatment,and follow-up information of inpatients with malignant tumors at the Affiliated Tumor Hospital of Xinjiang Medical University,analyze the distribution and composition of malignant tumor types,mortality,and survival status,and provide reference for the prevention and treatment of malignant tumors in the local area.Methods The case and mortality data of inpatients with malignant tumor from 2010 to 2020 were calculated,and the survival status was collected by follow-up.The composition,different pathological stage,composition and sequential changes of malignant tumors,as well as survival rates of the 1-year,3-year and 5-year were analyzed.Results A total of 111,418 patients with malig-nant tumor were admitted to the hospital from 2010 to 2020.Breast cancer accounted for 20.67％of inpatients,followed by lung canc-er,thyroid cancer,cervical cancer and gastric cancer;The leading cause of malignant tumor death was lung cancer(accounting for 26.70％),followed by gastric cancer,esophageal cancer,liver cancer and colorectal cancer.The 1-year,3-year,and 5-year sur-vival rates were 87.20％,65.80％and 57.20％,respectively.The overall survival rates of patients with stages Ⅰ and Ⅱ malignant tumors were significantly higher than those of patients with stages Ⅲ and Ⅳ(P=0.003).Conclusion Breast cancer,lung cancer,thyroid cancer,cervical cancer and gastric cancer are the high incidence of malignant tumors in Xinjiang,among which thyroid cancer,breast cancer,and cervical cancer have a higher 5-year survival rate.Early screening,diagnosis and treatment of malignant tumors should be strengthened,and prevention strategies and resource allocation should be adjusted in time according to the distribution of malignant tumors to reduce the incidence and mortality of malignant tumor and improve the health level of people in Xinjiang.