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 evaluate the efficacy,safety and economy of teriparatide in the treatment of osteoporosis.Methods PubMed,Embase,Cochrane Library,Web of Science,CNKI,WanFang Data,VIP databases and websites related to health technology evaluation were systematically searched to collect high-quality clinical evidence and economic evaluation literature of teriparatide in the treatment of osteoporosis from the inception to January 20,2023.Two researchers independently identified studies,extracted data,assessed the quality of included studies,and descriptive analyzed and summarised the results.Results A total of 25 literatures were included,involving 3 HTA reports,15 systematic review/Meta-analyses and 7 economic studies were included.In terms of effectiveness,the evaluation results showed that teriparatide could improve bone mineral density in patients with osteoporosis,reduce the incidence of vertebral/non-vertebral fractures in primary and secondary osteoporosis and prevent the fractures in postmenopausal osteoporosis compared to bisphosphonates and placebos.In terms of safety,teriparatide was proven to be safe with no elevated risk of adverse drug reactions.In terms of economic cost,teriparatide has a higher cost and economic disadvantage compared with bisphosphonates,however,for people with severe postmenopausal osteoporosis and high risk of fracture,teriparatide can be considered as a potential cost-effect treatment option.Conclusion Teriparatide is effective and safe in the treatment of osteoporosis,but it is not cost-effective advantages compared with the existing other anti-osteoporosis medications.

Objective To exploring the effect of human amniotic mesenchymal stem cells(hAMSCs)on the re-pair of rat uterine scars.Methods The hAMSCs were isolated and cultured,Female SPF grade SD rats were selected for full-thickness incision of uterine wall and then implanted with hAMSCs.On the 30th day after op-eration,the uterine incision was examined histologically.ImageJ image analysis software was used to analyze and to compare the thickness of uterine myometrium and the percentage of fibrotic area in each group.Immuno-histochemical method was used for detecting the percentage of positive areas of α-SMA,TGF-β1,and Ki-67.Results Compared with the PBS group,the hAMSCs group showed significant thickening of the uterine mus-cle layer and fibrotic area was decreased,The positive expression of α-SMA,and Ki-67 significantly increased(P＜0.05),while the expression of TGF-β1 was significantly reduced(P＜0.05).Conclusions The hAMSCs may promote the repair of uterine incision scars by reducing the formation of scar fibrosis and promoting the proliferation of smooth muscle cells in uterine scars.

Objective To conduct a survey on students for their common needs for the course and the support to their research training,to provide reference for course reform and curriculum of ideology and politics.Methods A survey before and after course was conducted in 704 graduates who selected the course of"Experiments of Molecu-lar Biology"from the autumn of 2018 to the spring of 2024.After collecting the survey,they were summarized,counted,and analyzed.Results The students selected this course were mainly research-oriented graduate students.Their professional background was mainly in clinical medicine,and there was a relatively lack of training in tech-nology and laboratory skill in molecular biology experiment.The follow-up survey showed that experimental operation and implementation as well as analysis of experimental results were the two most helpful aspects for students;PCR,RNA extraction and detection,and Western blot were the most useful techniques for student learning and scientific research.Conclusions Through the survey,the professional background of students,dynamic changes in their course selection needs are well acknowledged and so thus able to optimize,provide good reference for teaching and learning in this field,and provide a basis for curriculum reform and construction of ideological and political courses.

Critically ill patients are at high risk for hospital acquired infections, which can significantly increase the mortality rate and treatment costs for these patients. Therefore, in the process of treating the primary disease, strict prevention and control of new hospital infections is an essential component of the treatment for critically ill patients. The treatment of critically ill patients involves multiple steps and requires a concerted effort from various aspects such as theory, management, education, standards, and supervision to achieve effective prevention and control of hospital infections. However, there is currently a lack of unified understanding and standards for hospital infection prevention and control. To address this, in March 2024, a group of experts in critical care medicine, infectious diseases, and hospital infection from China discussed the current situation and issues of hospital infection control in the intensive care unit together. Based on a review of the latest evidence-based medical evidence from both domestic and international sources, 2024 Expert Consensus on Hospital Acquired Infection Control Principles in the Department of Critical Care Medicine was formed, aiming to provide a basis for the development of hospital infection prevention and control strategies in the field of critical care medicine.

Objective:To construct an analytic method aimed at the characteristics of the commonly method of supplementing and pouring of acupuncture based on the analysis and modeling of ultrasound images around acupoint region in the process of acupuncture.Methods:A total of 7 healthy subjects who underwent physical examination in Beijing Zhongguancun Hospital from June,2022 to June,2023 were selected,and their Kongzui acupoints were acupunctured by 10 acupuncturists with associate senior title as 4 kinds of acupuncture manipulations included reinforcing by twisting and rotating(RFTR),reducing by twisting and rotating(RDTR),reinforcing by lifting and thrusting(RFLT),and reducing by lifting and thrusting(RDLT).The B-ultrasound diagnostic device was used to collect the images of muscle and fascial tissue below the acupoint,so as to construct the model of images.The definition of virtual acupuncture point was adopted to study the regulation of perturbation of subcutaneous tissue that was caused after the skin was acupunctured by needle.The change regulation of the virtual acupuncture point of muscle bundle below skin at Zuikong acupoint of subjects was analyzed.Results:The difference value of average absolution value between peak and trough of the trajectory of virtual acupuncture point of twisting and rotating was 0.066±0.045,and the average value of amplitude of this method was less than that(0.428±0.276)of lifting and thrusting method,and the twisting and rotating method was uniform and symmetrical,and there was difference between two kinds of acupuncture methods.The characteristics of computer graphics was used to qualify the work effect of lifting and thrusting,and reinforcing and reducing,which showed the heavy insertion and light lifting of RFLT,and showed heavy lifting and light insertion of RDLT,thus distinguished the two methods[(RFLT)and(RDLT)].Conclusions:The ultrasound imaging and computer graphics can be used to analyze the regularity of the common"reinforcing and reducing"method of acupuncture and moxibustion.

Objective:To analyze the etiology and typology of cerebral palsy (CP) in preschool children with comorbid epilepsy, and their gross motor function (GMFCS) and cranial magnetic resonance (MRICS) classifications.Methods:A total of 837 children (aged 6 months to 6 years) hospitalized with cerebral palsy were divided into an epileptic group ( n=174) and a non-epileptic group ( n=663). Their general data, CP type, CP etiology, GMFCS classifications, MRICS classifications and Gesell development scores were analyzed. Results:Among the 174 children with epilepsy, 158 (90.8%) were under 3 years old. The most common type of CP in the epilepsy group was spastic quadriplegia (50.0%). In the non-epilepsy group it was spastic diplegia (42.1%), a significant difference. There were also significant differences between the two groups in terms of etiology. The number of cases of abnormal brain development differed significantly, as did genetic factors and history of asphyxia. There were also significant differences between the two groups in terms of GMFCS classifications and the distribution of MRICS classes. In the epileptic group, the proportion of gray matter injury was 31.6%. However, white matter injury ranked first in both the epileptic group and the non-epileptic group, reaching 40.8% and 53.7%, respectively. In terms of cognitive functioning there were significant differences in the groups′ mean Gesell developmental quotients: epileptic group 52.21 and non-epileptic group 70.59.Conclusions:The clinical characteristics of CP children with comorbid epilepsy differ with age, CP cause and type, as well as GMFCS and MRICS classifications. Children less than 3 years old with brain mal-developments and genetic factors or asphyxia-hypoxia etiology mostly display spastic quadriplegia CP. They mainly suffer from gray matter injury. The higher the GMFCS classification, the greater the proportion of CP with co-occurring epilepsy and the more severe the cognitive lag tends to be.

Objective To investigate the impact of overweight on the prognosis of patients with acute mild ischemic stroke or moderate-high risk transient ischemic attack (TIA). Methods A total of 366 patients with acute mild ischemic stroke or moderate-high risk TIA who carried CYP2C19 loss-of-function alleles were included in the study. Baseline data were collected at admission, and clinical outcomes were collected within 3 months post-onset (primary outcomes: stroke recurrences within 3 months post-onset; secondary outcomes: composite outcome of stroke recurrence or death within 3 months post-onset, vascular events, and quality of life within 3 months). Kaplan-Meier method was used to plot the cumulative incidence curve of outcomes. Multivariate Cox proportional hazards model and multivariate Logistic regression model were used to evaluate the relationship between overweight and clinical outcomes within 3 months post-onset in patientswith ischemic stroke or TIA. The integrated discrimination improvement index (IDI) and net reclassification improvement index (NRI) were calculated to assess the predictive value of adding body mass index (BMI, whether overweight or not) based on traditional models for predicting the prognosis of acute ischemic stroke or TIA. Results After 3 months of follow-up, 28 patients had stroke recurrence, 1 patient died, and 31 patients had vascular events. The Kaplan-Meier cumulative incidence curve showed that the cumulative incidences of stroke recurrence, stroke recurrence or death, and vascular events after 3 months of onset were lower in overweight patients compared with non-overweight patients (Log-rank P < 0.05). Multivariate analysis showed that compared with non-overweight patients, overweight patients had significantly reduced risks of stroke recurrence within 3 months (HR=0.24; 95%CI, 0.08 to 0.71), composite outcome of stroke recurrence or death (HR=0.24; 95%CI, 0.08 to 0.69), and vascular events (HR=0.22; 95%CI, 0.07 to 0.63), and significantly improved quality of life within 3 months (OR=0.39; 95%CI, 0.20 to 0.76). The IDI and NRI calculations showed that compared with traditional models, the new model adding BMI (whether overweight) had significantly improved predictive ability for the prognosis of acute ischemic stroke or TIA. Conclusion Overweight may be a protective factor for the prognosis of TIA patients with acute mild ischemic stroke or moderate-high risk who carry CYP2C19 loss-of-function alleles. Compared with non-overweight patients, overweight patients have reduced risks of stroke recurrence, composite outcome of stroke recurrence or death, and vascular events within 3 months post-onset, and improved quality of life within 3 months post-onset.

Objective:To systematically evaluate the effect of bariatric and metabolic surgery on bone metabolism in obese patients.Methods:Search terms for the present meta-analysis included "bariatric surgery, metabolic surgery, sleeve gastrectomy, gastric bypass, bone metabolic indicators, bone mineral density", both in English and corresponding Chinese. PubMed, WOS, Cochrane, CNKI, and VIP databases were searched for longitudinal studies from the establishment of the database to September 20, 2022. The data on bone mineral density and bone metabolic markers in obese patients before and after bariatric surgery were extracted. RevMan5.4 and Stata17.0 software were used for Meta-analysis.Results:A total of 8 clinical studies with 420 patients were included. The results of the meta-analysis showed that compared with the preoperative baseline, lumbar spine bone mineral density ( WMD=0.05, 95% CI: -0.00~0.1), femoral neck bone mineral density( WMD=0.10, 95% CI: 0.05-0.15), hip bone mineral density( WMD=0.14, 95% CI: 0.10-0.17), and serum vitamin D 3 ( WMD=-4.87, 95% CI: -6.34--3.40)were decreased, while parathyroid hormone ( WMD=10.04, 95% CI: 5.32-14.76) was elevated after surgery. Conclusions:Current evidence demonstrates that metabolic and bariatric surgery can lead to decreased bone mineral density and impairs in bone metabolic markers early after surgery. Roux-en-Y gastric bypass surgery cause more adverse effects on bone metabolism than sleeve gastrectomy. The results imply that all patients undergoing metabolic and bariatric surgery should be monitored for bone metabolism and routinely take vitamin D and calcium supplements.

Objective:To investigate whether endoplasmic reticulum aminopeptidase 1 ( ERAP1) is a susceptible gene for pre-eclampsia (PE) and the possible mechanism in the pathogenesis. Methods:This retrospective study included 990 PE patients (case group) and 1 240 healthy pregnant women (control group) in six prefecture-level tertiary hospitals in Shandong Province, including the Affiliated Hospital of Qingdao University and Zaozhuang Maternal and Child Health Hospital, from September 2018 to April 2021. Peripheral blood were collected for DNA extraction. Single-nucleotide polymorphisms in the ERAP1 gene (rs30187, rs27044, and rs469783 loci) were analyzed by Taqman probe polymerase chain reaction (PCR). Two missense mutant plasmids, rs30187(c.1583A>G) and rs27044(c.2188C>G), were constructed by point mutation induction based on wild-type plasmids. Six groups (knock-down control, knock-down, over-expression control, over-expression, variant 1 and 2 groups) were set up in this study. After transfecting Htr8 cells with different transfection molecules, the expression of ERAP1 at mRNA and protein levels were detected. Besides, the effects of different transfections on cell function were detected using Transwell migration assay, Transwell invasion assay, cell scratch assay, and CCK-8 assay. Statistical analysis was performed using two independent samples t-test, rank sum test, and Chi-square test. Results:(1) There were significant differences in the genetic distribution of rs30187 (Genotype: χ2=29.25, Allele: χ2=4.68) and rs469783 (Genotype: χ2=7.01, Allele: χ2=6.45) as well as the genotype distribution of rs27044 ( χ2=28.95) between the case group and the control group (all P<0.05). Statistical analysis of the genetic model revealed that rs30187 and rs27044, both recessive models, were statistically different between the two groups with a higher frequency of CC genotypes in the case group ( χ2=20.82 and 19.97, both P<0.05), but a lower frequency in CC dominant gene pattern for rs469783 ( χ2=5.82, P=0.016). (2) Compared with the knock-down control group, the knock-down group showed significantly inhibited expression of ERAP1 (mRNA: 0.5±0.1 vs 1.0±0.0, t=7.49; protein: 0.4±0.1 vs 0.7±0.1, t=2.81; both P<0.05), reduced cell migration rate after 48 h of scratching [(16.5%±1.8%) vs (23.8%±2.4%), t=3.33, P=0.031] and decreased number of cells crossing Transwell chambers after 24 h of culture (423.7±21.3 vs 499.0±24.6, t=3.29, P=0.031). Compared with the over-expression group, variant 1 group and variant 2 group showed significantly inhibited expression of ERAP1 at mRNA (both P<0.001) and protein ( P=0.003 and 0.006) levels after transfection, decreased number of cells crossing Transwell chambers ( P=0.001 and 0.032) and down-regulated cell migration rate after 48 h of scratching [variant 1: P=0.004; variant 2: (21.1±4.6)% vs (28.3±1.1)%, t=2.10, P=0.099]. ERAP1 expression at both mRNA ( P<0.001) and protein ( P=0.008) levels, as well as cell proliferation ( P<0.001) and invasion ability ( P<0.001), were all enhanced in the over-expression group than those in the over-expression control group. Moreover, the migration rate of cells after 48 h of scratching ( P=0.002) and the number of cells crossing Transwell chambers after 24 h of culture ( P=0.001) were also increased. Conclusions:The rs30187, rs27044, and rs46978 on ERAP1 gene were all associated with PE susceptibility, with more carriers of the CC genotype in PE patients at rs30187 and rs27044 loci and more carriers of the CC genotype in healthy gravida at rs469783 locus. ERAP1 may be involved in the pathogenesis of PE by affecting the migratory and invasive ability of trophoblast cells.