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.

The Piezo protein is a non-selective mechanosensitive cation channel that exhibits sensitivity to mechanical stimuli such as pressure and shear stress. It converts mechanical signals into bioelectric activity within cells, thus triggering specific biological responses. In the digestive system, Piezo protein plays a crucial role in maintaining normal physiological activities, including digestion, absorption, metabolic regulation, and immune modulation. However, dysregulation in Piezo protein expression may lead to the occurrence of several pathological conditions, including visceral hypersensitivity, impairment of intestinal mucosal barrier function, and immune inflammation.Therefore, conducting a comprehensive review of the physiological functions and pathological roles of Piezo protein in the digestive system is of paramount importance. In this review, we systematically summarize the structural and dynamic characteristics of Piezo protein, its expression patterns, and physiological functions in the digestive system. We particularly focus on elucidating the mechanisms of action of Piezo protein in digestive system tumor diseases, inflammatory diseases, fibrotic diseases, and functional disorders. Through the integration of the latest research findings, we have observed that Piezo protein plays a crucial role in the pathogenesis of various digestive system diseases. There exist intricate interactions between Piezo protein and multiple phenotypes of digestive system tumors such as proliferation, apoptosis, and metastasis. In inflammatory diseases, Piezo protein promotes intestinal immune responses and pancreatic trypsinogen activation, contributing to the development of ulcerative colitis, Crohn’s disease, and pancreatitis. Additionally, Piezo1, through pathways involving co-action with the TRPV4 ion channel, facilitates neutrophil recruitment and suppresses HIF-1α ubiquitination, thereby mediating organ fibrosis in organs like the liver and pancreas. Moreover, Piezo protein regulation by gut microbiota or factors like age and gender can result in increased or decreased visceral sensitivity, and alterations in intestinal mucosal barrier structure and permeability, which are closely associated with functional disorders like irritable bowel sydrome (IBS) and functional consitipaction (FC). A thorough exploration of Piezo protein as a potential therapeutic target in digestive system diseases can provide a scientific basis and theoretical support for future clinical diagnosis and treatment strategies.

Objective:To explore the application value of posture adaptation training combined with continuous pas-sive exercise rehabilitation for patients after coronary artery bypass grafting(CABG).Methods:A total of 100 pa-tients with coronary heart disease(CHD)undergoing CABG in our hospital were enrolled,divided into single group(n=50,received single continuous passive exercise rehabilitation intervention)and combined group(n=50,re-ceived posture adaptation training based on single group)according to color grouping method.Both groups were in-tervened for two months.Clinical indexes,cardiac function indexes,cognitive function,exercise endurance,serum levels of neuron specific enolase(NSE),S-100β protein and satisfaction were analyzed and compared between two groups.Results:Compared with single group after intervention,there were significant reductions in first out of bed time,first anal exhaust time and length of hospital stay,and significant rise in left ventricular ejection fraction(LVEF),cardiac index(CI),left ventricular fractional shortening(LVFS),score of Montreal cognitive assessment(MoCA)scale,6min walking distance,and significant reductions in serum levels of NSE[(19.93±1.90)μg/L vs.(16.59±2.25)μg/L]and S-100β protein[(6.72±0.34)μg/L vs.(3.96±0.19)μg/L]in combined group,P=0.001 all.Satisfaction in combined group was significantly higher than that of single group(94.00％vs.80.00％,P=0.037).Conclusion:Posture adaptation training combined with continuous passive exercise rehabilitation can sig-nificantly improve the clinical indexes,promote cardiopulmonary function and cognitive function recovery in pa-tients undergoing coronary artery bypass grafting after operation.

Objective To assess the risk factors for carbapenem-resistant Acinetobacter baumannii(CRAB)bloodstream infection(BSI)and 28-day short-term mortality in elderly patients,and provide reference for the pre-vention and treatment of CRAB BSI.Methods Clinical data of patients aged ≥60 years and diagnosed with AB BSI in a hospital in Yulin City from January 2013 to December 2022 were retrospectively analyzed,including demogra-phic and microbiological characteristics,as well as clinical outcomes of the patients.Variables which were significant in univariate analysis were selected for multivariate analysis using binary logistic regression model and Cox propor-tional hazards model.Independent risk factors for infection were further determined,and survival analysis was per-formed using Kaplan-Meier curve.Results A total of 150 patients were included in the study,out of which 16 pa-tients(10.7％)had CRAB BSI and 134 had carbapenem-sensitive AB(CSAB)BSI.The 28-day short-term mortali-ty of AB BSI in elderly patients was 15.3％(23/150,95％CI:9.6％-21.1％),and the short-term mortality of CRAB BSI was higher than that of CSAB([56.3％,9/16]vs[10.4％,14/134]).Deep venous catheterization(OR:15.598,95％CI:1.831-132.910)and combined infections of other sites(OR:15.449,95％CI:1.497-159.489)were related to CRAB BSI in elderly patients.The independent risk factors for 28-day mortality in elderly patients with AB BSI were hemodialysis(OR:11.856,95％CI:2.924-48.076),intensive care unit admission(OR:9.387,95％CI:1.941-45.385),and pulmonary infection being suspected source of bacteremia(OR:7.019,95％CI:1.345-36.635).Conclusion The occurrence of CRAB BSI in elderly patients is related to the combined infection of other sites and deep vein catheterization.Hemodialysis,admission to ICU,and pulmonary infection being suspected source of bacteremia are independent risk factors for the prognosis of AB BSI in elderly patients.

Professor ZHOU Peng has deeply discussed the pathological characteristics of psoriasis vulgaris,emphasizing that the disease is usually manifested deficiency interweaved with excess,leading to frequent recurrence and persistent refractory,which may lead to psychological and emotional problems of patients.This paper further expounds the effect of blood stasis on the pathogenesis,progression and prognosis of psoriasis,and puts forward a new method of combining Lingnan fire needling and filiform needling acupuncture technique to treat psoriasis vulgaris with blood stasis syndrome.Professor ZHOU Peng believes that the treatment principle of this disease is"regulating the mind first,rectifying blood as a base,syndrome differentiating and eliminating pathogenic factors",aiming at comprehensively considering the etiology and symptoms,in order to achieve more effective treatment results.Combined with the analysis of dermoscopic signs,it provides a possible improvement direction for the treatment of psoriasis vulgaris from a new perspective.

Objective To develop a portable collection device of human exhaled breath condensate(EBC)based on natural breathing to meet the needs for rapid screening of human respiratory tract(especially lower respiratory tract)infections.Methods The device consisted of a refrigeration unit,a heat dissipation unit and a condensation unit.The refrigeration unit adopted a TES1-7102 thermoelectric Peltier cooler semiconductor as the refrigeration element;the heat dissipation unit was composed of a high thermal conductivity aluminum heat sink and a high-speed brushless cooling fan;the condensation unit was made up of a cold guide plate and a condenser,in which the cold guide plate was made of thin sheet of aluminum alloy,and the condenser was prepared by 3D printing technology and made of hydrophobic polylactic acid,with primary and secondary 2-stage guide grooves and an ultra-thin condensing surface.The performance of the device was verified in terms of cooling,thermal conductivity,condensation and human EBC collection and content analysis.Results Performance analysis showed that after refrigeration began the temperature difference between the condenser surface and the exhaled gas met the requirements of the condenser,and no obvious thermal resistance was found on the condensing surface so that large droplets could be formed rapidly and then be collected after the gas-liquid phase change of the exhaled gas on the condensing surface.Human EBC collection and content analysis indicated the device realized home self-collection of EBCs from people of all ages,and the concentrations of interleukins,C-reactive protein and other inflammation-related indexes and the pH value of the collected EBC samples were all correlated with respiratory infections in the subjects.Conclusion The device developed with easy operation avoids the discomfort of blowing collection and the risk of saliva contamination,and is worthy promoting for rapid diagnosis and dynamic monitoring of respiratory tract infection and other related diseases.[Chinese Medical Equipment Journal,2024,45(8):32-37]

Methamphetamine abuse is a major public health problem in the world,and in recent years,methamphetamine is also the most abused synthetic drug in China.The neurotoxic or addiction mechanism of methamphetamine has not been fully clarified,and there is still a lack of specific withdrawal methods and drugs for methamphetamine abuse.Mitochondria are not on-ly the organelles to which methamphetamine directly produces toxic effects,but also participate in regulating the neurotoxic damage process of methamphetamine.Mitochondrial quality is the regulatory basis for maintaining mitochondrial homeostasis and is regulated by three main mechanisms,which are mitochon-drial biogenesis,mitochondrial dynamic,and mitophagy.This review summarizes the research progress of mitochondrial quality control in methamphetamine-induced neurotoxicity,which may provide theoretical support for further research on the mechanism of methamphetamine neurotoxicity and development the mito-chondria-targeting drugs.

Objective To analyze the genetic subtypes of human immunodeficiency virus (HIV) and the prevalence of pretreatment drug resistance in the newly reported HIV-infected men in Guangxi. Methods The stratified random sampling method was employed to select the newly reported HIV-infected men aged≥50 years old in 14 cities of Guangxi from January to June in 2020.The pol gene of HIV-1 was amplified by nested reverse transcription polymerase chain reaction and then sequenced.The mutation sites associated with drug resistance and the degree of drug resistance were then analyzed. Results A total of 615 HIV-infected men were included in the study.The genetic subtypes of CRF01_AE,CRF07_BC,and CRF08_BC accounted for 57.4% (353/615),17.1% (105/615),and 22.4% (138/615),respectively.The mutations associated with the resistance to nucleoside reverse transcriptase inhibitors (NRTI),non-nucleoside reverse transcriptase inhibitors (NNRTI),and protease inhibitors occurred in 8 (1.3%),18 (2.9%),and 0 patients,respectively.M184V (0.7%) and K103N (1.8%) were the mutations with the highest occurrence rates for the resistance to NRTIs and NNRTIs,respectively.Twenty-two (3.6%) patients were resistant to at least one type of inhibitors.Specifically,4 (0.7%),14 (2.3%),4 (0.7%),and 0 patients were resistant to NRTIs,NNRTIs,both NRTIs and NNRTIs,and protease inhibitors,respectively.The pretreatment resistance to NNRTIs had much higher frequency than that to NRTIs (2.9% vs.1.3%;χ²=3.929,P=0.047).The prevalence of pretreatment resistance to lamivudine,zidovudine,tenofovir,abacavir,rilpivirine,efavirenz,nevirapine,and lopinavir/ritonavir was 0.8%, 0.3%, 0.7%, 1.0%, 1.3%, 2.8%, 2.9%, and 0, respectively. Conclusions CRF01_AE,CRF07_BC,and CRF08_BC are the three major strains of HIV-infected men≥50 years old newly reported in Guangxi,2020,and the pretreatment drug resistance demonstrates low prevalence.
Male ; Humans ; Middle Aged ; Reverse Transcriptase Inhibitors/therapeutic use* ; HIV Infections/drug therapy* ; Drug Resistance, Viral/genetics* ; China/epidemiology* ; Mutation ; HIV-1/genetics* ; Protease Inhibitors/therapeutic use* ; Genotype

OBJECTIVE: To investigate the clinical efficacy of posterior cervical pedicle screw short-segment internal fixation for the treatment of atlantoaxial fracture and dislocation. METHODS: The clinical data of 60 patients with atlantoaxial vertebral fracture and dislocation underwent surgery between January 2015 and January 2018 were retrospectively analyzed. The patients were divided into study group and control group according to different surgical methods. There were 30 patients in study group, including 13 males and 17 females, with an average age of (39.32±2.85) years old, were underwent short-segment internal fixation with posterior cervical pedicle screws. There were 30 patients in control group, including 12 males and 18 females, with an average age of (39.57±2.90) years old, were underwent posterior lamina clip internal fixation of the atlas. The operation time, intraoperative blood loss, postoperative ambulation time, hospitalization time and complications between two groups were recorded and compared. The pain visual analogue scale(VAS), Japanese Orthopedic Association(JOA) score of neurological function, and fusion status were evaluated between two groups. RESULTS: All patients were followed up for at least 12 months. The study group was better than control group in operation time, intraoperative blood loss, postoperative off-bed activity time, and hospital stay (P=0.000). One case of respiratory tract injury occurred in study group. In control group, 2 cases occurred incision infection, 3 cases occurred respiratory tract injury, and 3 cases occurred adjacent segmental joint degeneration. The incidence of complications in study group was lower than that in control group (χ²=4.705, P=0.030). At 1, 3, 7 days after operation, VAS of study group was lower than that of control group(P=0.000). At 1, 3 months after operation, JOA score of study group was higher than that of control group(P=0.000). At 12 months after operation, all the patients in the study group achieved bony fusion. In control group, there were 3 cases of poor bony fusion and 3 cases of internal fixation fracture, the incidence rate was 20.00%(6/30). The difference between two groups was statistically significant (χ²=4.629, P=0.031). CONCLUSION Posterior cervical short-segment pedicle screw fixation for atlantoaxial fracture and dislocation has the advantages of less trauma, shorter operation time, fewer complications, and less pain, and can promote the recovery of nerve function as soon as possible.
Male ; Female ; Humans ; Adult ; Pedicle Screws ; Retrospective Studies ; Fractures, Bone ; Fracture Fixation, Internal/methods* ; Joint Dislocations/surgery* ; Spinal Fractures/surgery* ; Treatment Outcome ; Postoperative Hemorrhage

Objective: To explore the value of cardiac magnetic resonance imaging (CMR) in the risk stratification of hypertrophic cardiomyopathy (HCM). Methods: HCM patients who underwent CMR examination in Fuwai Hospital between March 2012 and May 2013 were retrospectively enrolled. Baseline clinical and CMR data were collected and patient follow-up was performed using telephone contact and medical record. The primary composite endpoint was sudden cardiac death (SCD) or and equivalent event. The secondary composite endpoint was all-cause death and heart transplant. Patients were divided into SCD and non-SCD groups. Cox regression was used to explore risk factors of adverse events. Receiver operating characteristic (ROC) curve analysis was used to assess the performance and the optimal cut-off of late gadolinium enhancement percentage (LGE%) for the prediction of endpoints. Kaplan-Meier and log-rank tests were used to compare survival differences between groups. Results: A total of 442 patients were enrolled. Mean age was (48.5±12.4) years and 143(32.4%) were female. At (7.6±2.5) years of follow-up, 30 (6.8%) patients met the primary endpoint including 23 SCD and 7 SCD equivalent events, and 36 (8.1%) patients met the secondary endpoint including 33 all-cause death and 3 heart transplant. In multivariate Cox regression, syncope(HR=4.531, 95%CI 2.033-10.099, P<0.001), LGE% (HR=1.075, 95%CI 1.032-1.120, P=0.001) and left ventricular ejection fraction (LVEF) (HR=0.956, 95%CI 0.923-0.991, P=0.013) were independent risk factors for primary endpoint; Age (HR=1.032, 95%CI 1.001-1.064, P=0.046), atrial fibrillation (HR=2.977, 95%CI 1.446-6.131, P=0.003),LGE% (HR=1.075, 95%CI 1.035-1.116, P<0.001) and LVEF (HR=0.968, 95%CI 0.937-1.000, P=0.047) were independent risk factors for secondary endpoint. ROC curve showed the optimal LGE% cut-offs were 5.1% and 5.8% for the prediction of primary and secondary endpoint, respectively. Patients were further divided into LGE%=0, 0P<0.001) and the accumulated incidence of primary endpoint was 1.2% (2/161), 2.2% (2/89), 10.5% (16/152) and 25.0% (10/40), respectively. Conclusion: LGE is an independent risk factor for SCD events as well as all-cause death and heart transplant. LGE is of important value in the risk stratification in patients with HCM.
Humans ; Female ; Adult ; Middle Aged ; Male ; Contrast Media ; Retrospective Studies ; Stroke Volume ; Gadolinium ; Ventricular Function, Left ; Magnetic Resonance Imaging ; Cardiomyopathy, Hypertrophic/diagnostic imaging* ; Death, Sudden, Cardiac ; Risk Assessment