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.

This article introduced the basic theory of non-parametric regression and its application in medical and public health research for methodological reference.We conducted Cox proportional hazard models with restricted cubic splines using chronic disease management data from a Center for Disease Control and Prevention.We aimed to explore the separate and combined effects of mean fasting blood glucose level and glucose variability on all-cause mortality among individuals with type 2 diabetes.A non-linear association was observed between glucose variability and the risk of all-cause mortality.The association between glucose variability and all-cause mortality was stronger at higher mean fasting blood glucose levels compared to lower levels.The non-parametric regression methods comprehensively explored dose-response relationships between continuous exposure and outcome,revealing the combined effects of continuous exposures,which provided recommendations for targeted interventions.The method showed promising application value in medical and public health research.

Nanozyme is novel nanoparticle with enzyme-like activity, which can be classified into peroxidase-like nanozyme, catalase-like nanozyme, superoxide dismutase-like nanozyme, oxidase-like nanozyme and hydrolase-like nanozyme according to the type of reaction they catalyze. Since researchers first discovered Fe₃O₄ nanoparticles with peroxidase-like activity in 2007, a variety of nanoparticles have been successively found to have catalytic activity and applied in bioassays, inflammation control, antioxidant damage and tumor therapy, playing a key role in disease diagnosis and treatment. We summarize the use of nanozymes with different classes of enzymatic activity in the diagnosis and treatment of diseases and describe the main factors influencing nanozyme activity. A Mn-based peroxidase-like nanozyme that induces the reduction of glutathione in tumors to produce glutathione disulfide and Mn²⁺, which induces the production of reative oxygen species (ROS) in tumor cells by breaking down H₂O₂ in physiological media through Fenton-like action, thereby inhibiting tumor cell growth. To address the limitation of tumor tissue hypoxia during photodynamic tumor therapy, the effect of photodynamic therapy is significantly enhanced by using hydrogen peroxide nanozymes to catalyze the production of oxygen from H₂O₂. In pathological states, where excess superoxide radicals are produced in the body, superoxide dismutase-like nanozymes are able to selectively regulate intracellular ROS levels, thereby protecting normal cells and slowing down the degradation of cellular function. Based on this principle, an engineered nanosponge has been designed to rapidly scavenge free radicals and deliver oxygen in time to save nerve cells before thrombolysis. Starvation therapy, in which glucose oxidase catalyzes the hydrolysis of glucose to gluconic acid and hydrogen peroxide in cancer cells with the involvement of oxygen, attenuates glycolysis and the production of intermediate metabolites such as nucleotides, lipids and amino acids, was used to synthesize an oxidase-like nanozyme that achieved effective inhibition of tumor growth. Furthermore, by fine-tuning the Lewis acidity of the metal cluster to improve the intrinsic activity of the hydrolase nanozyme and providing a shortened ligand length to increase the density of its active site, a hydrolase-like nanozyme was successfully synthesized that is capable of cleaving phosphate bonds, amide bonds, glycosidic bonds and even biofilms with high efficiency in hydrolyzing the substrate. All these effects depend on the size, morphology, composition, surface modification and environmental media of the nanozyme, which are important aspects to consider in order to improve the catalytic efficiency of the nanozyme and have important implications for the development of nanozyme. Although some progress has been made in the research of nanozymes in disease treatment and diagnosis, there are still some problems, for example, the catalytic rate of nanozymes is still difficult to reach the level of natural enzymes in vivo, and the toxic effects of some heavy metal nanozymes material itself. Therefore, the construction of nanozyme systems with multiple functions, good biocompatibility and high targeting efficiency, and their large-scale application in diagnosis and treatment is still an urgent problem to be solved. (1) To improve the selectivity and specificity of nanozymes. By using antibody coupling, the nanoparticles are able to specifically bind to antigens that are overexpressed in certain cancer cells. It also significantly improves cellular internalization through antigen-mediated endocytosis and enhances the enrichment of nanozymes in target tissues, thereby improving targeting during tumor therapy. Some exogenous stimuli such as laser and ultrasound are used as triggers to control the activation of nanozymes and achieve specific activation of nanozyme. (2) To explore more practical and safer nanozymes and their catalytic mechanisms: biocompatible, clinically proven material molecules can be used for the synthesis of nanoparticles. (3) To solve the problem of its standardization and promote the large-scale clinical application of nanozymes in biomonitoring. Thus, it can go out of the laboratory and face the market to serve human health in more fields, which is one of the future trends of nanozyme development.

Objective:To investigate the associations of onset age, diabetes duration, and glycated hemoglobin (HbA1c) levels with ischemic stroke risk in type 2 diabetes patients.Methods:The participants were from Comprehensive Research on the Prevention and Control of the Diabetes in Jiangsu Province. The study used data from baseline survey from December 2013 to January 2014 and follow-up until December 31, 2021. After excluding the participants who had been diagnosed with stroke at baseline survey and those with incomplete information on onset age, diabetes duration, and HbA1c level, a total of 17 576 type 2 diabetes patients were included. Cox proportional hazard model was used to calculate the hazard ratio ( HR) and 95% CI of onset age, diabetes duration, and HbA1c level for ischemic stroke. Results:During the median follow-up time of 8.02 years, 2 622 ischemic stroke cases were registered. Multivariate Cox proportional risk regression model showed that a 5-year increase in type 2 diabetes onset age was significantly associated with a 5% decreased risk for ischemic stroke ( HR=0.95, 95% CI: 0.92-0.99). A 5-year increase in diabetes duration was associated with a 5% increased risk for ischemic stroke ( HR=1.05, 95% CI: 1.02-1.10). Higher HbA1c (per 1 standard deviation increase: HR=1.17, 95% CI: 1.13-1.21) was associated with an increased risk for ischemic stroke. Conclusion:The earlier onset age of diabetes, longer diabetes duration, and high levels of HbA1c are associated with an increased risk for ischemic stroke in type 2 diabetes patients.

Objective To explore the feasibility of electrical impedance tomography(EIT)for real-time and accurate monitoring of respiration during HP anti-G movements and the key parameters of pulmonary ventilation.Methods Twelve healthy male students in our university were enrolled in September 2023 and subjected in this study.HP anti-G movements were performed 3 times each for 30 s in the anti-G physiological training apparatus,during which EIT and ophthalmic horizontal arterial pressure were measured to analyze the relationship of the global and local parameters of pulmonary ventilation,including inspiratory volume(IV),expiratory uniform(EU),expiratory speed(ES),center of ventilation(COV)and right-to-left lung ventilation ratio(RtoL)with anti-G ability of anti-G straining maneuver(AGSM).Results The average eye horizontal systolic blood pressure(SBP)at the eye level was 148.82±22.75 mmHg during HP anti-G movements,which was significantly higher than that during quiet breathing(PJ)(95.17±8.51 mmHg,P＜0.001).From the global pulmonary ventilation,the participants had significantly increased IV during HP anti-G movements(P＜0.001).According the d value(mean increase of eye horizontal SBP=SBPHP-SBPPJ),the subjects were divided into 3 groups,with the d value of＞60,30～60 and＜30 mmHg,respectively.The inspiratory volume ratio(IVHP/IVPJ)was the highest in the＞60 mmHg group and the smallest in the＜30 mmHg group(P＜0.01).The subjects had significantly decreased EU and more evenly expiration(P＜0.05),but no change was seen in the expiratory uniformity ratio(EUHP/EUPJ)among the 3 groups.ES was obviously faster during HP anti-G movements(P＜0.001),and the expiratory speed ratio(ESHP/ESPJ)had no significant difference among the 3 groups.The inspiratory time and expiratory time were 0.77±0.32 and 1.59±0.21 s,respectively,and both of them were notably shorter during HP anti-G movements(P＜0.001,P＜0.01).From the local pulmonary ventilation,COV during HP anti-G movements was significantly smaller than that during PJ(P＜0.001),and the ventilation center deviated to the ventral side,and RtoL was decreased and the ventilation distribution deviated to the left lung(P＜0.05).Conclusion EIT can perform real-time imaging of pulmonary global and local ventilation during HP anti-G movements,and it has a great application prospect in AGSM training and monitoring.

Objective:To compare the perioperative outcomes of laparoscopic duodenal-preserving pancreatic head resection(LDPPHR) with laparoscopic pancreaticoduodenectomy(LPD) in the treatment of borderline and benign diseases of the pancreatic head.Methods:This is a retrospective cohort study. Perioperative data from 87 patients with non-malignant pancreatic head diseases who underwent LDPPHR or LPD were retrospectively collected in the Department of Biliary-Pancreatic Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from January 2020 to December 2022. There were 49 male and 38 female patients with an age ( M(IQR)) of 57.0(16.5) years (range: 20 to 75 years). Forty patients underwent LDPPHR and 47 patients underwent LPD. Quantitative data following a normal distribution were compared using Student′s t-test, while quantitative data not following a normal distribution were compared using the Mann-Whitney U test. Comparisons of categorical or ordinal variables were made using χ2 test or Fisher′s exact test. Logistic regression analysis was used to estimate the risk factors associated with the rate of complications. Results:There were no statistically significant differences between the LDPPHR group and the LPD group in terms of reoperation rate,total hospital stay duration,postoperative hospital stay duration,90-day mortality rate,30-day and 90-day readmission rates,and 2-year tumor recurrence rate (all P>0.05). The complication rate was higher in the LDPPHR group compared to the LPD group (80.0%(32/40) vs. 51.1%(24/47), χ2=7.89, P=0.005),but there was no difference in the rate of Clavien-Dindo classification of surgical complications ≥Ⅲ between the two groups (10.0%(4/40) vs. 12.8%(6/47), χ2<0.01, P=0.947). Additionally,the rate of delayed gastric emptying (DGE) was higher in the LDPPHR group compared to the LPD group ( χ2=10.79, P=0.001),but there was no statistically significant difference in the rate of B,C grade DGE between the two groups ( χ2=0.48, P=0.487). There were no statistically significant differences in the rates of postoperative pancreatic fistula,bile leakage,post-pancreatectomy hemorrhage,intra-abdominal infection,and pulmonary infection between the two groups (all P>0.05). The results of the univariate logistic regression analysis showed that LDPPHR (compared to LPD, OR=3.83, 95% CI: 1.46 to 10.04, Z=2.73, P=0.006) and preoperative biliary stent placement (compared to non-use of biliary stent, OR=5.30, 95% CI: 1.13 to 25.00, Z=2.11, P=0.035) were risk factors for the complication rate,but neither was an independent risk factor for complication rate (all P>0.05). Conclusion:The preliminary results suggest that LDPPHR can achieve perioperative safety and effectiveness comparable to LPD.

Objective To study the effect of Qingke Pingchuan Granule on the clinical efficacy in patients with phlegm-heat obstructing lung syndrome(AECOPD).Methods A total of 80 patients with acute exacerbation of chronic obstructive pulmonary disease(syndrome of phlegm-heat stagnation in the lung)hospitalized in the respiratory department of our hospital were selected and divided into the conventional group and the combinational group,with 40 cases in each group.The CAT score,TCM syndrome score,serum IL-6,CRP,lung function FEV1%pred,and FEV1/FVC were retrospectively observed before treatment,at the end of the second week of treatment,and at the follow-up after 1 month of treatment in the two groups.Results The total effective rate was significantly better in the combinational group than that of the conventional group(92.5%vs.75.0%,P＜0.05).At the end of the second week of treatment,the CAT score,each single syndrome score,serum IL-6 and CRP levels were all improved than those before treatment in the two groups(P＜0.05),and the improvement degree was better in the combined group than that of the conventional group(P＜0.05).The severity of airflow limitation and respiratory failure were significantly improved compared with those before treatment in both groups.At the follow-up after 1 month of treatment,the recovery rate of scores of each single syndrome score and CAT score were significantly lower in the combined group than those in the routine group(P＜0.05).There were no significant differences in adverse drug reactions between the two groups(12.5%and 2.5%,P＞0.05).Conclusion Qingke Pingchuan Granule can effectively relieve the symptoms and improve lung function and the quality of life of AECOPD patients.

Hemophilia encompasses a group of hereditary bleeding disorders characterized by impaired clotting factor activity,leading to prolonged clotting times.Patients display a tendency toward clotting issues following minor injuries,and severe cases may experience spontaneous bleeding.Acquired von Willebrand syndrome(AvWS)occurs due to the reduction of von Willebrand factor(vWF)levels,resulting in impaired platelet adhesion to endothelial cells,thereby compromising clotting function and leading to bleeding events.The increasing use of extracorporeal membrane oxygenation(ECMO)in clinical settings has brought attention to ECMO-related AvWS.During ECMO support,patients'blood exposure to high shear forces and non-physiological conditions can exacerbate the reduction of vWF levels,further impacting coagulation function.The precise mechanisms triggering AvWS during ECMO support are not conclusively defined,however,studies indicate that high shear forces and systemic inflammation response syndrome(SIRS)are key factors.Mechanical shear stress induced by ECMO damages endothelial cells,releasing factors associated with von Willebrand disease(vWD).Additionally,ECMO-induced SIRS may further compromise vWF functionality.Understanding these mechanisms is crucial for formulating effective preventive and treatment strategies.Diagnosing AvWS during ECMO support can be complex.Typically,assessing a patient's coagulation function and related factor levels is necessary,while cautious interpretation is vital due to potential ECMO interferences.Treatment strategies for managing AvWS during ECMO support are still under investigation.Some studies suggest that using plasma products may improve coagulation function.However,specific treatment approaches should be tailored to individual patient conditions and adjusted based on close monitoring.In summary,diagnosing and treating AvWS during ECMO support remains complex and challenging.Further research holds promise for better understanding the mechanisms involved and for developing more effective treatment strategies to enhance patient prognosis and quality of life.

Objective:To evaluate the long-term constancy of image uniformity and noise of cone-beam computed tomography (CBCT) for the on-board imager (OBI) system of a Varian linac.Methods:Monthly quality assurance (QA) tests were carried out for the OBI system of a Clinac iX linac, and CBCT images of Catphan 504 phantom were obtained with six scanning protocols. The 6 protocols were high-quality head (HQH), low-dose head (LDH), pelvis spot light (PSL), standard-dose head (SDH), low-dose thorax (LDT) and pelvis, respectively. The 144 series of CBCT images acquired from Nanjing First Hospital, Nanjing Medical University between January 2020 and December 2021 were analyzed, and the data of image uniformity and noise were obtained by delineating regions of interest (ROI) in the images of CTP486 module. Image uniformity was expressed by the absolute value of the maximum difference between the average CT value of the ROI in the 3, 6, 9 and 12 o'clock directions and the central ROI. Image noise was expressed by the standard deviation of CT value of large circular ROI. The smaller the values of image uniformity and noise, the better the image quality. Statistical description was applied to obtain data of the maximum, minimum, mean and standard deviation for the above mentioned two parameters. Y was defined as the difference between the average CT value of ROI in each direction and the average CT value of central ROI, which was used to represent the monthly changes of image quality.Results:The image uniformity and noise of CBCT images of the OBI system were generally stable during 2 years. For the 6 protocols of HQH, LDH, PSL, SDH, LDT and pevlis, the image uniformity was (21.5±1.0), (21.4±2.2), (21.3±0.9), (18.3±1.3), (3.4±1.9) and (7.2±1.9) HU, respectively. The image noise was (19.2±0.2), (41.0±0.3), (14.2±0.3), (38.2±0.2), (16.0±0.9) and (13.5±0.9) HU, respectively. The average image uniformity of LDT was the smallest, and the average image noise of pelvis was the smallest. Under the 6 scanning protocols, the average CT values of central ROI involved in image uniformity were (32.3±2.7), (24.0±3.3), (19.3±2.4), (11.1±2.5), (67.2±2.1), (-24.6±1.7) HU, respectively. The average CT values were stable. The standard deviation of Y was < 3 HU, suggesting that the stability of image quality was favorable every month.Conclusions:The image uniformity and noise of CBCT images for the OBI system are generally stable in 2 years. Among the 6 scanning protocols, LDT yields the best image uniformity, and pelvis has the lowest image noise.

Objective To investigate the correlation between the level of N-terminal pro-Brain natriuretic peptide(NT-proBNP)and cardiorespiratory fitness following acute exposure to high altitude.Methods Forty-six subjects were recruited from the Second Affiliated Hospital of Army Medical University in June 2022,including 19 males and 27 females.After completing cardiopulmonary exercise test(CPET),serological detection of myocardial cell-related markers,and multiple metabolites at a plain altitude(300 meters above sea level),all subjects flew to a high-altitude location(3900 meters above sea level).Biomarker testing and CPET were repeated on the second and third days after arrival at high altitude.Changes in serum biomarker and key CPET indicators before and after rapid ascent to high altitude were compared,and the correlation between serum levels of various myocardial cell-related markers and metabolites and high altitude cardiorespiratory fitness was analyzed.Results Compared with the plain altitude,there was a significant decrease in maximal oxygen uptake after rapid ascent to high altitude[(25.41±6.20)ml/(kg.min)vs.(30.17±5.01)ml/(kg.min),P<0.001].Serum levels of NT-proBNP,Epinephrine(E),plasma renin activity(PRA),angiotensin Ⅱ(Ang Ⅱ),angiotensin-converting enzyme 2(ACE2)and leptin(LEP)significantly increased,with all differences being statistically significant(P<0.05)after acute high altitude exposure.In contrast,no statistically significant differences were observed for creatine kinase MB(CK-MB),cardiac troponin I(cTnI),myoglobin(Myo)and norepinephrine(NE)(P>0.05).Correlation analysis showed a significant negative correlation between NT-proBNP at plain altitude(r=-0.768,P<0.001)and at high altitude(r=-0.791,P<0.001)with maximal oxygen uptake at high altitude.Multivariate linear regression analysis indicated that maximal oxygen uptake at plain altitude(t=2.069,P=0.045),NT-proBNP at plain altitude(t=-2.436,P=0.020)and at high altitude(t=-3.578,P=0.001)were independent influencing factors of cardiorespiratory fitness at high altitude.Conclusion Cardiorespiratory fitness significantly decreases after rapid ascent to high altitude,and the baseline NT-proBNP level at plain altitude is closely related to cardiorespiratory fitness at high altitude,making it a potential predictor indicator for high altitude cardiorespiratory fitness.