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 investigate the current status of frailty in patients on maintenance hemodialysis(MHD),and explore the correlation of frailty with anxiety and depression.Methods General information,clinical data and blood biochemical data of 101 cases who underwent MHD in Department of Nephrology,Shunde Hospital Affiliated to Jinan University from January 2023 to January 2024 were collected.FRAIL scale was applied to evaluate the frailty of the patients,and they were accordingly classified into frailty group and non-frailty group(including pre-frail and non-frail participants).Anxiety and depression were evaluated by GAD-7 and PHQ-9 scale.Univariate analysis and logistic regression were used to explore the association of frailty with anxiety,depression and other possible influencing factors.Results Among the 101 cases,29 cases(28.71%)were includedin frailty group and 72 cases(71.29%)in non-frailty group.There were 42 patients with depression(41.58%)and 25 with anxiety(24.75%).In the frailty group,the prevalence of depression was 65.52%and that of anxiety 55.17%.There were significant differences in age,grip strength,exercise,stroke and coronary heart disease,anxiety and depression,ferritin and CRP between the two groups(P＜0.01).Multivariate regression analysis showed that depression,anxi-ety,no exercise,stroke and high ferritin concentration were independent risk factors for frailty in MHD patients(P＜0.05).Conclusion In patients on MHD,frailty is closely associated with depression,anxiety,and lack of exercise,and stroke as well as high ferritin concentration are independent risk factors for frailty.

Objective　To investigate the expression of protein tyrosine kinase 2 (MFGE8) in patients with ischemic brain injury (IBI) and its regulation on macrophage polarization.Methods　ELISA was used to detect the expression of MFGE8 protein in peripheral blood of patients with ischemic stroke and middle cerebral artery occlusion (MCAO) rat models;IF was used to detect the localization and expression of MFGE8 in brain;BV-2 microglia was treated with the culture supernatant of N2a neuronal cells (Mfge8CA) stably transformed with Mfge8.The polarization ratio of macrophages was detected by flow cytometry.Western blot detection Mfge8,αv/β 3-integrin,FAK,NF-κB.ERK1/2,JNK1/2,P38,PI3K,AKT,mTOR protein expression.Results　The relative content of MFGE8 in peripheral blood of IBI patients and MCAO model rats was significantly lower than that of the control group (Ctrl,P=0.0446,P=0.0259).MFGE8 was highly co-localized with neuron cell marker (NeuN);the proportion of M1 type (CD45+F4/80+iNOS+Arginase1-) macrophages in the brain tissue of MCAO model was significantly higher than that in the Ctrl (P=0.0004).The proportion of M2 type (CD45+F4/80+iNOS-Arginase1+) macrophages was significantly lower than that of the Ctrl (P<0.0001).The proportion of M1 macrophages of BV-2 microglia after supernatant of N2a (mfge8CA) treatment was significantly lower than that of Wild type (WT,P=0.0230).The proportion of M2 macrophages was significantly higher (P<0.0001).The protein expressions of α v/β3-integrin,FAK,p-P85,P85,p-AKT (Ser473),p-mTOR (Ser2481) and p-mTOR (Ser2488) in BV-2 microglia after supernatant of N2a (mfge8CA) treatment were significantly higher than those in WT group.The expression of p-P65 protein was significantly lower than that in WT group.Conclusion　MFGE8 is highly expressed in peripheral blood of patients with IBI.MFGE8 derived from neuronal cells may promote BV-2 microglia M2 macrophages polarization by activating PI3K/AKT/mTOR signals,and inhibit the polarization of M1 macrophages.

Objective:To observe and compare the changes of pulmonary function in patients with pulmonary tuberculosis regular treatment for 3 months.Methods:From April 2018 to June 2019, 500 tuberculosis patients who received regular anti tuberculosis treatment in our hospital were selected.The pulmonary function of patients with pulmonary tuberculosis was measured before treatment and at the end of three months; the results of pulmonary ventilation function, lung volume, diffusing capacity, and the value of forced vital capacity (FVC), maximum expiratory volume in 1 second (FEV 1), maximum expiratory volume in 1 second/forced vital capacity (FEV 1/FVC), total lung volume (TLC), residual volume (RV), carbon monoxide diffusing capacity (D LCO) were compared. Results:252 patients with pulmonary tuberculosis were included. Before treatment and at the end of three months, the abnormal pulmonary function results were 204 cases (80.95%) and 193 cases (76.59%), respectively, and the difference was not statistically significant ( P>0.05). Among them, abnormal pulmonary ventilation function is the most common, especially with obstructive, followed by abnormal diffusing capacity. At the end of three months, the proportions of patients with normal pulmonary ventilation function and normal lung volume were higher than that before treatment ( P<0.05), but there was no significant difference in the proportion of normal diffusing capacity before and after treatment ( P>0.05). The values of FVC, FEV 1, TLC and D LCO at the end of three months were higher than those before treatment, and the difference was statistically significant ( t=-6.414, -6.754, -3.863, -3.311, all P<0.01). Conclusions:Most patients with pulmonary tuberculosis have abnormal pulmonary function. At the end of the three months treatment, the normal rates of the pulmonary ventilation function and lung volume as well as the values of FVC, FEV 1, TLC and D LCO in patients with pulmonary tuberculosis were significantly improved compared with those before treatment.

Objective:To explore the application effect of timed, step-by-step and segmented sputum suction in airway management of patients with inhalation injury.Methods:From January 2017 to December 2019, 104 patients with inhalation injury admitted to the Department of Burns and Plastic Surgery, the Fourth Medical Center of the PLA General Hospital were selected as research objects. A non-randomized controlled study was adopted, and the patients were divided into control group ( n=49) and experimental group ( n=55) according to the single and even day of admission. The control group received the routine sputum suction, and the experimental group received the method of timed, step-by-step and segmented sputum suction. We compared the general information, incidence of lung infection and the number of daily sputum suction of patients between the two groups. Results:There was no statistically significant difference in the general information of patients between the two groups ( P>0.05) . The incidence of lung infection in the experimental group was 29.09% (16/55) , which was lower than 51.02% (25/49) in the control group with a statistically significant difference ( P<0.05) . In the experimental group, the number of daily sputum suction for patients with tracheotomy was 6 (3, 6) times, the number of daily sputum suctions for patients without tracheotomy was 1 (1, 2) times, and the number of daily sputum suctions for patients with severe inhalation injury was (6.56±2.96) times, which were less than 14 (11, 19) , 3 (3, 7) , (15.40±3.75) times respectively in the control group, and the differences were statistically significant ( P<0.01) . Conclusions:The timed, step-by-step and segmented sputum suction can reduce the number of sputum suctions for patients with inhalation injury and the workload of nursing, and effectively decrease the rate of lung infection, which is worthy of clinical promotion.

Objective:To establish a clustered management plan for pulmonary care of massive burn casualties (hereinafter referred to as the clustered management plan for pulmonary care), and to explore its application effects.Methods:(1) A clustered care intervention group was established, including the medical and nursing staff from the Department of Burns and Plastic Surgery, Department of Respiratory Medicine, and Department of Infection Control at the Fourth Medical Center of PLA General Hospital (hereinafter referred to as our hospital). Four major links, including pulmonary care assessment, chest and lung physical therapy, artificial airway management, and specialized infection control were sorted out according to the key points and difficulties in pulmonary care for massive burn casualties. Evidence-based nursing methods were employed to retrieve articles related to the above-mentioned four links from PubMed, Chinese Journal Full- Text Database, VIP Database and Wanfang Data using terms of " mass burn, respiratory management and airway management" and terms of "成批烧伤,肺部护理,集束化管理" , and the clustered management plan for pulmonary care was established based on reading and discussion in combination with clinical practice and experience. (2) In this non-randomized controlled study, the clustered management plan for pulmonary care was applied to 73 massive burn patients (48 males and 25 females, aged 32 (25, 38) years) who were admitted to our hospital from January 2016 to December 2019 and met the inclusion criteria, and they were included into the clustered care group; 43 massive burn patients (25 males and 18 females, aged 35 (17, 45) years) who were admitted to our hospital from January 2013 to December 2015, received routine care and met the inclusion criteria were retrospectively included into routine care group. The pulmonary infection rate and mortality of patients in the two groups were recorded during the hospital stay. Data were statistically analyzed with chi-square test, Mann-Whitney U test, and independent sample t test. Results:(1) The clustered management plan for pulmonary care included a total of 12 specific measures covering four aspects of pulmonary care. The contents in pulmonary care assessment clearly stated to include the previous medical history, history of injury, respiratory status, hoarseness, pulmonary auscultation, etc. Chest and lung physical therapy included how to guide patients to effectively cough and do pursed lip breathing and abdominal breathing exercise, etc. Artificial airway management specified the preparation for the establishment of artificial airway at clinical reception, the observation index and frequency after tracheotomy, the method of humidification, the method and frequency of sputum suction, and the management of mechanical ventilation, etc. Specialized infection control required to strengthen hand hygiene and ventilator management. (2) The pulmonary infection rate and mortality of patients in the clustered care group were 2.74% (2/73) and 4.11% (3/73), respectively, significantly lower than 25.58% (11/43) and 18.60% (8/43) in routine care group ( χ2=11.986, 5.043, P<0.05 or P<0.01). Conclusions:The clustered management plan for pulmonary care developed for massive burn casualties focuses on the major links and key points. The measures are systemic and comprehensive, simple but precise, and highly operable, covering the entire process of massive burn care, hereby reducing the pulmonary infection rate significantly and improving the success rate of treatment.

Objective: To investigate the effect of immunophenotyping on prognosis of multiple myeloma (MM) patients treated with bortezomib regimen as main treatment. Methods: Seventy-six MM patients in the Department of Hematology in the Affiliated Hospital of Qingdao University from January 2012 to January 2017 were retrospectively analyzed. The effects of the expressions of CD45, CD56 and other factors on progression free survival (PFS) and overall survival (OS) in MM patients treated with bortezomib-containing regimen were also analyzed. Results: Univariate analysis showed that statistical differences of the median PFS (12 months vs. 19 months, P < 0.001) and median OS (19 months vs. 23 months, P= 0.001) were significant in the group of CD45 positive and negative of MM patients; the median PFS (14 months vs. 21 months, P= 0.014) and median OS (16 months vs. 25 months, P= 0.026) for MM patients with hemoglobin (Hb) < 100 g/L and Hb ≥ 100 g/L were statistically significant; the median PFS (13 months vs. 18 months, P= 0.004) and median OS (14 months vs. 24 months, P= 0.008) for MM patients with albumin (ALB) < 35 g/L and ALB ≥ 35 g/L were statistically significant. The median PFS time and the median OS time in female MM patients were shorter than those in male MM patients (13 months vs. 19 months, P= 0.008; 16 months vs. 25 months, P= 0.008). Multivariate analysis showed that female and CD45 positive were the independent poor prognostic factors for PFS and OS in MM patients (P < 0.05). Conclusion CD45 positive and female are important prognostic factors for MM patients treated with bortezomib regimen as main treatment.

Objective To explore the application and early efficacy of modified Veil nerve-sparing technique during laparoscopic radical prostatectomy(LRP).Methods Fifty-seven modified Veil nerve-sparing during LRP procedures were performed in patients with clinically localized prostate cancer between 2012 and 2016 by the same surgeon.Preoperative PSA level was 10.9 μg/ml,and Gleason score was 6.06(5-8).TNM clinical stage showed cT1 in 39 cases and cT2in 18 cases.All patients underwent transrectal ultrasonography before operation. Prostate volume was 40.2 (26- 99) ml. ECT bone scan excluded bone metastasis.MRI or CT examination showed no obvious prostate invasion and lymph node metastasis. The key technology was anatomical separation of detrusor apron, dorsal vascular complex (DVC) and the level between the prostate capsule, and a complete reservation was accomplished. Measurements: the rates and location of positive surgical margins (PSM) and tumor biochemical recurrence rate as well as functional outcomes were presented.Questionnaires were used to assess urine function and IIEF-5 score was used to estimate sexual function.Results Fifty-seven cases were followed up,and the average follow-up of 27.3(6-65)months.Five cases showed biochemical recurrence after 23 months.Five patients had a PSM(2 patients in apical margins,1 patient in left side,1 patient in right side and 1 patient in the bottom).At catheter removal,49 of 57 patients(86%)were dry(0 pads),and 8 of 57 patients(14%)needed one security pad.After 3 months and 6 months,42%(24 of 57 patients)and 60%(34 of 57 patients)presented an International Index of Erectile Function score>15(with or without phospho-diesterasetype-5inhibitors). Conclusions The modified Veil nerve-sparing technique during LRP can retain the fascia around the prostate more completely and restore postoperative urine and erectile function early.For selective cases, it will not increase the positive rate of surgical margins and biochemical recurrence rate.

Objective To describe a novel pubovesical complex preserving technique for laparoscopic radical prostatectomy and to evaluate its postoperative outcomes.Methods From January 2011 to May 2017,168 patients who underwent laparoscopic radical prostatectomy were enrolled and analyzed retrospectively.Their mean age were 62.8 (46-74) years,preoperative PSA 11.3ng/ml,Gleason score 6.7,preoperative prostate volume 46.5 ml.They all got preoperative potency (IIEF-5 score ≥ 15 score).TNM clinical stage:cT1 123 cases,45 cases cT2.There were 59 patients with pubovesical complex preserving technique for laparoscopic radical prostatectomy (group A):without pelvic fascia cut and deep vein complex suture.The preservation of the periprostatic anatomy was kept by preserving the pubovesical complex,including detrusor apron with pubovesical ligaments,DVC and NVB.There were 46 patients with conventional intrafascial laparoscopic radical prostatectomy (group B) and 63 patients with interfascial laparoscopic radical prostatectomy(group C).No differences were found between the three groups in terms of preoperative age,clinical staging,prostate-specific antigen (PSA) values,Gleason score at biopsy and preoperative good potency (IIEF-5 score)(P ＞0.05).Continence was defined as zero to one security pad per day.The three groups were compared for perioperative variables,PSM (positive surgical margin,PSM)rate,postoperative urinary continence functional and potency (IIEF-5 score).Biochemical recurrence-free survival was by Kaplan-Meier and log-rank.Results No differences were found in the three groups in terms of operative times,blood loss,catheterization time and postoperative stay and histologic status (PSM was similar to that of the groups (8.5％ in group A,13.0％ in group B vs.11.1％ in group C).Urinary incontinence:group A,the continence rate was 71％,82％,92％ and 100％ at 1,3 and 6 months after catheter removal,respectively;group B,the continence rate was 63％,80％,89％ and 96％ respectively;group C,it was 24％,54％,79％ and 86％ respectively.The group A showed a significantly earlier recovery from incontinence compared with that in the group C at immediately after catheter removal and 1 month after catheter remove (x2 =27.47,P ＜ 0.001;x2 =15.20,P ＜ 0.01).The group B showed a significantly earlier recovery from incontinence compared with that in the group C at immediately after catheter removal and 1 month,(x2 =17.00,P ＜ 0.01;x2 =8.20,P ＜ 0.05).No differences were found between the A and B groups at immediately after catheter removal and 1 month,(P ＞ 0.05).Regarding sexual function,at the postoperative 1,3,6 months,median IIEF-score was 10,11,16 in the group A,respectively,8,9,13 in the group B respectively,and 7,8,12 in the group C respectively.No differences were found in the three groups in potency (IIEF-5 score).Baseline IIEF-score was reached by 53％,35％ and 21％ at postoperative 6 months.There were significant differences between the A and the C groups.(x2 =13.45,P ＜0.01).There were no significant differences between the A and the B groups.(x2 =3.30,P ＞ 0.05).Follow-up was 31.6 (6-69) months.Biochemical recurrence-free survival at 3 years was 79.3％,76.3％ and 76.4％ by A,B and C group,respectively.Conclusions The pubovesical complex preserving technique for laparoscopic radical prostatectomy provides early recovery from incontinence,faster recovery of sexual function preoperative levels.

Objective To compare the efficacy of programmed intermittent epidural bolus and continuous epidural infusion of ropivacaine in labor analgesia.Methods From May 2014 to May 2017,170 patients,24 -32 years,for full-term primipara in the Maternal and Child Health Care Hospital of Quzhou were selected as study objects,and they were randomly divided into intermittent epidural injection group (T group) and continuous epidural pump group(C group) by computer random software,with 85 cases in each group.All patients were epidurally injected 2%lidocaine 3mL and 0.2% ropivacaine 2mL at the opening of the uterus,less than 3cm.T group was given programmed intermittent epidural bolus 0.1% ropivacaine 6mL/h.C group was given continuous epidural infusion 0.1%ropivacaine 6mL/h.The pain of maternal(NRS score) and motor block situation of maternal (Bromage score) were monitored.The number of PCEA,PCEA pressure times,the rate of instrumental delivery and APGAR score were also recorded.Results The number of Bromage score≥2 in C group was higher than that of T group at 4-10h after labor analgesia (3 cases vs.11 cases,3 cases vs.15 cases,4 cases vs.17 cases,4 cases vs.18 cases,6 cases vs. 19 cases,6 cases vs.21 cases,7 cases vs.22 cases;χ2＝4.982,8.947,9.182,10.230,7.926,9.907,9.354,all P＜0.05).There was no statistically significant difference in NRS score between the two groups (P＞0.05).The number of PCEA,PCEA pressure times and the rate of instrumental delivery in T group were lower than those in C group [8 cases vs.18 cases,22 cases vs.41 cases,(3.5 ±1.5) times vs.(4.9 ±2.2) times;χ2＝4.541,9.104;t＝2.666,all P＜0.05].There was no statistically significant difference in Apgar score between the two groups (P＞0.05).Conclusion Compared with continuous epidural infusion,programmed intermittent bolus of ropivacaine for labor analgesia exerts good analgesic effect,it has minor effects on exercise function and can decrease the rate of instrumental delivery .