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 paper reports a case of eosinophilic esophagitis who presented with dysphagia. The patient was a 54-year-old woman with diffuse esophageal thickening on ultrasonographic gastroscopy. Pathology demonstrated scattered eosinophilic infiltration within the squamous epithelium of the esophagus, accompanied by eosinophilic microabscess, and the counting density of eosinophilic cells was about 30/HPF, which was consistent with the diagnostic criteria of eosinophilic esophagitis (moderately active). After oral administration of prednisone acetate 30 mg/d and gradual reduction of the dose, the patient's clinical symptoms were significantly eased, and the imaging confirmed the improvement of the lesions. This article summarizes the patient's diagnostic and therapeutic process, and reviews the relevant literature in order to enhance clinicians' understanding of this disease.

Objective:To analyze the epidemiological characteristics and clinical features of pertussis cases reported in Shandong Province of China.Methods:Data on pertussis cases in Shandong Province from 2007 to 2022 were collected from China Information System for Disease Control and Prevention. At the same time, some case information was collected from the database of notifiable pertussis in Shandong Province from 2007 to 2022. The distribution characteristics and clinical features of pertussis were analyzed. A spatial distribution map of pertussis cases in Shandong Province was drawn.Results:A total of 26 122 pertussis cases were reported in Shandong Province during 2007-2022, with an annual incidence rate ranging from 0.11 to 5.77 cases per 100 000 people. Cases occurred throughout the whole year, with a seasonal peak occurring in spring and summer, especially in July and August. In recent years, reported cases were mainly distributed in the central and western regions of Shandong Province, with fewer cases in the eastern region. The hot spots of the disease shifted from Heze and Dezhou City in 2007-2013 to Jinan and Tai′an city in 2014-2022. The age range of onset was from 1 day to 93 years old. The proportion of cases with age≤1 year was the largest (41.81%, 10 922/26 122), and the proportion of cases aged 0-6 months decreased from 32.21% (67/208)-55.67% (157/282) within the period of 2007 to 2013 to 16.78% (883/5 263)-41.97% (444/1 058) within the period of 2014 to 2022, with a statistically significant trend ( χ2 trend=670.01, P<0.001). There were 13 682 male cases and 12 440 female cases, with a male-female ratio of 1.10∶1. The male-female ratio was 1.45∶1 (806∶556) from 2007 to 2013 and 1.08∶1 (12 876∶11 884) from 2014 to 2022. The proportion of women increased from 42.31% (88/208) in 2007 to 47.84% (2 518/5 263) in 2022, and with a significant trend ( χ2 trend=22.25, P<0.001). In pertussis cases, the proportions of scattered children, kindergarten children and students were 71.38% (18 645/26 122), 15.13% (3 951/26 122), and 11.60% (3 031/26 122), respectively. The top five clinical symptoms of pertussis cases were paroxysmal spasmodic cough (86.33%, 21 411 cases), flushing (39.61%, 9 824 cases), restless sleep (34.51%, 8 558 cases), fever (30.80%, 7 638 cases), and crowing (27.53%, 6 829 cases). Among 24 802 cases, there were 15 542 cases (62.66%) with a history of immunization against pertussis vaccine. Conclusion:From 2007 to 2022, the incidence rate of pertussis cases in Shandong Province shows an upward trend, with the majority being young children, and the clinical symptoms are relatively typical.

Objective:To understand the incidence of diabetes and influencing factors, the trend of FPG change and risk for mortality in HIV-infected individuals after antiretroviral therapy (ART) in Dehong Dai and Jingpo Autonomous Prefecture (Dehong).Methods:The HIV/AIDS treatment database was collected from China Information System for Disease Control and Prevention. This retrospective cohort study was conducted in HIV-infected individuals with access to ART in Dehong during 2004-2020.The Cox proportional hazard regression model was used to analyze the incidence density of diabetes, the influencing factors and risk for mortality in HIV-infected individuals with access to ART, mixed linear effects model was used to analyze the trend of FPG change and predict FPG in those with different glucose metabolic status at baseline survey. Statistical analysis was performed using software SAS 9.4.Results:A total of 8 763 HIV-infected individuals were included, in whom 8 432 (96.2%) had no diabetes, 331 had diabetes. The incidence density of diabetes was 2.31/1 000 person years. Multivariate Cox proportional hazard regression analysis revealed that 30- 59 years old, BMI ≥24.0 kg/m 2, Efavirenz (EFV) based initial treatment regimen and impaired fasting glucose (IFG) at baseline survey were significantly and positively associated with incidence of diabetes. Mixed effect model revealed that FPG was positively correlated with the duration of ART, age and baseline FPG. Suffering from diabetes was a risk factor for mortality in HIV-infected individuals both at baseline survey and during follow-up. Conclusions:The risk for diabetes increased in HIV-infected individuals who were 30-59 years old, baseline BMI ≥24.0 kg/m 2, received EFV based initial treatment, and IFG in HIV-infected individuals after antiretroviral therapy in Dehong, 2004-2020. It is important to pay close attention to their blood glucose, and patients with high blood glucose should receive treatment as early as possible.

Objective:To explore the curative efficacy of tandem autologous stem cell transplantation (ASCT) for high-risk multiple myeloma (HRMM).Methods:From January 2017 to December 2021, retrospective analysis was conducted for 240 initially diagnosed HRMM patients. According to different treatment protocols after induction chemotherapy, they were further assigned into three groups of tandem ASCT (n= 20) ,single ASCT (n=80) and non-transplantation (n= 140). Rates of deep response (very good partial response and above) before and after transplantation and differences in 2-year progression-free survival (PFS) and overall survival (OS) were compared among three groups. The prognostic factors of HRMM were examined by univariate and multivariate analyses.Results:In single ASCT group, the rates of deep responses were 67.50% (54/80) after induction chemotherapy and 80.00 % (64/80) post-ASCT ( P=0.072). There were no significant statistical differences. In tandem ASCT group, the rates of deep response were 65.00% (13/20) after induction chemotherapy and 95.00 % (19/20) post-ASCT ( P=0.018). There were significant statistical differences. The 2-year PFS of tandem ASCT, single ASCT and non-transplantation groups were (75.00±2.90) %, (71.25±3.00) % and (61.43±3.10) % respectively. No statistically significant difference existed in 2-year PFS rates between single ASCT and non-transplantation groups, as well as between tandem ASCT and single ASCT groups ( P=0.365 and P=0.052). Significant difference existed in 2-year PFS between tandem ASCT and non-transplantation groups ( P<0.032). Two-year OS rates of tandem ASCT, single ASCT and non-transplantation groups were (90.00±3.50) %, (78.75±2.70) % and (62.86±2.50) % respectively. No statistically significant difference existed in 2-year OS rate between single ASCT and non-transplantation groups, as well as between tandem ASCT and single ASCT groups ( P=0.071 and P=0.057). Significant difference existed in 2-year OS between tandem ASCT and non-transplantation groups ( P=0.003). Univariate and multivariate analyses indicated that the independent prognostic factors affecting PFS were multi-hit, stages RISS-Ⅲ and failure to achieve very good partial response (VGPR) after four cycles of induction therapy and non-tandem ASCT. The independent prognostic factors affecting OS were multi-hit, stages RISS-Ⅲ and non-tandem ASCT. Conclusion:Tandem ASCT not only significantly improves the depth of remission but also further enhances 2-year PFS/OS of HRMM patients. It is a recommended treatment for HRMM.

Objective:To further improve the understanding of paroxysmal nocturnal hemoglobinuria (PNH), we retrospectively analyzed and summarized the clinical characteristics, treatment status, and survival status of patients with PNH in Zhejiang Province.Methods:This study included 289 patients with PNH who visited 20 hospitals in Zhejiang Province. Their clinical characteristics, comorbidity, laboratory test results, and medications were analyzed and summarized.Results:Among the 289 patients with PNH, 148 males and 141 females, with a median onset age of 45 (16-87) years and a peak onset age of 20-49 years (57.8% ). The median lactic dehydrogenase (LDH) level was 1 142 (604-1 925) U/L. Classified by type, 70.9% (166/234) were classical, 24.4% (57/234) were PNH/bone marrow failure (BMF), and 4.7% (11/234) were subclinical. The main clinical manifestations included fatigue or weakness (80.8%, 235/289), dizziness (73.4%, 212/289), darkened urine color (66.2%, 179/272), and jaundice (46.2%, 126/270). Common comorbidities were hemoglobinuria (58.7% ), renal dysfunction (17.6% ), and thrombosis (15.0% ). Moreover, 82.3% of the patients received glucocorticoid therapy, 70.9% required blood transfusion, 30.7% used immunosuppressive agents, 13.8% received anticoagulant therapy, and 6.3% received allogeneic hematopoietic stem cell transplantation. The 10-year overall survival (OS) rate was 84.4% (95% CI 78.0% -91.3% ) . Conclusion:Patients with PNH are more common in young and middle-aged people, with a similar incidence rate between men and women. Common clinical manifestations include fatigue, hemoglobinuria, jaundice, renal dysfunction, and recurrent thrombosis. The 10-year OS of this group is similar to reports from other centers in China.

Objective:To investigate the effect of oral immunotherapy with donor human milk on feeding tolerance in premature infants with very low birth weight.Methods:A total of 94 extremely low birth weight preterm infants admitted to the neonatal Intensive Care Unit of Cangzhou People's Hospital from August 2022 to February 2024 were selected, These infants were randomized at 1:1 into 2 groups (47 cases each) using random number method. The control group were given oral 0.9% sodium chloride (oral drip), while the experimental group were given donor human milk (oral drip). General information were collected, including gender, delivery method, twins or not, small for gestational age or not, birth weight, gestational age, intestinal feeding of dairy products, and so on. Total intestinal feeding time, length of hospital stay and feeding intolerance were compared between groups.Results:The total intestinal feeding time and length of hospital stay were significantly shorter in the experimental group compared with the control group ( P<0.05). The incidence of feeding intolerance in the experimental group was also lower than that in the control group ( P<0.05). Conclusion:Oral immunotherapy with donor human milk can improve the feeding tolerance in premature infants with very low birth weight and shorten the hospital stay.

Objective:To describe the detail sampling design,weighting,instruments,filed procedures and quality control methods of the epidemiological survey on dementia among community residents in Tongliao City.Methods:A three-stage disproportionate probability sampling design was used to investigate the inhabitants aged 65 years and over in Tongliao City,Inner Mongolia Autonomous Region.The 10/66 Dementia Research Group(10/66 DRG)assessment instruments were used to diagnose dementia,using computer-assisted personal interview mode in the selected older people.Comprehensive quality control methods were implemented throughout the field-work.Results:A total of 166 villages or communities were sampled from nine counties or districts in Tongliao Cit-y.Totally 4 345 older people were interviewed with 96.2％response rate.By calculating sampling design weights,non-response adjustment weights and post-stratification adjustment weights,these weights were multiplied and per-formed trimming adjustment and standardization adjustment to generate final weights.The 171 interviewers were well-trained and qualified to carry out filed interview.Quality control methods included computer data check,audio record check,and telephone check in order to ensure the quality of the survey.Conclusion:This survey is imple-mented using a rigorous sampling design and timely quality control methods,and uses the 10/66 DRG assessment instruments with satisfactory international validity and reliability as survey instruments,which has international cross-cultural comparability.It provides a valid and feasible methodology of epidemiological survey on dementia for further studies in different regions in China.

Objective:To compare the efficacy of endoscopic submucosal dissection (ESD) and modified-endoscopic mucosal resection (M-EMR) for G1 rectal neuroendocrine tumors (RNETs) .Methods:Data of 121 patients with pathologically confirmed G1 RNETs treated with ESD ( n=105) or M-EMR ( n=16) in Nanjing Drum Tower Hospital from January 2017 to September 2020 were retrospectively analyzed. The complete resection rate, complication incidence, hospital stay, treatment cost and other indicators of the two groups were compared by using inverse probability of treatment weighting (IPTW). Results:There were significant differences in tumor number ( χ2=8.76, P=0.003), tumor invasion depth ( χ2=6.96, P=0.008), utilization of metal clips [82.9% (87/105) VS 93.8% (15/16), χ2=8.78, P=0.003], number of metal clips ( χ2=8.41, P=0.016), hemostasis using hot clamp [78.1% (82/105) VS 18.7% (3/16), χ2=20.64, P<0.001], traction procedure [2.9% (3/105) VS 18.7% (3/16), χ2=4.45, P=0.035] and treatment cost (17 568.6 ± 8 911.0 yuan VS 8 120.8±1 528.2 yuan, t=3.65, P<0.001) between the ESD group and the M-EMR group. After verifying the stability of the results using IPTW sensitivity analysis, there was still significant difference in the treatment cost ( t=2.07, P<0.001). Conclusion:Both ESD and M-EMR demonstrate comparable efficacy in treating G1 RNETs; however, M-EMR exhibites lower treatment costs.

Objective:To explore the effect of Helicobacter pylori(HP)eradication on development of metachronous gastric cancer(MGC)after endoscopic submucosal dissection(ESD)in elderly patients with early gastric cancer.Methods:From January 2014 to December 2019, 748 early gastric cancer patients aged 60 years or older, receiving ESD in Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, were included.According to the situation of HP infection and eradication efficacy within 1 year postoperatively, patients were divided into three groups.The patients with HP infection and successful HP-eradication were enrolled into successful eradication group, those without eradicating or with eradication failure were enrolled into eradication failure group, those with HP negative were enrolled into HP-negative group.And then the occurrence and risk factors of MGC after ESD among the three groups were statistically analyzed.Results:MGC were detected in 58 cases(7.7%)in elderly patients with early gastric cancer after ESD.The median follow-up time was 39 months.The multivariate regression analysis results of MGC showed that no HP-eradication or HP eradication of failure( HR=2.231, 95% CI: 1.054-4.722, P=0.036)and multiple lesions( HR=1.857, 95% CI: 1.076-3.204, P=0.026)were independent risk factors.Non-smoking was a protective factor for the occurrence of MGC( HR=0.409, 95% CI: 0.234-0.716, P=0.002). After adjusting for confounding factors, Cox proportional risk regression analysis showed that the incidence of MGC was significantly higher in group of no HP-eradicating or HP-eradicating of failure than in group of successful HP-eradicating group( χ2=37.877, P<0.001). Conclusions:HP eradication can effectively prevent MGC in elderly patients with early gastric cancer after ESD.Multiple lesions and smoking are independent risk factors for MGC.