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 assess the health risks of fluoride in drinking water in rural schools in drinking-water fluorosis areas in Shaanxi Province, and to provide a scientific basis for formulating measures to prevent fluoride and improve water quality. Methods The drinking water of rural schools in Guanzhong and northern Shaanxi Province was monitored from 2017 to 2020. The fluoride concentration was evaluated in accordance with the ^“Sanitary Standards for Drinking Water^” (GB5749-2006). The health risk assessment method recommended by USEPA was used to assess the health risk of rural students exposed to fluoride through drinking water in the two regions. Results A total of 2 826 water samples were monitored from 2017 to 2020. The overall compliance rate of fluoride in water quality was 92.29%, with an average concentration of 0.500 mg/L. The non-carcinogenic health risk of fluoride in drinking water in rural schools in drinking-water fluorosis areas was <1. There was no statistically significant difference in non-carcinogenic health risk of fluoride in water quality between different regions of the same age group (P > 0.05). In the same age group, the non-carcinogenic health risk of fluoride in groundwater was higher than that in surface water (P < 0.05). The order of non-carcinogenic health risk of fluoride in drinking water with different water treatment methods from high to low was disinfection only > sedimentation filtration > conventional treatment > untreated (P < 0.05). Conclusion The non-carcinogenic risk of oral intake of fluoride in drinking water from rural schools in drinking-water fluorosis areas in Shaanxi Province is still at an acceptable level. In the future, it is necessary to continue to promote comprehensive prevention and treatment measures focusing on water improvement and fluoride reduction.

In order to learn from the advanced experience of postgraduate education in foreign first-class universities, Harvard University, Johns Hopkins University and London School of Hygiene and Tropical Medicine were selected as the objects in this study to analyze and compare the advantages and characteristics of their postgraduate training model, curriculum setting and teaching resources, thereby providing suggestions for the reform and development in the cultivation of master of public health and preventive medicine in China.

Objective:To evaluate the health risk of fluoride in rural drinking water in drinking-water-borne endemic fluorosis(referred to as drinking-water-borne fluorosis) areas of Shaanxi Province, and to provide scientific basis for the formulation of water improvement and fluoride reduction measures.Methods:The fluoride monitoring results of rural drinking water in Guanzhong Plain and Loess Plateau of Northern Shaanxi in drinking-water-borne fluorosis areas of Shaanxi Province in 2020 were collected from the "National Drinking Water Quality and Sanitation Monitoring Information System". Using the health risk assessment method recommended by the United States Environmental Protection Agency (USEPA), the level of fluoride exposure of adults in fluorosis areas through drinking water was evaluated, and the health risk value was calculated.Results:A total of 4 342 rural drinking water samples from drinking-water-borne fluorosis areas were monitored. The overall compliance rate of fluoride in water quality was 95.39% (4 142/4 342), and the fluoride content median was 0.470 mg/L; the health risk value was 0.368, and the non-carcinogenic risk was low. A total of 200 water samples with fluoride exceeding the standard were detected, and the fluoride content median was 1.450 mg/L; the health risk value of the fluoride excess water samples was 1.135, indicating a high non-carcinogenic risk. There were significant differences in fluoride content in rural drinking water between different regions, water sources and treatment methods ( H = - 7.73, - 7.60, 34.40, P < 0.05). Conclusions:The non-carcinogenic risk of fluoride exposure of adults in drinking-water-borne fluorosis areas through drinking water in Shaanxi Province is relatively low, and the non-carcinogenic risk caused by water samples with excessive fluoride is relatively high. In the future, it is necessary to continue to promote the comprehensive prevention and control measures focusing on improving water and reducing fluoride.

Objective:To examine the survival and influential factors of an integrated approach of novel agents, autologous hematopoietic stem cell (auto-HSCT) , and maintenance therapy in patients with multiple myeloma (MM) patients from a single center over the past 15 years.Methods:In our center, 300 MM patients who received an integrated strategy of new agents, auto-HSCT, and maintenance therapy over 15 years were retrospectively and prospectively analyzed.Results:The complete remission rates (CR) and ≥very good partial remission rates (VGPR) following induction therapy, transplantation, and maintenance therapy were respectively 35.3% and 55.2% , 72.4% and 80.0% , 89.2% , and 93.4% . When compared to patients receiving double-drug induction, the ≥VGPR and ORR of patients receiving triple-drug induction were improved. No difference existed in CR, ≥VGPR, and ORR between the PAD (bortezomib + liposome doxorubicin+ dexamethasone) and RAD (lenalidomide + liposome doxorubicin + dexamethasone) regimens, but the benefits speed differed. The negative rate of flow minimal residual disease following induction, transplantation, and maintenance was 18.8% (54 cases) , 41.4% (109 cases) , and 58.7% (142 cases) , respectively. The median time to progress (TTP) was 78.7 months and the median overall survival (OS) was 109 months. The median TTP for RISS-Ⅰ-Ⅲ patients were 111.8 months, 77.4 months, and 30.6 months, and the median OS was 118.8 months, 91.4 months, and 48.5 months, respectively. At various points during treatment, the TTP and OS of patients obtaining CR and MRD negative were longer than those of patients who did not obtain CR and MRD negative. TTP was noticeably shorter in high-risk cytogenetic patients compared to standard-risk patients even when CR was acquired during induction. There was no difference in TTP between patients with high-risk cytogenetics and those with standard-risk cytogenetics if MRD negative was acquired during induction. According to a multivariate analysis, the R-ISS stage was a poor predictor of TTP and OS at various treatment intervals. Therapeutic effectiveness was a newly independent prognostic factor following treatment.Conclusion:A median survival of almost 10 years is possible for MM patients who receive an integrated strategy of induction regimens followed by auto-HSCT and maintenance therapy, which significantly improves prognosis. However, this approach did not significantly benefit high-risk cytogenetic MM patients.

Objective To analyze the pollution characteristics of 12 kinds of metals and metalloid elements in PM_2.5 in Xi'an city, and to assess the health risks. Methods In 2018, PM2.5 samples were collected regularly every month at two monitoring points in Lianhu District and Yanta District of Xi'an City. The content of twelve metal and metalloid elements (Sb, Al, As, Be, Cd, Cr, Hg, Pb, Mn, Ni, Se, and Ti) in the samples were determined. The test results were statistically analyzed and evaluated according to different regions and seasons. The health risk assessment model recommended by the US Environmental Protection Agency (EPA) was used to assess the health risks of the metal and metalloid elements. Results A total of 165 PM_2.5 samples were collected and analyzed. The qualified rates of As and Cd were 51.52% and 83.03%, respectively, and there was no significant difference between regions (P＞0.05). The qualified rate of As in each season from high to low was summer> autumn> winter> spring. The average concentration of As was 8.21 ng/m³, being 1.37 times higher than the standard. The average concentration of As in each season exceeded the standard, and the order from high to low was winter> spring> autumn> summer. The average concentrations of other elements did not exceed the standard. HQ value and HI value of As, Cd, Cr, Pb, Mn, Ni, Hg, Ti and Se were all less than 1. The ILCR value of carcinogenic elements As, Cd, Cr and Ni was between 3.63×10^-07 ~2.58×10^-05. The ILCR value was highest for As, followed by Cr. The ILCR value was highest in winter, followed by spring and autumn, and lowest in summer. The order of ILCR value was adult males> adult females> children and adolescents. Conclusion The pollution of metal and metalloid elements in the atmospheric PM_2.5 in Xi'an in the winter is most serious. Arsenic and chromium in PM_2.5 pose a higher potential health risk to the population through the respiratory route.

Objective To understand the status and dynamic changes in the treatment of rural garbage and sewage in Shaanxi Province and provide the basis for relevant departments to formulate policies and measures. Methods Every year from 2016 to 2018, 600 administrative villages in 30 agricultural counties were randomly selected as monitoring points, and 3 000 households were selected as monitoring households. Monitoring data was obtained through data reading, interviews, and on-site observations. Results The three-year rural population coverage rate of the garbage treatment plant was 28.31%, 36.10%, 39.36%, respectively, and the sewage treatment plant coverage rate was 12.27%, 20.39%, 15.02%, respectively. The annual differences were statistically significant（χ²=23.24、22.42，P=0.00）. The proportion of monitoring points for the three-year unified collection of domestic garbage was 30.50%, 43.67%, 51.00%, respectively, and the percentage of monitoring points for incineration garbage was 16.67%, 15.00%, 8.33%, respectively, and the annual differences were statistically significant（χ²=53.25、20.19，P=0.00）. The proportion of domestic sewage discharge monitoring points through pipelines was 12.67%, 11.17%, 31.17%, respectively, and the proportion of monitoring points discharged into treatment plants was 4.33%, 6.00%, 15.17%, respectively, and the annual differences were both statistically significant（χ²=99.45、52.50，P=0.00）. Conclusion In recent years, the rural garbage and sewage treatment situation in Shaanxi Province had improved, but there was still much room for improvement. It is recommended to increase environmental protection publicity and government investment, strengthen daily supervision, pay equal attention to construction and management, control the random stacking and discharging of garbage and sewage, and enhance the disposal rate of garbage and sewage.

Objective: To understand the status and trend of heavy metal indicators of drinking water in rural schools in different regions of Shaanxi Province, so as to provide scientific basis for safety of drinking water in rural schools. Methods: In 2017-2019, 697 rural school water supply projects in Shaanxi Province were tested for heavy metal indicators in the peripheral water. According to the sanitary standard for drinking water (GB 5749—2006), five heavy metal indicators, including arsenic, cadmium, hexavalent chromium, lead and mercury, were analyzed and evaluated in different years and regions. Results: A total of 2 298 valid water samples were collected and analyzed in 3 years. Except that lead and mercury are all up to standard, the standard rates of other heavy metals such as arsenic, cadmium and hexavalent chromium were 98.83%, 99.91% and 96.95% respectively. Compared with the Northern Shaanxi plateau and Qinba mountain area, the standard rate of water arsenic in Guanzhong Plain was lower (χ2=5.67, 13.59,P<0.01). The standard rate of hexavalent chromium was the highest in Qinba mountain area, followed by Guanzhong Plain, and the lowest in Northern Shaanxi plateau (χ2=20.48, 17.05, 48.32, P<0.01). Two samples of cadmium exceeding standard were from the Northern Shaanxi plateau. Conclusion The heavy metal index of drinking water in rural schools in Shaanxi Province exceeds the standard, which has obvious regional characteristics. We should focus on the harm of arsenic, hexavalent chromium and other heavy metals to the health of students in the Northern Shaanxi plateau and Guanzhong Plain. Cadmium and mercury in drinking water in local areas should be paid continued attention. Safety of drinking water in schools should be ensured from the aspects of water source selection and water treatment technology.

Objective To analyze the change in trends and existing problems of the water quality testing capabilities of the Centers for Disease Control and Prevention (CDC) in different cities and counties (districts) in Shaanxi Province from 2017 to 2019, and to provide references for laboratory capacity building. Methods A unified questionnaire was developed to investigate the water quality testing ability of all CDCs in different regions of Shaanxi Province, and the data were reported through the ^“National Drinking Water Quality Inspection Information System^”. Results From 2017 to 2019, in the testing of conventional indicators, the average number detected by the municipal CDCs was 37, 37, and 38, respectively, and all of them passed the measurement certification/laboratory accreditation. The average number detected by the county (district) CDCs was 30, 29, and 30, respectively, and only 65.14% of the county (district) CDCs passed the measurement certification/laboratory accreditation. In the testing of unconventional indicators, the average detectable number by city-level CDCs was 3, 5, and 4, respectively, while the average detectable number by county (district)-level CDCs was at most 1 item. There was no statistically significant difference in the average detection ability of CDCs at the city and county (district) levels in different regions in the same year (P>0.05); there was no significant difference in the average detection ability of CDCs at the city and county (district) levels in the same region in different years (P>0.05). Conclusion There is no difference in the CDC water quality testing level in different regions of Shaanxi Province, and the testing capacity needs to be further improved. It is recommended that the government should increase funding for disease control institutions, optimize the allocation of equipment and strengthen the construction of professional teams.

Objective:To share related knowledge and experiences with countries along the line, literature regarding current cohort studies was summarized. Distribution, establishment and development of cohort studies among large prospective general population were analyzed in 17 countries of Western Asia and the 16 countries of Central and Eastern Europe.Methods:Literature review was conducted to collect basic information on cohort studies, with descriptive study used to analyze the characteristics of these cohort studies.Results:There were 562 cohort studies with sample size as more than 1 000 stated in Western Asia and Central and Eastern Europe, including 468 (83.27 %) carried out in the nation itself and 94 (16.73 %) with international multicentered collaboration. According to the nature of cohort studies, 347 (61.74 %) were etiologically based. As for the contents involved, 310 (55.16 %) of them targeted on chronic/non-communicable diseases, 125 (22.24 %) concentrated on maternal and child health. Among those on chronic/non-communicable diseases, 51 (16.45 %) were on cancers and 83 (26.77 %) on cardiovascular disease studies. There appeared 10 large prospective cohort studies targeting on general population, mainly ongoing in Iran and European countries, with a duration of 8-29 years, including 4 of them with sample size as more than 50 000. In terms of the contents, epidemiological investigation, physical examination and biological samples collection took the major parts. Few papers were published in 9 out of the 10 cohort studies at the early stage of those projects but the number of papers increased annually and stabilized to certain extent. Conclusions:The regional distribution of cohort studies carried out in countries from the Western Asia and Central and Eastern European areas appeared unbalanced. Contents of these designs would mainly involve etiological studies, with focus on non-communicable diseases as cancer, cardiovascular disease, diabetes, respiratory diseases, mental and psychological diseases, and maternal and infant health etc.. However, only few large prospective cohort studies would base on general population.