Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Effective annotation of in vivo drug metabolites using liquid chromatography-mass spectrometry (LC-MS) remains a formidable challenge. Herein, a metabolic reaction-based molecular networking (MRMN) strategy is introduced, which enables the "one-pot" discovery of prototype drugs and their metabolites. MRMN constructs networks by matching metabolic reactions and evaluating MS² spectral similarity, incorporating innovations and improvements in feature degradation of MS² spectra, exclusion of endogenous interference, and recognition of redundant nodes. A minimum 75% correlation between structural similarity and MS² similarity of neighboring metabolites was ensured, mitigating false negatives due to spectral feature degradation. At least 79% of nodes, 49% of edges, and 97% of subnetworks were reduced by an exclusion strategy of endogenous ions compared to the Global Natural Products Social Molecular Networking (GNPS) platform. Furthermore, an approach of redundant ions identification was refined, achieving a 10%-40% recognition rate across different samples. The effectiveness of MRMN was validated through a single compound, plant extract, and mixtures of multiple plant extracts. Notably, MRMN is freely accessible online at https://yaolab.network, broadening its applications.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective:To investigate the application value of self-pulling and latter transection (SPLT) technique in double anti-reflux double-tract reconstruction of totally laparoscopic proximal gastrectomy.Methods:The retrospective cohort study was conducted. The clinicopatholo-gical data of 103 patients with Siewert type Ⅱ adenocarcinoma of esophagogastric junction in clinical stage Ⅰ-Ⅱ who were admitted to Shanxi Cancer Hospital from January 2018 to January 2020 were collected. There were 65 males and 38 females, aged from 45 to 79 years, with a median age of 59 years. Of 103 patients, 49 cases undergoing totally laparoscopic proximal gastrectomy with double-tract reconstruction of SPLT were assigned into the SPLT group, 54 cases undergoing totally laparoscopic proximal gastrectomy with conventional double-tract reconstruction were assigned into the traditional group. Observation indicators: (1) intraoperative situations; (2) postoperative situations; (3) follow-up. Follow-up was conducted by outpatient examination and telephone inter-view to detect postoperative reflux esophagitis of patients up to December 2021. Measurement data with normal distribution were represented as Mean± SD, and the t test was used for comparison between groups. Measurement data with skewed distribution were represented as M(range) or M( Q1, Q3), and the Wilcoxon test was used for comparison between groups. Count data were described as absolute numbers or percentages, and comparison between groups was performed using the chi-square test. Comparison of ordinal data was analyzed using the non-parameter rank sum test. Results:(1) Intraoperative situations: the operation time, digestive tract reconstruction time, volume of intraoperative blood loss, the number of inferior mediastinal lymph nodes dissected, cases with auxiliary incisions for the SPLT group were (261±48)minutes, (26±4)minutes, (114±42)mL, 8.0(6.5,9.5), 1, respectively. The above indicators were (244±42)minutes, (30±6)minutes, (118±46)mL, 5.5(4.0,8.0), 9 for the traditional group, respectively. There were significant differences in the digestive tract reconstruction time, the number of inferior mediastinal lymph nodes dissected and cases with auxiliary incisions between the two groups ( t=-3.34, Z=-4.05, χ2=4.72, P<0.05). There was no significant difference in the operation time or volume of intraoperative blood loss between the two groups ( t=1.87, -0.47, P>0.05). (2) Postoperative situations: duration of postopera-tive hospital stay and cases with postoperative complications were (11.5±2.7)days and 4 for the SPLT group, versus (12.5±4.3)days and 9 for the traditional group, showing no significant difference between the two groups ( t=-1.47, χ2=1.68, P>0.05). There were 13 of 103 patients with postopera-tive complications, including 5 cases of left pleural effusion, 4 cases of anastomotic leakage, 2 cases of mild pneumonia, 1 case of incision infection, 1 case of chylous leakage. Four patients had anasto-motic leakage at the esophagojejunostomy, the abdominal esophagus of whom was invaded by more than 1 cm. During the operation, mediastinal drainage tubes were placed through the abdominal wall. The 4 patients were cured after enteral and parenteral nutrition support and adequate drainage, and the remaining patients with complications were cured after symptomatic treatment. (3) Follow-up: of 49 patients in the SPLT group, 43 cases were followed up for (18±4)months. During the follow-up, 1 case showed reflux esophagitis by gastroscopy, with the incidence of 2.33%(1/43). Of 54 patients in the traditional group, 53 cases were followed up for (17±4)months. During the follow-up, 4 cases showed reflux esophagitis by gastroscopy, with the incidence of 7.55%(4/53). There was no significant difference in the incidence of reflux esophagitis between the two groups ( χ2=0.47, P>0.05). Conclusions:SPLT technology is feasible for double anti-reflux double-tract reconstruction of proximal gastrectomy. Compared with traditional double-tract reconstruction of totally laparos-copic proximal gastrectomy, SPLT technology can reduce the auxiliary incisions, increase the number of lower mediastinal lymph nodes dissected, and shorten the digestive tract reconstruction time.

There are still many controversies in the surgical treatment of esophagogastric junction tumors in terms of surgical approach, cleaning range, and resection scope. The reason is the confusion about the scope of the esophagogastric junction. The previous domestic and foreign anatomy descriptions of this part are not enough to solve the current problems. Based on a large number of basic anatomy and clinical operations, this article proposes that the esophagogastric junction may be wrapped by a complete and separate esophagogastric junction membrane with independent anatomy other than infracardiac bursa. The structure of the transitional tissue, mainly from the distribution of submucosal veins, explained the relationship and significance of tissue transitional changes and clinical operations, and made a reasonable analysis of the current controversy based on the anatomical characteristics, which is worthy of further investigation.

There are still many controversies in the surgical treatment of esophagogastric junction tumors in terms of surgical approach, cleaning range, and resection scope. The reason is the confusion about the scope of the esophagogastric junction. The previous domestic and foreign anatomy descriptions of this part are not enough to solve the current problems. Based on a large number of basic anatomy and clinical operations, this article proposes that the esophagogastric junction may be wrapped by a complete and separate esophagogastric junction membrane with independent anatomy other than infracardiac bursa. The structure of the transitional tissue, mainly from the distribution of submucosal veins, explained the relationship and significance of tissue transitional changes and clinical operations, and made a reasonable analysis of the current controversy based on the anatomical characteristics, which is worthy of further investigation.