Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

Previous studies have shown that the diversity and composition of intestinal microbiota are related to the effect of tumor immunotherapy,but the mechanism of intestinal microbiota affecting tumor immunotherapy resistance has rarely been sum-marized.This article not only expounds the current clinical sta-tus of tumor immunotherapy resistance,but also summarizes the correlation and regulatory mechanism between the composition and homeostasis of intestinal microbiota and drug resistance to different types of tumor immunotherapy,so as to provide a refer-ence for the study of potential targets for improving tumor immu-notherapy resistance based on intestinal microbiota.

Objective To establish a stable,reliable,and clinically relevant porcine model of endotoxin-induced acute respiratory distress syndrome(ARDS).Methods Ten 8-month-old male Bama minipigs were deeply sedated,followed by invasive mechanical ventilation and electrocardiographic monitoring.Lipopolysaccharide(LPS)was intravenously pumped at 600 μg/(kg·h)for 3 hours,then maintained at 15 μg/(kg·h)thereafter.Dynamic monitoring was performed at five time points after LPS injection(LPS 0,1,3,5,and 8 h),including arterial blood gas analysis and chest computed tomography(CT)scans.Pathological examination of lung tissues obtained via bronchoscopic biopsy(HE staining and transmission electron microscopy)was conducted.These indicators were comprehensively used to evaluate the success of the animal model.Results At 5 hours after LPS administration,8 minipigs developed symptoms such as skin cyanosis,elevated body temperature,and respiratory distress.The oxygenation index decreased to<300 mmHg.Chest CT scans showed diffuse pulmonary infiltrates.Histopathology revealed alveolar edema and hyaline membrane formation.Transmission electron microscopy demonstrated disruption of pulmonary blood-air barrier,depletion of lamellar bodies in type Ⅱ pneumocytes,inflammatory cell infiltration,and exudation of plasma proteins and fibrin.Compared with LPS 0 h,at LPS 8 h,the oxygenation index and arterial blood pH were significantly decreased(P<0.001),while blood lactic acid and serum potassium were significantly increased(P<0.05);serum calcium and base excess were significantly decreased(P<0.05),and the lung injury score based on HE-stained lung sections was significantly increased(P<0.01).Conclusion The porcine ARDS model established by continuous LPS injection can dynamically simulate the pathophysiological characteristics and typical pathological manifestations of clinical septic ARDS,making it an effective tool to study the pathogenesis,prevention,and treatment strategies of septic ARDS.

OBJECTIVE: Recombination events are common and serve as the primary driving force of diverse human adenovirus (HAdV), particularly in children with acute respiratory tract infections (ARIs). Therefore, continual monitoring of these events is essential for effective viral surveillance and control. METHODS: Respiratory specimens were collected from children with ARIs between January 2022 and December 2023. The penton base, hexon, and fiber genes were amplified from HAdV-positive specimens and sequenced to determine the virus type. In cases with inconsistent typing results, genes were cloned into the pGEM-T vector to detect recombination events. Metagenomic next-generation sequencing (mNGS) was performed to characterize the recombinant HAdV genomes. RESULTS: Among 6,771 specimens, 277 (4.09%, 277/6,771) were positvie for HAdV, of which 157 (56.68%, 157/277) were successfully typed, with HAdV-B3 being the dominant type (91.08%, 143/157), and 14 (5.05%, 14/277) exhibited inconsistent typing results, six of which belonged to species B. The penton base genes of these six specimens were classified as HAdV-B7, whereas their hexon and fiber genes were classified as HAdV-B3, resulting in a recombinant genotype designated P7H3F3, which closely resembled HAdV-B114. Additionally, a partial gene encoding L1 52/55 kD was identified, which originated from HAdV-B16. CONCLUSION A novel recombinant, P7H3F3, was identified, containing sequences derived from HAdV-B3 and HAdV-B7, which is similar to HAdV-B114, along with additional sequences from HAdV-B16.
Humans ; Adenoviruses, Human/isolation & purification* ; Respiratory Tract Infections/epidemiology* ; Child, Preschool ; Child ; Recombination, Genetic ; Male ; Beijing/epidemiology* ; Infant ; Female ; Phylogeny ; Adenovirus Infections, Human/epidemiology* ; Acute Disease ; Genome, Viral

Objective:To explore the correlation between serum creatinine/cystatin C ratio (Scr/CysC) and muscle mass and muscle strength, and evaluate the predictive value of Scr/CysC for all-cause mortality in peritoneal dialysis patients.Methods:It was a prospective cohort study. The patients who received regular peritoneal dialysis treatment for more than 3 months and had stable conditions in the Renal Division of Peking University First Hospital from April 1, 2011 to August 1, 2012 were included, and the clinical data were collected. The patients were divided into the male group and the female group, and the differences of clinical data between the two groups were compared. The lean body mass (LBM) directly measured by the dual-energy X-ray absorptiometry (LBM-DEXA) was used as the reference gold standard and compared with the LBM estimated by the creatinine method (LBM-CK) and the anthropometric method (LBM-A). Muscle strength was measured by a grip strength meter for the dominant hand grip strength. Pearson correlation and multiple linear regression analysis method were used to analyze the correlations between Scr/CysC and LBM as well as grip strength, and subgroup analyses were conducted according to gender groups. Cox regression model was used to analyze the value of Scr/CysC in predicting all-cause mortality in peritoneal dialysis patients.Results:A total of 213 peritoneal dialysis patients were included in this study, including 95 males (44.6%) and 118 females (55.4%). The age was (56.46±12.42) years old. The dialysis age was 24.0 (9.0, 52.5) months. The baseline Scr/CysC was (1.77±0.73). LBM-DEXA ( t=-17.764, P<0.001), LBM-CK ( t=-7.702, P<0.001), LBM-A ( t=-16.813, P<0.001), grip strength ( t=-11.083, P<0.001) and Scr/CysC ( t=-2.965, P=0.003) in the male group were all significantly higher than those in the female group. Pearson correlation analysis showed that Scr/CysC was positively correlated with LBM-DEXA ( r=0.204, P=0.003), LBM-CK ( r=0.279, P<0.001), LBM-A ( r=0.198, P=0.004), and grip strength ( r=0.341, P<0.001). Multiple linear regression analysis showed that Scr/CysC wasn't independently correlated with LBM-DEXA, but was independently correlated with grip strength ( β=0.134, P=0.006). Cox regression analysis showed that baseline Scr/CysC was not an independent influencing factor of all-cause mortality in peritoneal dialysis patients ( HR=1.005, 95% CI 0.751-1.346, P=0.972). Conclusion:Scr/CysC is associated with muscle mass and muscle strength in peritoneal dialysis patients, but has no value in predicting all-cause mortality in peritoneal dialysis patients.

As the world's second largest vector of pathogens,ticks can spread a variety of pathogens by sucking the host's blood.Ticks not only threaten human life and health,but also cause great economic losses in animal husbandry.Artificial breeding of ticks can provide a stable environment for the growth and reproduction of ticks,thereby generating sufficient exper-imental materials for understanding ticks'biological characteristics,studying tick-borne pathogens,and developing anti-tick drugs and vaccines.Current methods of breeding ticks in the laboratory can be roughly divided into two categories:breeding methods using host animals or artificial membranes.The selection of breeding method must be comprehensively considered,ac-cording to tick types,blood-sucking habits,living environments,and other aspects.The development processes of the two methods,and their respective advantages and disadvantages,are described and discussed,to assist laboratories in artificial breeding of ticks.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Objective:To explore the correlation between serum creatinine/cystatin C ratio (Scr/CysC) and muscle mass and muscle strength, and evaluate the predictive value of Scr/CysC for all-cause mortality in peritoneal dialysis patients.Methods:It was a prospective cohort study. The patients who received regular peritoneal dialysis treatment for more than 3 months and had stable conditions in the Renal Division of Peking University First Hospital from April 1, 2011 to August 1, 2012 were included, and the clinical data were collected. The patients were divided into the male group and the female group, and the differences of clinical data between the two groups were compared. The lean body mass (LBM) directly measured by the dual-energy X-ray absorptiometry (LBM-DEXA) was used as the reference gold standard and compared with the LBM estimated by the creatinine method (LBM-CK) and the anthropometric method (LBM-A). Muscle strength was measured by a grip strength meter for the dominant hand grip strength. Pearson correlation and multiple linear regression analysis method were used to analyze the correlations between Scr/CysC and LBM as well as grip strength, and subgroup analyses were conducted according to gender groups. Cox regression model was used to analyze the value of Scr/CysC in predicting all-cause mortality in peritoneal dialysis patients.Results:A total of 213 peritoneal dialysis patients were included in this study, including 95 males (44.6%) and 118 females (55.4%). The age was (56.46±12.42) years old. The dialysis age was 24.0 (9.0, 52.5) months. The baseline Scr/CysC was (1.77±0.73). LBM-DEXA ( t=-17.764, P<0.001), LBM-CK ( t=-7.702, P<0.001), LBM-A ( t=-16.813, P<0.001), grip strength ( t=-11.083, P<0.001) and Scr/CysC ( t=-2.965, P=0.003) in the male group were all significantly higher than those in the female group. Pearson correlation analysis showed that Scr/CysC was positively correlated with LBM-DEXA ( r=0.204, P=0.003), LBM-CK ( r=0.279, P<0.001), LBM-A ( r=0.198, P=0.004), and grip strength ( r=0.341, P<0.001). Multiple linear regression analysis showed that Scr/CysC wasn't independently correlated with LBM-DEXA, but was independently correlated with grip strength ( β=0.134, P=0.006). Cox regression analysis showed that baseline Scr/CysC was not an independent influencing factor of all-cause mortality in peritoneal dialysis patients ( HR=1.005, 95% CI 0.751-1.346, P=0.972). Conclusion:Scr/CysC is associated with muscle mass and muscle strength in peritoneal dialysis patients, but has no value in predicting all-cause mortality in peritoneal dialysis patients.