This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

This study identified the types and pathogen carrying status of fleas on the surface of sheep in some areas of southern Xinjiang,and analyzed the genetic evolution differences with respect to related pathogens.The aim was to provide a reference for the local prevention and control of fleas and insect borne infectious diseases.A total of 1 586 fleas were collected from agricultural and pas-toral areas of Tumushuke City and Hotan Prefecture.Flea species were identified on the basis of morphology and the Pulex irritans mi-tochondrial COII gene.Flea DNA was extracted,and PCR was conducted to amplify the Bartonella gltA gene;Arsenophonus,Ana-plasma,Ehrlichia,and Wolbachia 16S rRNA genes;RickettsiaOmpA,17kDa,16S rRNA genes,and Yersinia pestis 16S rDNA gene.The amplified products were sequenced,and the homology of the genes of the three detected pathogens(gltA gene of Bartonella,16S rRNA gene of Wolbachia,and Anaplasma phagocytophilum)with respect to known corresponding genes of the same pathogen in Gen-Bank was analyzed.Phylogenetic trees were constructed with the adjacency method in MEGA 11.0.According to morphological and mo-lecular biology identification results,all fleas collected in this study were Pulex irritans.PCR indicated that the target gene fragments had been added to the mitochondrial COII,BartonellagltA,Wolbachia,and autophagosomal 16S rRNA genes of human fleas,all of which were consistent with the expected fragment sizes.Target bands were not amplified from Ehrlichia,Arsenophonus,spotted fever group Rickettsia,and Yersinia pestis.According to homology and genetic evolution analysis of human flea mitochondrial COII and the corresponding genes of the above-described pathogens,the COX2 gene(ON455234.1)of human fleas in Tumushuke city and Iran ob-tained in this study showed the highest homology(99.84%).The COII gene(NC_063709.1)of human fleas in Hetan City and Hunan region showed the highest homology(100%).Our findings further confirmed that the flea species was Pulex irritans.The PCR amplifi-cation results indicated that the collected Pulex irritans carried multiple pathogens,among which Bartonella and Wolbachia had the highest infection rates,and the infection rate with Anaplasma phagocytophilum was relatively low.This study is the first to discover flea species on the surface of sheep in some areas of southern Xinjiang.Our findings preliminarily confirmed that Bartonella,Wolba-chia,and Anaplasma phagocytophilum are the main Pulex irritans pathogens.

The aim of this experiment was to study the effects of different feeding modes on growth performance,blood biochemical indexes and intestinal flora of lactating Holstein male calves.Twenty-four newborn Holstein male calves with body mass of(40.00±1.01)kg and similar day old were selected and randomly divided into four groups of six calves each.The subgroups were low-milk group(LM),high-milk group(HM),high-milk milk replacer feeding group(HMR),and low-milk switching to high-milk milk replacer feeding group(CMR).The results showed that:At 45 d,the body mass of calves in the HM group was significantly higher than that of calves in the other groups(P＜0.05),and at 60 d,the body mass of calves in the HM group was significantly higher than that of calves in the LM &.CMR groups(P＜0.05).At 90 d,the body mass of calves in the LM group was significantly higher than that of calves in the HM group.Throughout the ex-perimental period,the average daily weight gain and average pellet feed intake of calves in the LM group were significantly higher than that of calves in the HM group(P＜0.05).The calf globulin level in the HMR group was significantly higher than that in the LM and HM groups(P＜0.05);the plasma immunoglobulin A level of calves in the HM group was significantly lower than that of calves in the LM and HMR groups(P＜0.05);and the plasma immunoglobulin M level of calves in the HM group was significantly higher than that of calves in the LM and CMR groups(P＜0.05),and HMR group was also significantly higher than that of LM group(P＜0.05);plasma glutathione peroxidase level of calves in HMR group was significantly higher than that of LM group(P＜0.05);plasma malondialdehyde level of calves in LM group was significantly higher than that of calves in HMR and HM groups(P＜0.05),and CMR group was also significantly higher than that of HM group(P＜0.05).Relative abundance of Thermodesulfovibrio was higher in the HM group(P＜0.05),relative abundance of Bacteroidetes in the LM group was significantly higher than that in the HMR and HM groups(P＜0.05),relative abundance of Blautia in the HM group(P＜0.05),and relative abundance of Corynebacterium in the CMR group was significantly higher than that in the LM and HM groups(P＜0.05).In summary,calves in the LM group had better weaning weights and pellet feed intake;calves in the CMR group could compensate for growth by supplemental feeding of milk replacer to obtain more optimal weaning weights and pel-let feed intake;the HMR group proved that milk-free feeding could ensure stable growth of calves;and calves in the HM group had a better pre-lactation growth performance,lower levels of oxida-tive stress,and a healthier fecal flora.

Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.

This article reports the case of an adolescent patient presenting with recurrent epistaxis and orthostatic hypoxemia. Chest imaging revealed multiple bilateral pulmonary nodules of varying sizes and mixed densities. The presence of intrapulmonary right-to-left shunting was confirmed through bubble contrast echocardiography, pulmonary first-pass perfusion imaging, and the pure oxygen inhalation formula method. Whole-genome sequencing identified a mutation in the SMAD4 gene, and subsequent family analysis confirmed the diagnosis of hereditary hemorrhagic telangiectasia (HHT). Currently, there is no international consensus on the management of such rare presentations. Based on relevant case reports in the literature, the patient was empirically treated with a combination of amlodipine and thalidomide. After one year of follow-up, significant improvement in hypoxemia was observed. The diagnostic and therapeutic process of this case offers valuable insights for the clinical management of patients with mixed-type PAVMs caused by HHT.

Objective To explore the value of oral contrast-enhanced ultrasonography (OCEUS) combined with contrast-enhanced CT in predicting preoperative T staging in patients with gastric cancer. Methods A retrospective analysis was conducted on 80 patients with gastric cancer confirmed via endoscopic biopsy or postoperative pathology at the First People’s Hospital of Jining from January 2021 to November 2024. The cohort included 56 males and 24 females, aged 38-79 years, with a median age of 55.9 years. All patients underwent both OCEUS and contrast-enhanced CT within one week prior to surgery. T staging of gastric cancer was determined using OCEUS, contrast-enhanced CT, or their combination. The results were compared with pathological T staging, and statistical differences in accuracy were analyzed. Results Pathological T staging identified T1 in 9 cases, T2 in 16 cases, T3 in 42 cases, and T4 in 13 cases. OCEUS indicated T1 in 6 cases, T2 in 14 cases, T3 in 50 cases, and T4 in 10 cases, with an accuracy rate of 80.0%. Contrast-enhanced CT indicated T1 in 4 cases, T2 in 12 cases, T3 in 52 cases, and T4 in 12 cases, with an accuracy rate of 75.0%. The combination of OCEUS and contrast-enhanced CT indicated T1 in 6 cases, T2 in 15 cases, T3 in 47 cases, and T4 in 12 cases, with an accuracy rate of 87.5%. The combined approach demonstrated significantly higher accuracy in preoperative T staging compared to either method alone (P < 0.05). Conclusion The combination of OCEUS and contrast-enhanced CT improves the accuracy of preoperative T staging in gastric cancer patients, providing valuable support for their diagnosis and treatment.

BACKGROUND: The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). METHODS: We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18 years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. RESULTS: The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80 mg/day and subsequently maintained the maximal dose up to 160 mg/day while the predictive curves of nefazodone were fairly flat in different dosages. CONCLUSIONS: Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit. REGISTRATION No. CRD42023427480; https://www.crd.york.ac.uk/prospero/display_record.php?
Humans ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Dose-Response Relationship, Drug ; Randomized Controlled Trials as Topic

Objective:To explore the potential value of dynamic changes of inflammatory factors in evaluating the efficacy of platinum regimen in the first-line treatment of advanced lung adenocarcinoma(LUAD).Methods:A total of 121 patients with advanced LUAD without common target mutations who were admitted to Dongtai People's Hospital to receive first-line treatment with platinum regimen from January 2021 to January 2023 were selected,and relevant clinical data such as general information,hematuria routine,angiogenic factors,serum tumor markers,inflammatory factors,immunoglobulin and T lymphocyte indexes were collected and statisti-cally analyzed.Patients in complete response(CR)group and partial response(PR)group were classified as chemotherapy sensitive group;stable(SD)group and progressive(PD)group were classified as chemotherapy insensitive group according to response evaluation criteria in solid tumors(RECIST).Through univariate and multi-factor Logistics regression analysis,the influencing factors of first-line treatment efficacy of platinum regimen in patients with advanced LUAD were analyzed,and the regression equation y=1-1/(1+e-z)prediction model was established and verified.Receiver operating characteristic(ROC)curve was used to analyze the potential value of dynamic changes of inflammatory factors in evaluating the efficacy of platinum-based first-line treatment for advanced LUAD.Results:①Univariate and multivariate Logistic regression analysis showed that CEA,TNF-α,IL-6,IL-8,IL-18,IL-1β and hs-CRP were still the influencing factors for the efficacy of first-line chemotherapy of platinum regimen in patients with advanced LUAD(P<0.05).②Inflammatory factors TNF-α,IL-6,IL-8,IL-18,IL-1β and hs-CRP were included in multivariate Logistic regression analysis.After correcting confounders(Model 5),high levels of TNF-α,IL-6,IL-8,IL-18,IL-1β and hs-CRP were positively correlated with insensitivity after first-line chemotherapy of platinum regimen in advanced LUAD patients(P<0.05).Restrictive cubic spline model analysis showed that the dynamic changes of inflammatory factors and the insensitivity of patients with advanced LUAD after first-line chemotherapy all had a nonlinear dose-response relationship.With the increases of TNF-α,IL-6,IL-8,IL-18,IL-1β and hs-CRP levels,patients with advanced LUAD have a greatly increased risk of desensitization after first-line chemotherapy.③Stratified interaction test analysis showed that tumor stage,differentiation degree and lymph node metastasis before and after correction factors were significantly correlated with expressions of inflammatory factors(all P<0.05,all P interaction<0.05).④Prediction model based on the influence factors of inflammatory factors was well distinguished and accurate,the area under ROC curve(AUC)before and after internal validation for detecting chemotherapy sensitivity in patients with advanced LUAD treated with platinum regimen first-line therapy was 0.87(95%CI:0.81～0.93)and 0.88(95%CI:0.82～0.95),respectively,and the sensitivity were 89.69%and 89.75%,respectively,the specificity were 91.77%and 91.85%,respectively.Conclusion:Dynamic changes of inflammatory factors is an important factor affecting the chemotherapy efficacy of patients with advanced LUAD treated with platinum-containing regimen.With the significant decrease of inflammatory factors,the sensitivity of patients to chemotherapy is also significantly increased.

This study identified the types and pathogen carrying status of fleas on the surface of sheep in some areas of southern Xinjiang,and analyzed the genetic evolution differences with respect to related pathogens.The aim was to provide a reference for the local prevention and control of fleas and insect borne infectious diseases.A total of 1 586 fleas were collected from agricultural and pas-toral areas of Tumushuke City and Hotan Prefecture.Flea species were identified on the basis of morphology and the Pulex irritans mi-tochondrial COII gene.Flea DNA was extracted,and PCR was conducted to amplify the Bartonella gltA gene;Arsenophonus,Ana-plasma,Ehrlichia,and Wolbachia 16S rRNA genes;RickettsiaOmpA,17kDa,16S rRNA genes,and Yersinia pestis 16S rDNA gene.The amplified products were sequenced,and the homology of the genes of the three detected pathogens(gltA gene of Bartonella,16S rRNA gene of Wolbachia,and Anaplasma phagocytophilum)with respect to known corresponding genes of the same pathogen in Gen-Bank was analyzed.Phylogenetic trees were constructed with the adjacency method in MEGA 11.0.According to morphological and mo-lecular biology identification results,all fleas collected in this study were Pulex irritans.PCR indicated that the target gene fragments had been added to the mitochondrial COII,BartonellagltA,Wolbachia,and autophagosomal 16S rRNA genes of human fleas,all of which were consistent with the expected fragment sizes.Target bands were not amplified from Ehrlichia,Arsenophonus,spotted fever group Rickettsia,and Yersinia pestis.According to homology and genetic evolution analysis of human flea mitochondrial COII and the corresponding genes of the above-described pathogens,the COX2 gene(ON455234.1)of human fleas in Tumushuke city and Iran ob-tained in this study showed the highest homology(99.84%).The COII gene(NC_063709.1)of human fleas in Hetan City and Hunan region showed the highest homology(100%).Our findings further confirmed that the flea species was Pulex irritans.The PCR amplifi-cation results indicated that the collected Pulex irritans carried multiple pathogens,among which Bartonella and Wolbachia had the highest infection rates,and the infection rate with Anaplasma phagocytophilum was relatively low.This study is the first to discover flea species on the surface of sheep in some areas of southern Xinjiang.Our findings preliminarily confirmed that Bartonella,Wolba-chia,and Anaplasma phagocytophilum are the main Pulex irritans pathogens.

Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.