Objective To explore the global and loci-specific genetic correlations and bidirectional causal relationships between spinal stenosis(SS)and constipation.Methods Utilizing the publicly available genome-wide association study data from the European population,linkage disequilibrium score regression and local analysis of variant association were used for quantifying genetic correlation at both global(genome-wide)and local(genomic regions)levels,and a two-sample Mendelian randomization(TSMR)analysis was conducted:Four distinct methods,namely the inverse variance weighting method,MR-Egger regression method,weighted median method,and weighted mode,were utilized for analysis and evaluation of the results;Cochran's Q test,leave-one-out method,MR-Egger intercept test,Mendelian randomization polymorphic residuals,and outlier tests were applied to examine the stability and reliability of the results.Results The analysis of linkage disequilibrium score regression and local analysis of variant association revealed that a total of 71 regions had at least one pair of traits with local genetic correlations.The TSMR analysis,with SS as the exposure and constipation as the outcome,based on the results of the inverse variance weighting method,suggested a causal relationship between two(OR=1.077,95％CI:1.034-1.122,P=0.000);Cochran's Q test and MR-Egger intercept test indicated the absence of heterogeneity or pleiotropy,and were verified by the analysis of Mendelian randomization polymorphic residuals,and outlier tests,demonstrating that the results of this study did not exhibit horizontal pleiotropy;The sensitivity analysis using the leave-one-out method indicated that the research results were stable.With constipation as the exposure factor and SS as the outcome,no eligible instrumental variables were found.Conclusion There are significant global and loci-specific genetic correlations between SS and constipation,and SS may be a risk factor for the occurrence of constipation.

Objective:To investigate immunotherapy effects and mechanism of BCG and recombinant BCG(rBCG)with c-di-AMP as adjuvant on melanoma in mice model.Methods:Melanoma mice model was established by B16F10 cell subcutaneous injec-tion in groin,and treated with 1×106 CFU of BCG and rBCG by adjacent injection of subcutaneous tumor for 3 times,respectively.Survival of melanotic mice,tumor growth and metastasis were observed.Tumor tissues of mice were isolated to prepare cell suspen-sion,and proportion of immune cells were detected by flow cytometry.Transcriptional levels of immune-related genes in tumor tissues were detected by qRT-PCR.Results:Both BCG and rBCG immunotherapy could significantly inhibit growth in melanoma mice and prolong survival time of mice.rBCG showed better inhibition on metastasis than BCG.Both strains significantly reduced proportion of M2-type macrophages and myeloid-derived suppressor cell associated with tumor growth and metastasis.Both two strains promoted infiltration of lymphocytes in tumor tissues,and rBCG significantly increased proportion of B cells in tumor.BCG immunotherapy upregulated transcription levels of metastasis-related cytokines,while rBCG therapy had no effects on transcriptions of these genes.Conclusion:Both BCG and rBCG have immunotherapeutic effects on melanotic mice,and rBCG with c-di-AMP as adjuvant shows better inhibition on tumor metastasis than BCG,which mechanism was related to regulation of immune response in tumor tissues.

Objective:To investigate immunotherapy effects and mechanism of BCG and recombinant BCG(rBCG)with c-di-AMP as adjuvant on melanoma in mice model.Methods:Melanoma mice model was established by B16F10 cell subcutaneous injec-tion in groin,and treated with 1×106 CFU of BCG and rBCG by adjacent injection of subcutaneous tumor for 3 times,respectively.Survival of melanotic mice,tumor growth and metastasis were observed.Tumor tissues of mice were isolated to prepare cell suspen-sion,and proportion of immune cells were detected by flow cytometry.Transcriptional levels of immune-related genes in tumor tissues were detected by qRT-PCR.Results:Both BCG and rBCG immunotherapy could significantly inhibit growth in melanoma mice and prolong survival time of mice.rBCG showed better inhibition on metastasis than BCG.Both strains significantly reduced proportion of M2-type macrophages and myeloid-derived suppressor cell associated with tumor growth and metastasis.Both two strains promoted infiltration of lymphocytes in tumor tissues,and rBCG significantly increased proportion of B cells in tumor.BCG immunotherapy upregulated transcription levels of metastasis-related cytokines,while rBCG therapy had no effects on transcriptions of these genes.Conclusion:Both BCG and rBCG have immunotherapeutic effects on melanotic mice,and rBCG with c-di-AMP as adjuvant shows better inhibition on tumor metastasis than BCG,which mechanism was related to regulation of immune response in tumor tissues.

Objective To explore the global and loci-specific genetic correlations and bidirectional causal relationships between spinal stenosis(SS)and constipation.Methods Utilizing the publicly available genome-wide association study data from the European population,linkage disequilibrium score regression and local analysis of variant association were used for quantifying genetic correlation at both global(genome-wide)and local(genomic regions)levels,and a two-sample Mendelian randomization(TSMR)analysis was conducted:Four distinct methods,namely the inverse variance weighting method,MR-Egger regression method,weighted median method,and weighted mode,were utilized for analysis and evaluation of the results;Cochran's Q test,leave-one-out method,MR-Egger intercept test,Mendelian randomization polymorphic residuals,and outlier tests were applied to examine the stability and reliability of the results.Results The analysis of linkage disequilibrium score regression and local analysis of variant association revealed that a total of 71 regions had at least one pair of traits with local genetic correlations.The TSMR analysis,with SS as the exposure and constipation as the outcome,based on the results of the inverse variance weighting method,suggested a causal relationship between two(OR=1.077,95％CI:1.034-1.122,P=0.000);Cochran's Q test and MR-Egger intercept test indicated the absence of heterogeneity or pleiotropy,and were verified by the analysis of Mendelian randomization polymorphic residuals,and outlier tests,demonstrating that the results of this study did not exhibit horizontal pleiotropy;The sensitivity analysis using the leave-one-out method indicated that the research results were stable.With constipation as the exposure factor and SS as the outcome,no eligible instrumental variables were found.Conclusion There are significant global and loci-specific genetic correlations between SS and constipation,and SS may be a risk factor for the occurrence of constipation.

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems

Objective:To investigate and analyse the current status of screening and management of diabetic kidney disease (DKD) in six provinces and cities in China.Methods:The qualitative research method of focus group interview was adopted, based on the semi-structured interview outline, the clinical medical and disease control personnel in Tianjin, Chongqing, Gansu, Hubei, Heilongjiang, and Guangdong were interviewed. The interview transcripts were analyzed using thematic analysis, and MAXQDA analysis software was used for data management and analysis.Results:A total of 6 interviews were conducted with 49 interviewees. Forty respondents (81.6%) claimed that DKD screening was critical; 53.1% think that it was not easy for patients to obtain DKD screening services; 40.8%, 26.5% and 14.3% of the people believed that the technology of DKD screening services was moderate, simple or very simple, respectively. Of the respondents,16.3% thought that the cost of DKD screening service was relatively expensive, while 83.7% thought that the cost was inexpensive; 75.5% of the respondents believed that the patients could receive early DKD screening service. The factors of fully implementing medical reform policies, changing concepts and actively serving patients, and integrating external resources in medical and health institutions at all levels and of all types were conducive to the development of DKD screening and management services. The lack of technology and personnel for DKD screening services at the grassroots level, the lack of trust in the service capabilities of grassroots medical institutions by patients, the low level of patient awareness, and the novel coronavirus infection epidemic had an adverse impact on the development of DKD screening and management services.Conclusion:The screening and management services for DKD are relatively limited in China, and there is a significant fragmentation in the management and care of diabetes and DKD.

Objective:To understand the etiology and clinical characteristics of hospitalized severe community-acquired pneumonia(SCAP) in Changchun, and provide scientific basis for its etiology diagnosis and targeted treatment.Methods:The study subjects included 618 children with clinical diagnosis of SCAP who were hospitalized from January 2016 to December 2019.We collected pharyngeal swabs and alveolar lavage fluid from children.Virus isolation, bacterial culture, time-of-flight mass spectrometry, PCR/RT-PCR, colloidal gold method and Optochin test were used to detect the antigen, nucleic acid and protein profiles in the specimen.Results:There were more boys than girls in hospitalized children with SCAP.The peak age of onset was 7 to 12 months.Most cases occurred in winter and spring.The highest detection rate of SCAP virus was 56.15%(347/618); 73.49%(255/347) were positive for one virus, among which the top five were respiratory syncytial virus (27.8%), influenza A virus (23.9%), influenza B virus (16.1%), rhinovirus (12.2%) and metapneumovirus (10.2%). Two viruses were positive for 19.88%(69/347); three viruses were positive for 4.32%(15/347); four viruses were positive for 2.31%(8/347). Atypical microbial infections were 29.77%(184/618), of which Mycoplasma pneumoniae accounted for 95.65%(176/184). Bacterial infections were 17.31%(107/618), mainly Streptococcus pneumoniae(39.25%, 42/107) and Staphylococcus aureus(24.30%, 26/107). The mixed infection of multiple pathogens was 7.61%(47/618), among which the mixed infection rates of Mycoplasma pneumonia with Streptococcus pneumoniae, virus were 40.43% and 34.04%, respectively.High fever, faster breathing, and perioral cyanosis were risk factors for SCAP, with OR and 95% CI of 7.71 and 4.56-13.04, 2.43 and 2.02-2.93, 3.53 and 2.56-4.86, respectively.Viral co-infection occurred in 36.96%(34/92) of complications such as heart failure, toxic encephalopathy, and myocardial damage; Mycoplasma pneumoniae and other pathogens co-infected 35.29% of children with pleural effusion. Conclusion:The pathogens of SCAP in Changchun are mainly viruses notably, respiratory syncytial virus is the dominant pathogen, followed by Mycoplasma pneumoniae.The bacterial pathogen is mainly Streptococcus pneumoniae.High fever, faster breathing, and cyanosis around the mouth are risk factors for severe pneumonia.Multi-pathogen mixed infection is prone to serious complications.

Background: Postherpetic neuralgia (PHN) is the most common complication of acute herpes zoster. The treatment of PHN remains a challenge for clinical pain management. Despite the effectiveness of anticonvulsants, antidepressants, and lidocaine patches in reducing PHN, many patients still face intractable pain disorders.In this randomized controlled study, we evaluated whether hydromorphone through intravenous patient-controlled analgesia (IV PCA) was effective in relieving PHN. Methods: Patients with PHN were randomly divided into two groups, one group received oral pregabalin with IV normal saline, another group received oral pregabalin with additional IV PCA hydromorphone for two weeks. Efficacy was evaluated at 1, 4, and 12 weeks after the end of the treatments. Results: Two hundred and one patients were followed up for 12 weeks. After treatment, numerical rating scale (NRS) score of patients in the hydromorphone group was significantly lower than that of the control group, and the difference of NRS scores between the two groups was statistically significant at 4 and 12 weeks after treatment. The frequency of breakthrough pain in the hydromorphone group was significantly lower than that in the control group 1 and 4 weeks after treatment.After treatment, the quality of sleep in the hydromorphone group was significantly improved compared with the control group. The most common adverse reactions in the hydromorphone group were dizziness and nausea, with no significant respiratory depression. Conclusions IV PCA hydromorphone combined with oral pregabalin provides superior pain relief in patients with PHN, which is worthy of clinical application and promotion.

Background: Postherpetic neuralgia (PHN) is the most common complication of acute herpes zoster. The treatment of PHN remains a challenge for clinical pain management. Despite the effectiveness of anticonvulsants, antidepressants, and lidocaine patches in reducing PHN, many patients still face intractable pain disorders.In this randomized controlled study, we evaluated whether hydromorphone through intravenous patient-controlled analgesia (IV PCA) was effective in relieving PHN. Methods: Patients with PHN were randomly divided into two groups, one group received oral pregabalin with IV normal saline, another group received oral pregabalin with additional IV PCA hydromorphone for two weeks. Efficacy was evaluated at 1, 4, and 12 weeks after the end of the treatments. Results: Two hundred and one patients were followed up for 12 weeks. After treatment, numerical rating scale (NRS) score of patients in the hydromorphone group was significantly lower than that of the control group, and the difference of NRS scores between the two groups was statistically significant at 4 and 12 weeks after treatment. The frequency of breakthrough pain in the hydromorphone group was significantly lower than that in the control group 1 and 4 weeks after treatment.After treatment, the quality of sleep in the hydromorphone group was significantly improved compared with the control group. The most common adverse reactions in the hydromorphone group were dizziness and nausea, with no significant respiratory depression. Conclusions IV PCA hydromorphone combined with oral pregabalin provides superior pain relief in patients with PHN, which is worthy of clinical application and promotion.

Objective:To construct a perioperative nursing planning for patients with esophageal cancer based on the concept of enhanced recovery after surgery (ERAS) , so as to provide a basis for the development of ERAS nursing for patients with esophageal cancer during perioperative period.Methods:From November 2019 to September 2020, a perioperative ERAS nursing planning for patients with esophageal cancer was constructed through literature retrieval, field observation, Delphi expert consultation, and analytic hierarchy process.Results:A total of two rounds of expert consultations were conducted. The valid recovery rates of the questionnaire were 95.24% (20/21) and 100.00% (20/20) , and the expert authority coefficients were 0.89 and 0.93. The Kendall harmony coefficients were 0.25 and 0.34 ( P<0.01) . The perioperative enhanced recovery nursing planning for patients with esophageal cancer included 5 first-level indicators, 17 second-level indicators and 49 third-level indicators. Conclusions:The perioperative enhanced recovery nursing planning for patients with esophageal cancer is scientific and reliable, and can effectively standardize and guide the development of clinical nursing work.