A Systematic Review and Meta-analysis of Renin-angiotensin System Inhibitors and Angiotensin Receptor Neprilysin Inhibitors in Preventing Recurrence After Atrial Fibrillation Ablation.

ABSTRACT: To systematically evaluate the efficacy and safety of renin-angiotensin system inhibitors (RASIs) and angiotensin receptor neprilysin inhibitors in preventing the recurrence of atrial fibrillation after atrial fibrillation ablation, we have written this meta-analysis. We systematically searched randomized controlled trials or cohort studies on RASIs and angiotensin receptor neprilysin inhibitor-sacubitril/valsartan (SV) in preventing the recurrence of atrial fibrillation. Two researchers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies. Afterward, the meta-analysis was performed using RevMan 5.3 software. This meta-analysis results showed that the recurrence rate of atrial fibrillation after ablation in subjects using RASIs was lower than that in subjects not using them [relative risk = 0.85, 95% confidence interval (CI) (0.72-0.99), P = 0.03]; the recurrence rate in subjects using SV was lower than that in subjects using RASIs [RR= 0.50, 95% CI (0.37-0.68), P < 0.00001]. These results show that both the use of RASIs and SV can prevent the recurrence of after atrial fibrillation ablation, among which the use of SV is more effective.

Complete Genome Sequence of Bacillus velezensis TH-1, a Candidate Biocontrol Bacterium from China.

Bacillus velezensis TH-1 is a plant growth-promoting rhizobacteria with biocontrol potential that was isolated from the rhizosphere of Sophora tonkinensis Radix. Our previous results showed that strain TH-1 demonstrated effective biocontrol activity against root rot of Sophora tonkinensis Radix and bacterial wilt of ginger. Currently, only a few whole-genome sequences of biocontrol strains isolated from the rhizosphere of medicinal plants are available. We report, here, the complete genome sequence of B. velezensis TH-1. The size of TH-1 genome is 3,929,846 bp that consists of 3,900 genes with a total GC content of 46.48%. The strain TH-1 genome has 3,661 coding genes, 86 transfer RNAs, 27 ribosomal RNAs, and 16 small RNAs. Moreover, we identified nine gene clusters coding for the biosynthesis of antimicrobial compounds. The genomic information of TH-1 will provide resources for the study of biological control mechanisms and plant-microbe interactions. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Fengycin produced by Bacillus subtilis XF-1 plays a major role in the biocontrol of Chinese cabbage clubroot via direct effect and defense stimulation.

Bacillus subtilis XF-1 is a well-investigated biocontrol agent against the biotrophic Plasmodiophora brassicae Woron., the causal agent of clubroot disease of cruciferous crops. The present study demonstrates that XF-1 could efficiently control clubroot disease via leaf spraying and provides an understanding of the biocontrol mechanisms. High-performance thin-layer chromatography (HTPLC) analysis indicated the presence of fengycin-type cyclopeptides in the supernatant. A ppsB deletion mutant of XF-1 resulted in no fengycin production, significantly reduced the lysis rate of testing spores in vitro and the primary infection rate of root hair in vivo, and decreased the protection value against clubroot disease under the greenhouse conditions. Confocal laser scanning microscopy proved that fengycin was not required for leaf internalization and root colonization. Moreover, the expression level of the ppsB gene in XF-1 was regulated by its cell density in root during interaction with P. brassicae. In addition, the ΔppsB mutant of XF-1 could not efficiently control disease because it led to a lower activation level of the jasmonic acid and salicylic acid signaling pathways in roots, which are necessary for the plant defense reaction upon pathogen invasion. Altogether, the present study provides a new understanding of specific cues in the interaction between B. subtilis and P. brassicae as well as insights into the application of B. subtilis in agriculture.

Comparative assessment of efficacy and safety of approved oral therapies for overactive bladder: a systematic review and network meta-analysis.

bladder based on a systematic review and network meta-analysis approach. METHODS: Pubmed, Embase, Web of Science, and the Cochrane Register of Clinical Trials databases were systematically searched. The search time frame was from database creation to June 2, 2022. Randomized controlled double-blind trials of oral medication for overactive bladder were screened against the protocol's entry criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 software. RESULT: A total of 60 randomized controlled double-blind clinical trials were included involving 50,333 subjects. Solifenacin 10mg was the most effective in mean daily micturitions and incontinence episodes, solifenacin 5/10mg in mean daily urinary urgency episodes and nocturia episodes, fesoterodine 8mg in urgency incontinence episodes/d and oxybutynin 5mg in voided volume/micturition. In terms of safety, solifenacin 5mg, ER-tolterodine 4mg, mirabegron, vibegron and ER-oxybutynin 10mg all showed a better incidence of dry mouth, fesoterodine 4mg, ER-oxybutynin 10mg, tolterodine 2mg, and vibegron in the incidence of constipation. Compared to placebo, imidafenacin 0.1mg showed a significantly increased incidence in hypertension, solifenacin 10mg in urinary tract infection, fesoterodine 4/8mg and darifenacin 15mg in headache. CONCLUSION: Solifenacin showed better efficacy. For safety, most anticholinergic drugs were more likely to cause dry mouth and constipation, lower doses were better tolerated. The choice of drugs should be tailored to the patient's specific situation to find the best balance between efficacy and safety.

Efficacy and safety of single-dose antiviral drugs for influenza treatment: A systematic review and network meta-analysis.

To conduct network meta-analysis (NMA) of clinical efficacy and safety of single-dose antiviral drugs, grouped by dosage, in treatment of influenza. Systematic retrievals were conducted in databases, including Pubmed, Embase, Web of Science, the Cochrane Register of Clinical Trials and from the website ClinicalTrials.gov, for clinical trials recorded between the interception of the databases and March 31, 2021. Randomized controlled trials (RCTs) of influenza treatment in which single-dose antiviral drugs were administered were selected according to preset inclusion and exclusion criteria by two researchers who screened the literature independently from each other. The quality of the included studies was assessed using the Cochrane bias risk assessment tool. Software such as Stata 16.0 and Review Manager 5.3 was adopted for statistical analysis. Pairwise meta-analysis and NMA were carried out under the random-effects model. For both binary and continuous variables, odds ratio (OR), mean difference (MD) and their 95% confidence intervals (CI) were used to rank treatment efficiencies and analyze the differences. A total of 12 RCTs involving 7296 participants were included in the analysis. According to the NMA results, peramivir 300 mg (MD = -17.68, 95% CI: [-34.05, -1.32]), peramivir 600 mg (MD = -16.15, 95% CI: [-29.35, -2.95]), baloxavir (MD = -14.67, 95% CI: [-26.75, -2.58]) and laninamivir 40 mg (MD = -12.42, 95% CI: [-22.53, -2.31]) remarkably outperformed laninamivir 20 mg in time to alleviation of symptoms (TTAS). However, no intervention statistically outperform others in antipyretic time, virus titer variations against the baseline 24 and 48 h after medication and adverse events (AEs). The efficacy rankings were: peramivir 300 mg (the surface under the cumulative ranking curve [SUCRA] = 80.3%) > peramivir 600 mg (SUCRA = 76.2%) > baloxavir (SUCRA = 68.4%) > laninamivir 40 mg (SUCRA = 55.0%) > laninamivir 20 mg (SUCRA = 16.6%) for TTAS; baloxavir (SUCRA = 76.3%) > peramivir 600 mg (SUCRA = 67.8%) > laninamivir 40 mg (SUCRA = 47.2%) > laninamivir 20 mg (SUCRA = 40.0%) for antipyretic time; baloxavir (SUCRA = 96.7%) > peramivir 300 mg (SUCRA = 64.5%) ≈ peramivir 600 mg (SUCRA = 63.2%), baloxavir (SUCRA = 93.2%) > peramivir 600 mg (SUCRA = 64.0%) ≈ peramivir 300 mg (SUCRA = 55.0%), for virus titer variations against the baseline 24 and 48 h after medication, respectively; and baloxavir (SUCRA = 83.4%) > peramivir 300 mg (SUCRA = 71.4%) > laninamivir 20 mg (SUCRA = 62.4%) > peramivir 600 mg (SUCRA = 56.2%) > laninamivir 40 mg (SUCRA = 36.8%) for adverse events. Among the single-dose anti-influenza virus drugs compared, peramivir is superior to baloxavir and laninamivir in TTAS, whereas baloxavir has the best efficacy in antipyretic time, virus titer variations against the baseline 24 and 48 h after medication and AEs. This study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO), with a registration number of CRD42021238220.

Gene-based association analysis reveals involvement of LAMA5 and cell adhesion pathways in nicotine dependence in African- and European-American samples.

Nicotine dependence (ND) is a chronic brain disorder that causes heavy social and economic burdens. Although many susceptibility genetic loci have been reported, they can explain only approximately 5%-10% of the genetic variance for the disease. To further explore the genetic etiology of ND, we genotyped 242 764 SNPs using an exome chip from both European-American (N = 1572) and African-American (N = 3371) samples. Gene-based association analysis revealed 29 genes associated significantly with ND. Of the genes in the AA sample, six (i.e., PKD1L2, LAMA5, MUC16, MROH5, ATP8B1, and FREM1) were replicated in the EA sample with p values ranging from 0.0031 to 0.0346. Subsequently, gene enrichment analysis revealed that cell adhesion-related pathways were significantly associated with ND in both the AA and EA samples. Considering that LAMA5 is the most significant gene in cell adhesion-related pathways, we did in vitro functional analysis of this gene, which showed that nicotine significantly suppressed its mRNA expression in HEK293T cells (p < 0.001). Further, our cell migration experiment showed that the migration rate was significantly different in wild-type and LAMA5-knockout (LAMA5-KO)-HEK293T cells. Importantly, nicotine-induced cell migration was abolished in LAMA5-KO cells. Taken together, these findings indicate that LAMA5, as well as cell adhesion-related pathways, play an important role in the etiology of smoking addiction, which warrants further investigation.

Genetic and Epigenetic Analysis Revealing Variants in the NCAM1-TTC12-ANKK1-DRD2 Cluster Associated Significantly With Nicotine Dependence in Chinese Han Smokers.

BACKGROUNDS: Although studies have demonstrated that the NCAM1-TTC12-ANKK1-DRD2 gene cluster plays essential roles in addictions in subjects of European and African origin, study of Chinese Han subjects is limited. Further, the underlying biological mechanisms of detected associations are largely unknown. METHODS: Sixty-four single-nucleotide polymorphisms (SNPs) in this cluster were analyzed for association with Fagerstrom Test for Nicotine Dependence score (FTND) and cigarettes per day (CPD) in male Chinese Han smokers (N = 2616). Next-generation bisulfite sequencing was used to discover smoking-associated differentially methylated regions (DMRs). Both cis-eQTL and cis-mQTL analyses were applied to assess the cis-regulatory effects of these risk SNPs. RESULTS: Association analysis revealed that rs4648317 was significantly associated with FTND and CPD (p = .00018; p = .00072). Moreover, 14 additional SNPs were marginally significantly associated with FTND or CPD (p = .05-.01). Haplotype-based association analysis showed that one haplotype in DRD2, C-T-A-G, formed by rs4245148, rs4581480, rs4648317, and rs11214613, was significantly associated with CPD (p = .0005) and marginally associated with FTND (p = .003). Further, we identified four significant smoking-associated DMRs, three of which are located in the DRD2/ANKK1 region (p = .0012-.00005). Finally, we found five significant CpG-SNP pairs (p = 7.9 × 10-9-6.6 × 10-6) formed by risk SNPs rs4648317, rs11604671, and rs2734849 and three methylation loci. CONCLUSIONS: We found two missense variants (rs11604671; rs2734849) and an intronic variant (rs4648317) with significant effects on ND and further explored their mechanisms of action through expression and methylation analysis. We found the majority of smoking-related DMRs are located in the ANKK1/DRD2 region, indicating a likely causative relation between non-synonymous SNPs and DMRs. IMPLICATIONS: This study shows that there exist significant association of variants and haplotypes in ANKK1/DRD2 region with ND in Chinese male smokers. Further, this study also shows that DNA methylation plays an important role in mediating such associations.

Demonstration of critical role of GRIN3A in nicotine dependence through both genetic association and molecular functional studies.

Nicotine dependence (ND) is a chronic disease with catastrophic effects on individual and public health. The glutamate receptor subunit gene, ionotropic N-methyl-d-aspartate 3A (GRIN3A), encodes a crucial subunit of N-methyl-d-aspartate receptors (NMDARs), which play an essential role in synaptic plasticity in the brain. Although various variants of GRIN3A have been associated with ND in European-American and African-American samples, no study has been reported for the association between GRIN3A and ND in Chinese Han population. We performed an association study of 16 single nucleotide polymorphisms (SNPs) in GRIN3A with ND in 2616 Chinese individuals. SNP-based association analysis indicated that SNP rs1323423 was significantly associated with the Fagerström Test for Nicotine Dependence (FTND) score after correction for multiple testing (P = 0.0026). Haplotype-based association analysis revealed that Block 3, formed by rs1323423-rs10989591, was significantly associated with the FTND score after correction for multiple testing (global P = 0.0183). Furthermore, luciferase reporter assay demonstrated that the DNA region containing rs1323423 was an enhancer element, the activity of which was significantly impacted by rs1323423 genotype. Considering that rs1323423 is located in a potential enhancer region, we performed GRIN3A editing in HEK293T cells with CRISPR/Cas9 and found that the DNA region around rs1323423 has a regulatory function and the expression of GRIN3A affects the expression of other NMDA subunits. Moreover, we demonstrated that nicotine at a concentration of 100 µM decreased expression of GRIN3A in SH-SY5Y and HEK293T cells at the RNA and protein level, respectively. This study provides novel evidence for the involvement of GRIN3A in ND.

An Exome-Wide Association Study Identifies New Susceptibility Loci for Age of Smoking Initiation in African- and European-American Populations.

INTRODUCTION: Cigarette smoking is one of the largest causes of preventable death worldwide. This study aimed to identify susceptibility loci for age at smoking initiation (ASI) by performing an exome-wide association analysis. METHODS: A total of 2510 smokers of either African-American (AA) or European-American (EA) origin were genotyped and analyzed at both the single nucleotide polymorphism (SNP) and gene levels. After removal of those SNPs with a minor allele frequency (<0.01), 48091 and 34933 SNPs for AAs and EAs, respectively, were used to conduct a SNP-based association analysis. Gene-based analyses were then performed for all SNPs examined within each gene. Further, we estimated the proportion of variance explained by all common SNPs included in the analysis. RESULTS: The strongest signals were detected for SNPs rs17849904 in the pitrilysin metallopeptidase 1 gene (PITRM1) in the AA sample (p = 9.02 × 10-7) and rs34722354 in the discoidin domain of the receptor tyrosine kinase 2 gene (DDR2) in the EA sample (p = 9.74 × 10-7). Both SNPs remained significant after Bonferroni correction for the number of SNPs tested. Subsequently, the gene-based association analysis revealed a significantly associated gene, DHRS7, in the AA sample (p = 5.00 × 10-6), a gene previously implicated in nicotine metabolism. CONCLUSIONS: Our study revealed two susceptibility loci for age of smoking initiation in the two ethnic samples, with the first being PITRM1 for AA smokers and the second DDR2 for EA smokers. In addition, we found DHRS7 to be a plausible candidate for ASI in the AA sample from our gene-based association analysis. IMPLICATIONS: PITRM1 and DHRS7 for African-American smokers and DDR2 for European-American smokers are new candidate genes for smoking initiation. These genes represent new additions to smoking initiation, an important but less studied phenotype in nicotine dependence research.

[Molecular Mechanism and family research of a pedigree with B(A).06 subtype].

OBJECTIVE: To explore the serological and genotypic characteristics of a pedigree with B(A).06 subtype. METHODS: Serological methods was used to identify the ABO phenotypes. Exons 6 and 7 of the ABO gene and flanking regions were subjected to direct sequencing and TA clonal sequencing in order to determine the genotype of individuals with inconsistent results for forward and reverse serological typing. RESULTS: Among 12 individuals from 4 generations, 5 were identified with a AwB phenotype, along with a c.803C>G mutation in exon 7 of the B allele, which was named as B(A).06. The B(A).06/O.01.01 phenotype may be easily missed due to its weak anti-A antibody in the serum upon initial serological test. CONCLUSION: A B(A).06 subtype family was identified. The serological phenotype of individuals carrying the B(A).06 allele may be affected by the opposite DNA strand.

Huanglongbing Control: Perhaps the End of the Beginning.

Huanglongbing (HLB) is one of the most destructive citrus plant diseases worldwide. It is associated with the fastidious phloem-limited α-proteobacteria 'Candidatus Liberibacter asiaticus', 'Ca. Liberibacter africanus' and 'Ca. Liberibacter americanus'. In recent years, HLB-associated Liberibacters have extended to North and South America. The causal agents of HLB have been putatively identified, and their transmission pathways and worldwide population structure have been extensively studied. However, very little is known about the epidemiologic relationships of Ca. L. asiaticus, which has limited the scope of HLB research and especially the development of control strategies. HLB-affected plants produce damaged fruits and die within several years. To control the disease, scientists have developed new compounds and screened existing compounds for their antibiotic and antimicrobial activities against the disease. These compounds, however, have very little or even no effect on the disease. The aim of the present review was to compile and compare different methods of HLB disease control with newly developed integrative strategies. In light of recent studies, we also describe how to control the vectors of this disease and the biological control of other citrus plant pathogens. This work could steer the attention of scientists towards integrative control strategies.

Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection.

Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.

Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

Association of variants in HLA-DP on chromosome 6 with chronic hepatitis B virus infection and related phenotypes.

Hepatitis B virus (HBV) infection affects more than 2 billion people throughout the world. Among them, more than 240 million have chronic infection. Every year, 0.5-1.2 million people die of chronic hepatitis B virus infection (CHBVI), and approximately 60% of liver cancers are related to CHBI and subsequent liver cirrhosis (LC). These HBVI-related diseases impose a considerable economic burden as well as morbidity on patients, families, and society. Family and twin studies have indicated that the host genetic constitution greatly influences the clinical outcomes of HBV infection. During the past several years, genome-wide association studies (GWAS) have identified susceptibility variants for various HBVI-related diseases. Of these variants, SNPs rs3077 and rs9277535 in HLA-DP on chromosome 6 show the strongest evidence for association with CHBVI and with viral clearance. However, whether there exists an association between HLA-DP variants and the progression of CHBVI remains to be determined. Thus, further study should focus not only on identifying more variants in HLA-DP that are associated with various HBVI-related diseases but also on characterizing any newly discovered functional variants at the molecular level. Further, given the complexity of CHBV infection and its progression, gene-gene and gene-environment interactions should also be taken into consideration. Moreover, because both smoking and alcohol affect HBV infection and progression, it is important to understand how these factors interact with genetics to influence HBV-related diseases.

Identification and characterization of poly(I:C)-induced molecular responses attenuated by nicotine in mouse macrophages.

To further our understanding of the effects of nicotine on the molecular responses of macrophages during virus or virus-like infections, poly(I:C)-stimulated macrophage-like RAW264.2 cells or mouse primary peritoneal macrophages were challenged with nicotine; and their molecular responses were evaluated using a qRT-PCR array, antibody array, ELISA, Western blotting, and Ca(2+) imaging. Of 51 genes expressed in the Toll-like receptor (TLR) and RIG-I-like receptor (RLR) pathways, mRNA expression of 15 genes in RAW264.7 cells was attenuated by nicotine, of which mRNA expression of IL-6, TNF-α, and IL-1ß was confirmed to be attenuated in peritoneal macrophages. Concurrently, nicotine treatment attenuated the release of IL-6 and TNF-α from poly(I:C)-stimulated macrophages. However, when poly(I:C)-stimulated macrophages were challenged with nicotine plus α-bungarotoxin (α-BTX), secretion of IL-6 and TNF-α was found to be in a level seen with poly(I:C) stimulation only, indicating that α7-nAChR, a highly Ca(2+) permeable ion channel sensitive to blockade by α-BTX, is involved in this process. Furthermore, results from an antibody array indicated that nicotine treatment attenuated the phosphorylation of 82 sites, including Thr286 on CaMKIIα, from poly(I:C)-stimulated RAW264.7 cells, of which 28 are expressed in the downstream cascade of Ca(2+) signaling. Coincidentally, poly(I:C)-stimulated macrophages showed attenuated expression of phosphorylated CaMKIIα when pretreated with nicotine. In addition, nicotine attenuated intracellular Ca(2+) signal from poly(I:C)-stimulated RAW264.7 cells. Collectively, these results indicate that poly(I:C)-induced molecular responses of macrophages could be significantly attenuated by nicotine.

Education plays a crucial role in the pathway from poverty to smoking: a Mendelian randomization study.

BACKGROUND AND AIMS: Disproportionately high rates of smoking have been found in low-income communities, but the causal direction and role of education in this relationship remains less well understood. Here, we used bidirectional Mendelian randomization (MR) to measure the causal relationships between smoking, income and education. DESIGN: Two-sample univariable and multivariable MR analyses were conducted to evaluate the total and direct effect of income and education on tobacco smoking. The effects of smoking on education and income were explored with reverse MR analysis. SETTING: European ancestry. PARTICIPANTS: The most recent large-scale genome-wide association study (GWAS) summary data on educational attainment, household income and smoking (n = 143 210-766 345). MEASUREMENTS: Genetic variants for exposures including income, education and smoking. FINDINGS: Both income and education had protective effects against smoking, especially for smoking initiation (education: ß = -0.447, 95% CI = -0.508 to -0.387, P < 0.001; income: ß = -0.290, 95% CI = -0.43 to -0.149, P < 0.001) and cessation (education: ß = -0.364, 95% CI = -0.429 to -0.298, P < 0.001; income: ß = -0.323, 95% CI = -0.448 to -0.197, P < 0.001). Here, higher scores in cessation indicated a lower likelihood of quitting according to the coding scheme. There was little evidence that income influenced smoking once education was controlled for, whereas education could significantly affect smoking behaviours independently of income (P = 3.40 × 10-10 -0.0272). The reverse MR results suggested that smoking may result in a loss of years of schooling (ß = -0.190, 95% CI = -0.297 to -0.083, P < 0.001) and reduced earnings (ß = -0.204, 95% CI = -0.347 to -0.060, P = 0.006). CONCLUSIONS: Education appears to play an important role in the relationship between income and smoking. There is a bidirectional association of smoking with socioeconomic status.

Clinical research progress of novel biologics for the treatment of lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is one of the most common manifestations of severe organ damage in SLE, and also an important cause of disability and death. Its pathogenesis is associated with immune abnormalities such as immune cells, cytokines, and immune complex deposition. Traditional immunosuppressive therapy has been unable to meet the treatment needs of patients while bringing them toxic effects. In recent years, targeted therapies have emerged, and several novel biologics have gradually entered people's sight. This review will briefly introduce the pathogenesis of LN and the mechanism of biological targets, and summarize and analyze the clinical trials of new biologics for treating LN. Although not all biologics show positive results in clinical trials, the experience learned from these trials can help researchers adjust and plan future trial programs to seek better treatment methods.

Rapid health technology assessment of the novel endonuclease inhibitor baloxavir for the treatment of influenza.

Through a Rapid Health Technology Assessment (RHTA), we evaluated the efficacy, safety and cost-effectiveness of baloxavir in the treatment of influenza, providing the necessary scientific information and evidence-based basis for healthcare professionals and health insurance decision-makers in making rational selections. Through systematic searches of Pubmed, Embase, Web of Science, The Cochrane Register of Clinical Trials database and the official website of Health Technology Assessment (HTA) agencies, we collected systematic reviews (SR)/Meta-analysis, cost-effectiveness evaluations and HTA reports of baloxavir for influenza, with a search time frame of date of database establishment to July 31, 2022. We then performed data extraction, literature screening and quality evaluation on the literature that met our selection criteria, after which the results of the studies were pooled and qualitatively described for analysis. 10 studies were included, including 6 SR/Meta-analysis, three economics studies, and 1 HTA report. In terms of efficacy, baloxavir had an advantage over oseltamivir for all three types of influenza patients (otherwise healthy patients, high-risk patients, and patients are not separated into groups with and without underlying health conditions) concerning change in virus titer from baseline at 24 and 48 h; about otherwise healthy patients and high-risk patients, baloxavir had an advantage over peramivir; pertaining to high-risk patients, baloxavir had an advantage over laninamivir; the above differences between groups were all statistically significant. In terms of safety, in otherwise healthy patients and patients are not separated into groups with and without underlying health conditions, baloxavir significantly reduced the incidence of DRAEs and nausea compared with oseltamivir, as well as significantly reduced the incidence of DRAEs compared with laninamivir; in patients are not separated into groups with and without underlying health conditions, baloxavir significantly reduced the incidence of AEs and diarrhoea compared with oseltamivir; the differences between the above groups were all statistically significant. Economically, in Japanese adult influenza patients and high-risk populations, the Quality-Adjusted Life Years (QALY) of baloxavir slightly triumphed over that of laninamivir (Δ = 0.000112 and 0.00209 QALY per 1 patient, respectively); moreover, the incremental cost-effectiveness ratio (ICER: 2,231,260 and 68,855 yen/QALY, respectively) was below the willingness-to-pay (WTP) threshold (5,000,000 yen/QALY); in Chinese adult influenza patients without underlying diseases and adult high-risk influenza patients, baloxavir had a higher QALY compared with oseltamivir (Δ = 0.000246 and 0.000186 respectively), however, their ICER (12,230 and 64,956 RMB/QALY) was above the local WTP threshold (10,000 RMB/QALY) and thus did not provide a cost-effectiveness advantage. Baloxavir had a favorable efficacy and safety profile compared to neuraminidase inhibitors (NAIs), and the currently available evidence suggested that it had an economic advantage only in Japan.

Efficacy and safety of novel biologics in the treatment of lupus nephritis based on registered clinical trials: a systematic review and network meta-analysis.

To compare the clinical effectiveness and safety of novel biologics for the treatment of lupus nephritis based on a reticulated meta-analysis approach. Registered clinical trials in 4 major databases (PubMed, Embase, Web of Science, The Cochrane Register of Clinical Trials) and ClinicalTrials.gov were systematically searched with a search time frame of build to June 2022. And we screened registered randomized controlled clinical trials of biologics for the treatment of lupus nephritis according to the protocol's nadir criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 and Review Manager 5.3 software to compare and rank differences in effectiveness and safety between the biologics. A total of 10 registered randomized controlled clinical trials involving 2148 subjects were included in this study. The interventions were ranked from best to worst in terms of the primary outcome indicator of effectiveness, renal complete remission: belimumab > anifrolumab (900 + 300) mg > obinutuzumab > ocrelizumab 400 mg > abatacept 30/10 mg/kg > belimumab + rituximab > abatacept 10/10 mg/kg > abatacept (30/10 + 10/10) mg/kg > placeo > ocrelizumab 1000 mg > rituximab > anifrolumab 300 mg, belimumab was superior to placebo [OR = 1.75, 95% CI (1.13, 2.70)] and anifrolumab 300 mg [OR = 3.27, 95% CI (1.05, 10.14)], anifrolumab (900 + 300) mg was superior to anifrolumab 300 mg [OR = 3.56, 95% CI (1.30, 9.76)], and all were statistically significant. The ranking of each intervention in terms of overall renal remission for secondary outcome indicators from best to worst was: obinutuzumab > belimumab + rituximab > anifrolumab (900 + 300) mg > ocrelizumab 1000 mg > ocrelizumab 400 mg > belimumab > rituximab 1000 mg > abatacept 30/10 mg/kg > abatacept (30/10 + 10/10) mg/kg > placeo > abatacept 10/10 mg/kg > anifrolumab 300 mg, obinutuzumab was superior to placebo [OR = 2.27, 95% CI (1.11, 4.67)] and belimumab was also superior to placebo [OR = 1.56, 95% CI (1.07, 2.27)], and all were statistically significant. In terms of safety, with a focus on serious adverse events and serious infections, the results were: Serious adverse events at 1 year of monitoring occurred better with ocrelizumab 1000 mg than ocrelizumab 400 mg [OR = 0.51, 95% CI (0.29, 0.89)] and were statistically different; serious adverse events at 2 years of monitoring infection adverse events occurred better with obinutuzumab than with abatacept (30/10 + 10/10) mg/kg [OR = 0.24, 95% CI (0.07, 0.81)] and were statistically different. The safety of the new biologics in combination with conventional standard therapies is generally good, but it is belimumab and obinutuzumab that are most effective in achieving complete and overall remission in the kidney. This study protocol has been registered with PROSPERO, with a registration number of CRD42021262498.