Long-term persistent immunogenicity after successful standard and triple-dosed hepatitis B vaccine in hemodialysis patients: A 3-year follow-up study in China

BackgroundAlthough the efficacy of hepatitis B vaccines among hemodialysis patients has been documented, the long-term persistence of immunogenicity in this population remains largely unknown. We explored the long-term persistence of immunogenicity induced by different hepatitis B vaccine regimens in hemodialysis patients.MethodsIn initial study, we conducted a randomized, multicenter, double-blind, parallel-controlled trial among hemodialysis patients in 13 hospitals in Shanxi Province, China. A total of 352 hemodialysis patients were allocated to receive 3-dose 20 μg (IM20 group) and 3-dose 60 μg (IM60 group) recombinant hepatitis B vaccine at months 0, 1, and 6. Vaccine-induced immune responses were measured at month 7. In this study, the responders (anti-HBs ≥ 10 mIU/mL) were followed up at months 18, 24, 30, 36 and 42, respectively. We used the generalized log-rank test and generalized estimating equations (GEE) to analyze the long-term durability of responses and the kinetics of anti-HBs levels, respectively.ResultsA total of 284 patients were involved in the extended follow-up period. The duration of vaccine-induced response with 75% of patients maintained protective antibody were 12 months and 18 months in the IM20 group and IM60 group, respectively (P = 0.291). The long-term persistent immunogenicity induced by 3-dose 60 μg was more satisfactory than that by 3-dose 20 μg hepatitis B vaccine in patients with hemodialysis duration ≥ five years (P = 0.023). The peak anti-HBs levels in 100–1000 mIU/mL or ≥ 1000 mIU/mL were more likely to maintain long-term protective antibody compared to anti-HBs levels in 10–100 mIU/mL (P ＜ 0.05). The kinetic profile was similar between the two groups (P = 0.334).ConclusionHigh-dose 60 μg hepatitis B vaccine could lead a satisfactory long-term durability of immunogenicity among patients with hemodialysis duration of five years or more. Peak anti-HBs level after vaccination was associated with the long-term persistence of immunogenicity.     

不同来源精子单精子卵胞浆内注射治疗不育症

目的：采用不同来源精子行单精子卵胞浆内注射术（ＩＣＳＩ）治疗不育症并进行疗效对比观察,方法：女性行常规超促排卵和经阴道超声引导下取卵。比较采用精液、附睾和睾丸精子行ＩＣＳＩ后的卵子损伤率、受精率、卵裂率、胚胎质量和临床妊娠率。结果：５３对不育夫妇共行６２仆ＩＣＳＩ周期。２７例临床妊娠,周期临床妊娠率为４３．５％,分别有３６、１２和１４个周期采用精液、附睾和睾丸精子,三组的卵子损伤率、受精率、卵裂率     

Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder

PurposeRPH3A encodes a protein involved in the stabilization of GluN2A subunit of N-methyl-D-aspartate (NMDA)-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition. We investigated the effect of variants in RPH3A in patients with neurodevelopmental disorders.MethodsBy using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified 6 heterozygous variants in RPH3A. In silico and in vitro models, including rat hippocampal neuronal cultures, have been used to characterize the effect of the variants.ResultsFour cases had a neurodevelopmental disorder with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and 2 cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder. Using neuronal cultures, we demonstrated that p.(Thr450Ser) and p.(Asn618Ser) reduce the synaptic localization of GluN2A; p.(Thr450Ser) also increased the surface levels of GluN2A. Electrophysiological recordings showed increased GluN2A-dependent NMDA ionotropic glutamate receptor currents for both variants and alteration of postsynaptic calcium levels. Finally, expression of the Rph3A^Thr450Ser variant in neurons affected dendritic spine morphology.ConclusionOverall, we provide evidence that missense gain-of-function variants in RPH3A increase GluN2A-containing NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to autism spectrum disorder.     

Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders

PurposeMissense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability.MethodsBy international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro.ResultsIn accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well.ConclusionBy identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.     

The role of bDMARDs in idiopathic inflammatory myopathies: A systematic literature review

Idiopathic inflammatory myopathies (IIM) are a group of different conditions typically affecting striate muscle, lung, joints, skin and gastrointestinal tract. Treatment typically relies on glucocorticoids and synthetic immunosuppressants, but the occurrence of refractory, difficult to treat, manifestations, may require more aggressive treatment, borrowed from other autoimmune diseases, including biologic disease modifying drugs (bDMARDs). In this regard, we conducted a systemic literature review in order to depict the current evidence about the use of bDMARDs in IIM. A total of 78 papers, published during the last 21 years, were retrieved. The majority of patients was treated with TNF-α inhibitors, whose effectiveness was assessed particularly in recalcitrant striate muscle, skin and joints involvement. Rituximab, whose evidence is supported by a large number of real-life studies and trials, seems to be an excellent option in case of ILD and anti-synthetase syndrome, while Tocilizumab, despite not meeting primary and secondary endpoints in a recently published clinical trial, proved its effectiveness in rapidly progressing ILD. Similarly, Abatacept, studied in a phase IIb clinical trial with conflicting evidence, was reported to be effective in some case reports of refractory dermatomyositis. Less data exist for anti-IL1 and anti-IL23 agents, which were employed particularly for inclusion body myositis and severe skin disease, respectively. This study provides an organ-focused assessment of bDMARDs in IIM, which display encouraging results in the treatment of refractory subsets of disease.     

Low-dose interleukin-2 treatment increases the proportion of regulatory T cells in patients with rheumatic diseases: A meta-analysis

BackgroundIt is now accepted that immune tolerance disorders caused by inadequate Treg cell function or number are important factors in the development and progression of rheumatic diseases. There is increasing evidence that ld IL-2 treatment increases the proportion of Treg cells in patients' peripheral blood, but this conclusion is still controversial. Here, we performed a meta-analysis of reports documenting the proportion of Treg cells and the rate of adverse events in patients with rheumatic disease before and after the administration of ld IL-2 to better understand its effect and safety on Treg cells in the field of rheumatic diseases.MethodsWe systematically searched PubMed, Embase, Scopus, Cochrane Library, and Web of science databases up to 15th November 2022 and identified studies that reported the proportion of peripheral blood Treg cells before and after ld IL-2 treatment in patients with rheumatic disease. Random-effects model was used to perform a meta-analysis of Treg cell proportions before and after ld IL-2 administration, and a meta-regression analysis was performed to explore heterogeneity. Inconsistency was evaluated using the I-squared index (I²), and publication bias was assessed by examining funnel plot asymmetry using the Egger tests.ResultsEighteen studies involving 1608 patients were included in the meta-analysis. The proportion of Treg cells in peripheral blood of these patients increased significantly after receiving ld IL-2 treatment [1.07 (95% CI 0.86,1.27), p < 0.001, I² = 67.3%]. Next, Meta-regression was performed for 5 variables including publish year, disease type, trail type and dosage and duration of the medication. The results suggest that these variables do not lead to high heterogeneity. (p = 0.698, 0.267, 0.502, 0.843, 0.560, respectively). And finally, statistical analysis showed no difference in adverse reactions between ld IL-2 group and control group in treatment [1.06 (95% CI 0.86,1.31), p = 0.586, I2 = 53.8%], which is unreliable because the data is so small.ConclusionsLd IL-2 does increase the proportion of peripheral blood Treg cells in patients with rheumatism, and single and cumulative doses must be considered when using ld IL-2. In addition, more studies on the safety of ld IL-2 are urgently needed.     

结肠癌免疫相关 lncRNA 风险预测模型的建立

目的 分析影响结肠癌预后的免疫相关 lncRNA, 并构建预测结肠癌患者预后的相关预测模型。 方法 下载 TCGA 数据库中的结肠癌 lncRNA 表达谱, 数据经 TPM 标准化后分析所有 lncRNA 的差异性表 达, 其中缺失值的补充采用 KNN 法, 通过共表达方法提取并鉴定免疫相关 lncRNA, 然后对差异性表达的 lncRNA 进行 LASSO 回归分析, 再进行单因素和多因素 COX 回归分析。 最后使用 R 4. 0. 2 统计学软件的 ggplot2 包基于 lncRNA 风险评分与基因表达关系, 构建风险因子关联图、 KM 曲线及评价模型预测价值的 ROC 曲线。 结果 经过表达差异性分析发现, 共有 2 258 个 lncRNA 在癌和癌旁组织中差异性表达, 其中上 调的有 1 648 个, 下调的有 610 个。 选取差异表达前 100 位的免疫相关 lncRNA 进行 LASSO 回归分析, 共筛 选出 12 个 lncRNA, 再进行单因素和多因素 COX 回归分析后显示 AC092723. 1、 AC007182. 1 和 AC004947. 1 与预后明显相关, 使用 R 4. 0. 2 统计学软件构建预后风险因子关联图, ROC 曲线显示其预测 1 年、 3 年和 5 年的预测价值均较高, 其 AUC 分别为 0. 79 (95 % CI: 0. 67 ~ 0. 91), 0. 78 (95 % CI: 0. 66 ~ 0. 9), 0. 7 (95 % CI: 0. 51 ~ 0. 9)。 结论 研究使用 TCGA 公共数据库进行生物信息学分析并构建的预后模型显示有 较高的预测价值, 除具有一定的临床意义外, 对未来 lncRNA 相关结肠癌的研究也提供了一定的方向。