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Background: To explore the relationship between vitamin D levels and risk of SARS-CoV-2 infection and its severity in children and adolescents, and provide a theoretical basis for clinical practice., Methods: The PubMed, Web of Science, Embase, MEDLINE, and Cochrane Library databases were searched for comprehensive cohort and case-control studies on the association between childhood vitamin D deficiency and the risk and prognosis of coronavirus disease-2019 (COVID-19). The search period was set from December 1, 2019, to December 31, 2023., Results: The vitamin D insufficiency rate in children with COVID-19 was 80.78% (95% CI, 62.6% to 93.89%), with a deficiency rate of 32% (95% CI: 19.01% to 46.61%). Vitamin D insufficiency was more common in children with COVID-19 than in healthy children (OR, 4.86; 95% CI: 2.56-9.26). The incidence of severe illness was higher (OR, 4.73; 95% CI: 1.39-16.11) whereas that of asymptomatic illness was lower (OR, 0.38; 95% CI: 0.38-0.81) in children with COVID-19 who had vitamin D insufficiency than in those who did not., Conclusions: Vitamin D insufficiency in children may increase the risk of COVID-19 infection and is associated with poor prognostic outcomes. Further research is required to confirm the optimal Vitamin D dose to prevent insufficiency in various sections of the population., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder, and recent research suggests that gut microbiota and inflammatory cytokines may play a significant role in its pathogenesis. However, the specific effects of these factors on ITP and their relationships remain unclear. We conducted a two-step, two-sample Mendelian randomization study using an inverse variance-weighted approach to investigate the causal role of the gut microbiota in ITP and the mediating effect of inflammatory cytokines on their association. The results showed that among the 473 gut microbiota species, 11 were positively associated and 12 were negatively associated with the risk of ITP. Among the 91 screened inflammatory cytokines, five (CXCL10, CXCL5, IL-12RA, TRAIL, and VEGF-A) were found to have a causal relationship with ITP. Mediation analysis revealed that the gut microbiota UBA1066 promoted the occurrence of ITP through CXCL10 mediation, with a mediation effect of 0.118932 (95% CI: 0.049471-0.188393) accounting for 9.95% of the total effect. Gut microbiota Treponema promoted ITP through VEGF-A mediation, with a mediation effect of 0.045873 (95% CI: 0.01456-0.07718) accounting for 4.28% of the total effect. Gut microbiota Haloplasma promoted the occurrence of ITP via CXCL5. The mediating effect of CXCL5 was 0.038409 (95% CI = 0.00107718-0.07575082), with a mediating ratio of 16.79%. This study revealed a causal relationship between gut microbiota composition and ITP risk, highlighting three inflammatory cytokines as potential causal mediators of this relationship. These findings provide potential targets and biomarkers for the prevention and treatment of ITP with significant clinical implications., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To systematically analyze adverse events (AEs) in treatment of spinal muscular atrophy (SMA) with Nusinersen in children and adolescents., Methods: The study is registered on PROSPERO (CRD42022345589). Databases were searched and literature relating to Nusinersen in the treatment of spinal muscular atrophy in children from the start of database establishment to December 1, 2022, was retrospectively analyzed. R.3.6.3 statistical software was used, and random effects meta-analysis was performed to calculate weighted mean prevalence and 95% confidence intervals (CI)., Results: In total, 15 eligible studies were included, with a total of 967 children. Rate of definite Nusinersen-related AEs was 0.57% (95% CI: 0%-3.97%), and probable Nusinersen-related AEs 7.76% (95% CI: 1.85%-17.22%). Overall rate of AEs was 83.51% (95% CI: 73.55%-93.46%), and serious AEs 33.04% (95% CI: 18.15%-49.91%). For main specific AEs, fever was most common, 40.07% (95% CI: 25.14%-56.02%), followed by upper respiratory tract infection 39.94% (95% CI: 29.43%-50.94%), and pneumonia 26.62% (95% CI: 17.99%-36.25%).The difference in overall AE rates between the two groups (Nusinersen group and placebo group) was significant (OR = 0.27,95% CI: 0.08-0.95, P  = 0.042). Moreover, incidence of serious adverse events, and fatal adverse events were both significantly lower than in the placebo group (OR = 0.47, 95%CI: 0.32-0.69, P  < 0.01), and (OR = 0.37, 95%CI: 0.23-0.59, P  < 0.01), respectively., Conclusion: Nusinersen direct adverse events are rare, and it can effectively reduces common, serious, and fatal adverse events in children and adolescents with spinal muscular atrophy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Zhong, Zheng, Dou and Wang.)

Objectives: To understand the global incidence of the adverse events associated with fecal microbiota transplantation (FMT) in children over the past 20 years., Methods: We searched PubMed, Web of Science, Embase, and three Chinese databases (CNKI, Wanfang, and Chongqing Weipu) for high-quality articles written over the past 20 years and made selections based on the quality standard score. The study characteristics and incidences of adverse events were extracted from each article, meta-analysis was performed using the R.3.6.3 software, and randomized-effect or fixed-effect meta-analyses were used to determine the incidence of adverse events. Subgroup analysis was performed to determine heterogeneity., Results: A total of 18 articles involving 681 children were included in the analysis. The total effective rate of FMT in children was 85.75% (95% CI: 76.23-93.15%), of which the overall efficacy of FMT for the treatment of Clostridium difficile infection was 91.22% (95% CI: 83.49-96.68%) and the overall adverse event rate was 28.86% (95% CI: 19.56-39.15%), with a mild to moderate adverse event rate of 27.72% (95% CI: 17.86-38.83%) and a severe adverse event rate of 0.90% (95% CI: 0.33-1.76%). The most common mild to moderate adverse events were as follows: bellyache, 14.02% (95% CI: 5.43-25.77%); diarrhea, 7.75% (95% CI: 2.69-15.11%); and bloating, 7.36% (95% CI: 1.79-16.28%). Other adverse events included fever, 2.34%; vomiting, 3.12%; nausea, 1.50%; hematochezia, 2.30%; anorexia, 1.94%; and fatigue, 0.03%. The only death reported was in a study from China, in which the patient died of sepsis and liver failure 4 weeks after FMT. The other serious adverse event was an immunodeficiency patient with severe hematochezia. Another study in the United States described seven serious adverse events including one death that was not considered to be related to FMT; however, they did not describe the events in detail. There was no difference in the incidence of adverse events between the upper and lower gastrointestinal tracts (OR = 0.61, 95% CI: 0.02-15.42, P = 0.76)., Conclusion: Adverse events related to FMT in children are mostly mild to moderate, of short duration, and self-limiting. Therefore, the use of FMT in children is safe and worthy of widespread promotion., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Since the revolutionary discovery of RNA interference (RNAi) more than 20 years ago, synthetic small interfering RNAs (siRNAs) have held great promise as therapeutic agents for treating human diseases by the specific knockdown of disease-causing gene products. To facilitate the development of siRNA therapeutics, a robust, high-throughput in vitro assay for measuring gene silencing is imperative during the initial siRNA lead sequence identification and, later, during the lead optimization with chemically modified siRNAs. There are several potential assays for measuring gene expression. Quantitative reverse transcription PCR (qRT-PCR) has been widely used to quantitate messenger RNA (mRNA). This method has a few disadvantages, however, such as the requirement for RNA isolation, complementary DNA (cDNA) generation, and PCR reaction, which are labor-intensive, limit the assay throughput, and introduce variability. We chose a high-content imaging assay, bDNA FISH, that combines the branched DNA (bDNA) technology with fluorescence in situ hybridization (FISH) to measure gene silencing by siRNAs because it is sensitive and robust with a short reagent procurement and assay development time. We also built a fully automated liquid-handling platform for executing bDNA FISH assays to increase throughput, and the system has a capacity of generating 192 concentration-response curves in a single run. We have successfully developed and executed the bDNA FISH assays for multiple targets using this automated platform to identify and optimize siRNA candidate molecules. Examples of the bDNA FISH assay for selected targets are presented.

We investigated the influence of different fluid resuscitation techniques on the number of myeloid-derived suppressor cells (MDSCs) in rats. Seventy-two healthy Sprague-Dawley rats were randomly divided into groups that received sham operation (Sham group), hypertonic saline (HRS group), lactated ringer's solution (LRS group), or crystalloid solution (LCRS group). Six rats from each group were sacrificed by cervical dislocation at 12, 24, and 48 h after resuscitation. The spleens were harvested under sterile conditions and spleen cell suspension was prepared. The number of MDSCs was detected using flow cytometry. The number of MDSCs in the Sham group did not differ significantly among the different time points. Compared with the Sham group, the number of MDSCs after the use of the different fluid resuscitation techniques increased to varying extents and the differences among the groups were significant. The number of MDSCs in the HRS group was much lower than that of the LRS and LCRS groups at both 24 and 48 h (P < 0.05). At 12 h, the number of MDSCs in the HRS group was significantly lower than that of the LRS group (P < 0.05). The differences between the HRS and LCRS groups were not statistically significant. Shortly after hemorrhagic shock resuscitation, the immune function of rats was suppressed to a varying extent and was gradually restored over time. Resuscitation with HRS alleviated the immunosuppression at the early stage after shock.

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)