Network Meta-analysis of Heat-clearing and Detoxifying Oral Liquid of Chinese Medicines in Treatment of Children’s Hand-foot-mouth Disease：a protocol for systematic review

Review question / Objective: The type of study was clinical randomized controlled trial (RCT). The object of study is the patients with HFMD. There is no limit to gender and race. In the case of clear diagnosis standard, curative effect judgment standard and consistent baseline treatment, the experimental group was treated with pure oral liquid of traditional Chinese medicine(A: Fuganlin oral liquid, B: huangzhihua oral liquid, C: Lanqin oral liquid, D: antiviral oral liquid, E: Huangqin oral liquid, F: Pudilan oral liquid, G: Shuanghuanglian oral liquid.)and the control group was treated with ribavirin or any oral liquid of traditional Chinese medicine. The data were extracted by two researchers independently, cross checked and reviewed according to the pre-determined tables. The data extraction content is (1) Basic information (including the first author, published journal and year, research topic). (2) Relevant information (including number of cases, total number of cases, gender, age, intervention measures, course of treatment of the experimental group and the control group in the literature). (3) Design type and quality evaluation information of the included literature. (4) Outcome measures (effective rate, healing time of oral ulcer, regression time of hand and foot rash, regression time of fever, adverse reactions.). The seven traditional Chinese medicine oral liquids are comparable in clinical practice, but their actual clinical efficacy is lack of evidence-based basis. Therefore, the purpose of this study is to use the network meta-analysis method to integrate the clinical relevant evidence of direct and indirect comparative relationship, to make quantitative comprehensive statistical analysis and sequencing of different oral liquid of traditional Chinese medicine with the same evidence body for the treatment of the disease, and then to explore the advantages and disadvantages of the efficacy and safety of different oral liquid of traditional Chinese medicine to get the best treatment plan, so as to provide reference value and evidence-based medicine evidence for clinical optimization of drug selection. Condition being studied: Hand foot mouth disease (HFMD) is a common infectious disease in pediatrics caused by a variety of enteroviruses. Its clinical manifestations are mainly characterized by persistent fever, hand foot rash, oral herpes, ulcers, etc. Because it is often found in preschool children, its immune system development is not perfect, so it is very vulnerable to infection by pathogens and epidemic diseases, resulting in rapid progress of the disease. A few patients will also have neurogenic pulmonary edema Meningitis, myocarditis and other serious complications even lead to death, so effectively improve the cure rate, shorten the course of disease, prevent the deterioration of the disease as the focus of the study. In recent years, traditional Chinese medicine has played an important role in the research of antiviral treatment. Many clinical practices have confirmed that oral liquid of traditional Chinese medicine can effectively play the role of antiviral and improve the body's immunity.

​Response of In ovo Supplementation of Amino Acid and Minerals on Egg Hatchability of Broiler Chicken

Background: In ovo supplementation of nutrients either amino acids or minerals in broiler chicken has been common more often individually or few nutrients with positive results. In view of the above, in ovo supplementation with combination of amino acids and minerals as a complete nutrient capsule for the gut and immune system development was tested for hatchability since the modern commercial broilers are very fragile to any changes in the internal environment. Methods: Four trials were conducted to study the response of in ovo supplementation of combinations of Lys, Met, Arg, Thr, Glu, Zn, Se and Cu on hatchability of broiler eggs. In trial I, the fertile eggs on day 18 were divided into five groups of 32 eggs in each group. Group I served as control without any amino acids and mineral supplementation. Group II, III, IV and V supplemented with Lys, Met, Arg, Thr, Glu, Zn, Se and Cu @ 2.2, 1, 2.5, 1.6, 2.5 mg, 80, 0.3, 16 µg; 4.4, 2, 5, 3.2, 5 mg, 80, 0.3, 16 µg; 11, 5, 12.5, 8, 12.5 mg, 80, 0.3, 16 µg and 22, 10, 25, 16, 25 mg, 80, 0.3, 18 µg respectively. In trial II, seventy fertile eggs were divided into seven groups, Group I served as control. Group II, III, IV, V, VI and VII were supplemented with graded levels (1x to 6x) of amino acids. The 1x consisted of Lys, Met, Arg, Thr and Glu @ 2.2, 1, 2.5, 1.6 and 2.5 mg, respectively. On day 18, 10 eggs per group were supplemented with graded levels of AA combination into the amniotic fluid. In trail III and IV it was similar to trial II but was without Lys and Met, respectively. Result: Results indicated that hatchability (Trial 1) in Group V, IV, III, II and I were 0, 18, 21.8, 71 and 90.6%, respectively. The Combination of five amino acids (Trial II) (Lys, Met, Thr, Arg, Glu) for in ovo supplementation reduced the hatchability, whereas, combination of four amino acids (Trial III) (Met, Thr, Arg, Glu) without Lys at lower doses resulted in good hatchability (86.6%). In ovo supplementation of amino acid or mineral-amino acid combinations in commercial broiler eggs should be restricted to few amino acids.

The impact of environmental mycobiomes on geographic variation in COVID-19 mortality

Mortality rates during the COVID-19 pandemic have varied by orders of magnitude across communities in the United States. Individual, socioeconomic, and environmental factors have been linked to health outcomes of COVID-19. It is now widely appreciated that the environmental microbiome, composed of microbial communities associated with soil, water, atmosphere, and the built environment, impacts immune system development and susceptibility to immune-mediated disease. The human microbiome has been linked to individual COVID-19 disease outcomes, but there are limited data on the influence of the environmental microbiome on geographic variation in COVID-19 across populations. To fill this knowledge gap, we used taxonomic profiles of fungal communities associated with 1,135 homes in 494 counties from across the United States in a machine learning analysis to predict COVID-19 Infection Fatality Ratios (the number of deaths caused by COVID-19 per 1000 SARS-CoV-2 infections; 'IFR'). Here we show that exposure to increased fungal diversity, and in particular indoor exposure to outdoor fungi, is associated with reduced SARS-CoV-2 IFR. Further, we identify seven fungal genera that are the predominant drivers of this protective signal and may play a role in suppressing COVID-19 mortality. This relationship is strongest in counties where human populations have remained stable over at least the previous decade, consistent with the importance of early-life microbial exposures. We also assessed the explanatory power of 754 other environmental and socioeconomic factors, and found that indoor-outdoor fungal beta-diversity is amongst the strongest predictors of county-level IFR, on par with the most important known COVID-19 risk factors, including age. We anticipate that our study will be a starting point for further integration of environmental mycobiome data with population health information, providing an important missing link in our capacity to identify vulnerable populations. Ultimately, our identification of specific genera predicted to be protective against COVID-19 mortality may point toward novel, proactive therapeutic approaches to infectious disease.

Effects of drinking water, sanitation, handwashing, and nutritional interventions on immune status in young children: a cluster-randomized controlled trial in rural Bangladesh

While studies have speculated that immune function may play a role in how water, sanitation, hygiene, and nutritional (N+WSH) interventions may individually impact child growth and development, the combined effects of these interventions on immune system development are unknown. Here, we report on a trial in rural Bangladesh, where we cluster-randomized pregnant women into control and N+WSH arms. Among the birth cohort, we quantified plasma IL-1β, IL-6, TNF-α, IL-2, IL-12p70, IFN-γ, IL-4, IL-5, IL-13, IL-17A, IL-21, IL-10, and GM-CSF at ages 14 and 28 months. Cytokine ratios were included as prespecified outcomes to examine the net inflammatory environment. We assessed 704 children. After one year, TNF-α/IL-10, IL-12/IL-10, and IL-17A/IL-10 ratios were lower in the intervention group compared to the control group (mean difference: -0.12 to -0.19, p<0.05), indicating the intervention promoted IL-10 driven immunoregulation. Similar reductions in ratios of pro-inflammatory cytokines to IL-10 were sustained in the intervention group after two years. After one year, IL-12/IL-4, IL-12/IL-5, IFN-γ/IL-5, and IL-12/IL-13 ratios were lower in the intervention group (-0.18 to -0.27, p<0.05), suggesting a shift towards a Th2 cytokine response. These findings suggest that the N+WSH intervention enhanced the immunoprotective and immunoregulatory responses, and suppressed/counteracted the inflammatory/immunopathological response, of the immune triad.

Long Chain Polyunsaturated Fatty Acids Docosahexaenoic Acid and Arachidonic Acid Supplementation in the Suckling and the Post-weaning Diet Influences the Immune System Development of T Helper Type-2 Bias Brown Norway Rat Offspring

Background: Dietary long chain polyunsaturated fatty acids (LCPUFA) such as arachidonic acid (ARA) and docosahexaenoic acid (DHA) play an important role in the development of the infant immune system. The role of LCPUFA in the T helper type 2 (Th2) biased immune system is unknown. We aimed to understand the effect of feeding LCPUFA during suckling and post-weaning on immune system development in Th2 bias Brown Norway rat offspring.Methods: Brown Norway dams were randomly assigned to nutritionally adequate maternal diet throughout the suckling period (0–3 weeks), namely, control diet (0% ARA, 0% DHA; n= 8) or ARA + DHA (0.45% ARA, 0.8% DHA; n = 10). At 3 weeks, offspring from each maternal diet group were randomized to either a control (0% ARA, 0% DHA; n = 19) or ARA+DHA post-weaning (0.5% ARA, 0.5% DHA; n = 18) diet. At 8 weeks, offspring were killed, and tissues were collected for immune cell function and fatty acid composition analyses.Results: ARA + DHA maternal diet resulted in higher (p &lt; 0.05) DHA composition in breast milk (4×) without changing ARA levels. This resulted in more mature adaptive immune cells in spleen [T regulatory (Treg) cells and B cells], mesenteric lymph nodes (MLN, lower CD45RA+), and Peyer's patches (PP; higher IgG+, B cells) in the ARA+DHA group offspring at 8 weeks. ARA+DHA post-weaning diet (3–8 weeks) resulted in 2 × higher DHA in splenocyte phospholipids compared to control. This also resulted in higher Th1 cytokines, ~50% higher TNF-α and IFNγ, by PMAi stimulated splenocytes ex vivo, with no differences in Th2 cytokines (IL-4, IL-13, and IL-10) compared to controls.Conclusion: Feeding dams a diet higher in DHA during the suckling period resulted in adaptive immune cell maturation in offspring at 8 weeks. Providing ARA and DHA during the post-weaning period in a Th2 biased Brown Norway offspring model may support Th1 biased immune response development, which could be associated with a lower risk of developing atopic diseases.

Characterization of the gut microbiome in a porcine model of thoracic spinal cord injury

Background The gut microbiome is a diverse network of bacteria which inhabit our digestive tract and is crucial for efficient cellular metabolism, nutrient absorption, and immune system development. Spinal cord injury (SCI) disrupts autonomic function below the level of injury and can alter the composition of the gut microbiome. Studies in rodent models have shown that SCI-induced bacterial imbalances in the gut can exacerbate the spinal cord damage and impair recovery. In this study we, for the first time, characterized the composition of the gut microbiome in a Yucatan minipig SCI model. We compared the relative abundance of the most dominant bacterial phyla in control samples to those collected from animals who underwent a contusion-compression SCI at the 2nd or 10th Thoracic level. Results We identify specific bacterial fluctuations that are unique to SCI animals, which were not found in uninjured animals given the same dietary regimen or antibiotic administration. Further, we identified a specific time-frame, “SCI-acute stage”, during which many of these bacterial fluctuations occur before returning to “baseline” levels. Conclusion This work presents a dynamic view of the microbiome changes that accompany SCI, establishes a resource for future studies and to understand the changes that occur to gut microbiota after spinal cord injury and may point to a potential therapeutic target for future treatment.

Influence of Sex in the Molecular Characteristics and Outcomes of Malignant Tumors

BackgroundSex is frequently underestimated as a prognostic biomarker in cancer. In this study, we evaluated a large cohort of patients and public datasets to determine the influence of sex on clinical outcomes, mutational status, and activation of immune pathways in different types of cancer.MethodsA cohort of 13,619 Oncosalud-affiliated patients bearing sex-unrelated cancers was followed over a 20-year period. Hazard ratios (HRs) for death were estimated for female vs. male patients for each cancer type and then pooled in a meta-analysis to obtain an overall HR. In addition, the mutational status of the main actionable genes in melanoma (MEL), colorectal cancer (CRC), and lung cancer was compared between sexes. Finally, a gene set enrichment analysis (GSEA) of publicly available data was conducted, to assess differences in immune processes between sexes in MEL, gastric adenocarcinoma (GC), head and neck cancer (HNC), colon cancer (CC), liver cancer (LC), pancreatic cancer (PC), thyroid cancer (TC), and clear renal cell carcinoma (CCRCC).ResultsOverall, women had a decreased risk of death (HR = 0.73, CI95: 8%–42%), with improved overall survival (OS) in HNC, leukemia, lung cancer, lymphoma, MEL, multiple myeloma (MM), and non-melanoma skin cancer. Regarding the analysis of actionable mutations, only differences in EGFR alterations were observed (27.7% for men vs. 34.4% for women, p = 0.035). The number of differentially activated immune processes was higher in women with HNC, LC, CC, GC, MEL, PC, and TC and included cellular processes, responses to different stimuli, immune system development, immune response activation, multiorganism processes, and localization of immune cells. Only in CCRCC was a higher activation of immune pathways observed in men.ConclusionsThe study shows an improved survival rate, increased activation of immune system pathways, and an enrichment of EGFR alterations in female patients of our cohort. Enhancement of the immune response in female cancer patients is a phenomenon that should be further explored to improve the efficacy of immunotherapy.

Genetic and phenotypic analysis of the causal relationship between aging and COVID-19

Background Epidemiological studies revealed that the elderly and those with comorbidities are most affected by COVID-19, but it is important to investigate shared genetic mechanisms between COVID-19 risk and aging. Methods We conducted a multi-instrument Mendelian Randomization analysis of multiple lifespan-related traits and COVID-19. Aging clock models were applied to the subjects with different COVID-19 conditions in the UK-Biobank cohort. We performed a bivariate genomic scan for age-related COVID-19 and Mendelian Randomization analysis of 389 immune cell traits to investigate their effect on lifespan and COVID-19 risk. Results We show that the genetic variation that supports longer life is significantly associated with the lower risk of COVID-19 infection and hospitalization. The odds ratio is 0.31 (P = 9.7 × 10−6) and 0.46 (P = 3.3 × 10−4), respectively, per additional 10 years of life. We detect an association between biological age acceleration and future incidence and severity of COVID-19 infection. Genetic profiling of age-related COVID-19 infection indicates key contributions of Notch signaling and immune system development. We reveal a negative correlation between the effects of immune cell traits on lifespan and COVID-19 risk. We find that lower B-cell CD19 levels are indicative of an increased risk of COVID-19 and decreased life expectancy, which is further validated by COVID-19 clinical data. Conclusions Our analysis suggests that the factors that accelerate aging lead to an increased COVID-19 risk and point to the importance of Notch signaling and B cells in both. Interventions that target these factors to reduce biological age may reduce the risk of COVID-19.

The Roles of Prebiotics on Impaired Immune System in Preterm Infants: A Narrative Literature Review

ABSTRACT Background: After birth, preterm infants face numerous challenges, including short and long-term morbidities, to survive and grow well with impaired immune and gastrointestinal systems. According to data from 184 countries, preterm birth rate ranges from 5-18%, accounting for 35% of all new born deaths. Purpose: This literature review aimed to summarize the evidence for the impact of prematurity on immune system development and the benefit of prebiotics on gut microbiota and immune responses. Discussion: Various studies in this narrative literature review showed that preterm infants have both qualitative and quantitative immune response deficits compared to term infants. Preterm newborns also have impaired intestinal immunity, underdeveloped intestinal mucosa barrier, and gut dysbiosis, which predisposes them to life-threatening infections. Early balanced gut microbiota in infants believed to be essential for adequate intestinal physiological functions and immune system maturation. The use of prebiotics, including human milk oligosaccharides (HMOs) in human breast milk, has been found to decrease the risk of various infections and cognitive impairment. A previous study found that prebiotic oligosaccharides supplementation was well-tolerated, significantly increased Bifidobacteria growth, and reduced the presence of gut pathogens. Conclusions: There was robust evidence that breast milk and prebiotics supplementation may support the gut microbiome and immune system in preterm infants. However, different types of synthetic prebiotics offer different benefits, and the protective effect seems to depend on the supplementation duration and dosage.