Observational studies have shown increased COVID-19 risk among cancer patients, but the causality has not been proven yet. Mendelian randomization analysis can use the genetic variants, independently of confounders, to obtain causal estimates which are considerably less confounded. We aimed to investigate the causal associations of cancers with COVID-19 outcomes using the MR analysis. The inverse-variance weighted (IVW) method was employed as the primary analysis. Sensitivity analyses and multivariable MR analyses were conducted. Notably, IVW analysis of univariable MR revealed that overall cancer and twelve site-specific cancers had no causal association with COVID-19 severity, hospitalization or susceptibility. The corresponding p-values for the casual associations were all statistically insignificant: overall cancer (p = 0.34; p = 0.42; p = 0.69), lung cancer (p = 0.60; p = 0.37; p = 0.96), breast cancer (p = 0.43; p = 0.74; p = 0.43), endometrial cancer (p = 0.79; p = 0.24; p = 0.83), prostate cancer (p = 0.54; p = 0.17; p = 0.58), thyroid cancer (p = 0.70; p = 0.80; p = 0.28), ovarian cancer (p = 0.62; p = 0.96; p = 0.93), melanoma (p = 0.79; p = 0.45; p = 0.82), small bowel cancer (p = 0.09; p = 0.08; p = 0.19), colorectal cancer (p = 0.85; p = 0.79; p = 0.30), oropharyngeal cancer (p = 0.31; not applicable, NA; p = 0.80), lymphoma (p = 0.51; NA; p = 0.37) and cervical cancer (p = 0.25; p = 0.32; p = 0.68). Sensitivity analyses and multivariable MR analyses yielded similar results. In conclusion, cancers might have no causal effect on increasing COVID-19 risk. Further large-scale population studies are needed to validate our findings.

Acute diarrhea is a major cause of morbidity and mortality in children under five. Probiotics are beneficial for treating acute diarrhea in children, but unclear which specific probiotic is the most effective. We performed a Bayesian network meta-analysis to examine the comparative effectiveness of probiotics. By searching EMBASE, PubMed, and the Cochrane Library up to 31 March 2021, randomized clinical trials (RCTs) on probiotics for treating acute diarrhea in children were included. Primary outcomes included the duration of diarrhea and diarrhea lasting ≥2 days, and secondary outcomes included the mean stool frequency on day 2 and duration of hospitalization, fever, and vomiting. We assessed the certainty of the evidence of outcomes according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guideline. Eighty-four studies with twenty-one different interventions in 13,443 children were included. For the primary outcomes, moderate evidence indicated that, Lactobacillus reuteri [mean difference (MD) = −0.84 day; 95% confidence interval (CI), −1.39, −0.29], Bifidobacterium lactis (MD = −0.98 day; 95%CI, −1.82, −0.14), Saccharomyces boulardii (MD = −1.25 day; 95%CI, −1.59, −0.91), Lactobacillus species (spp.) plus Bifidobacterium spp. plus Saccharomyces spp. (MD = −1.19 day; 95%CI, −1.81, −0.58), and Bacillus spp. plus Enterococcus spp. plus Clostridium spp. (MD = −1.1 day; 95%CI, −1.84, −0.35) significantly reduced the duration of diarrhea when compared with placebo. Saccharomyces boulardii [Odds ratio (OR) = 0.22; 95%CI, 0.11, 0.41] and Lactobacillus reuteri (OR = 0.23; 95%CI, 0.090, 0.60) significantly reduced the risk of diarrhea lasting ≥2 days when compared with placebo or no treatment, with moderate evidence. Among all probiotics, Saccharomyces boulardii may be the most effective in reducing both duration of diarrhea (compared with placebo) and risk of diarrhea lasting ≥2 days (compared with placebo or no treatment), with moderate evidence. To be conclusive, Saccharomyces boulardii may be the most effective probiotic for treating acute diarrhea in children, followed by several other single-strain and multi-strain probiotics.

BackgroundThe association between gut microbiome and coronavirus disease 2019 (COVID-19) has attracted much attention, but its causality remains unclear and requires more direct evidence.MethodsIn this study, we conducted the bidirectional Mendelian randomization (MR) analysis to assess the causal association between gut microbiome and COVID-19 based on the summary statistics data of genome-wide association studies (GWASs). Over 1.8 million individuals with three COVID-19 phenotypes (severity, hospitalization and infection) were included. And 196 bacterial taxa from phylum to genus were analyzed. The inverse-variance weighted (IVW) analysis was chosen as the primary method. Besides, false discovery rate (FDR) correction of p-value was used. To test the robustness of the causal relationships with p-FDR < 0.05, sensitivity analyses including the secondary MR analyses, horizontal pleiotropy test, outliers test, and “leave-one-out” analysis were conducted.ResultsIn the forward MR, we found that 3, 8, and 10 bacterial taxa had suggestive effects on COVID-19 severity, hospitalization and infection, respectively. The genus Alloprevotella [odds ratio (OR) = 1.67; 95% confidence interval (95% CI), 1.32–2.11; p = 1.69×10−5, p-FDR = 2.01×10−3] was causally associated with a higher COVID-19 severity risk. In the reverse MR, COVID-19 severity, hospitalization and infection had suggestive effects on the abundance of 4, 8 and 10 bacterial taxa, respectively. COVID-19 hospitalization causally increased the abundance of the phylum Bacteroidetes (OR = 1.13; 95% CI, 1.04–1.22; p = 3.02×10−3; p-FDR = 2.72×10−2). However, secondary MR analyses indicated that the result of COVID-19 hospitalization on the phylum Bacteroidetes required careful consideration.ConclusionOur study revealed the causal association between gut microbiome and COVID-19 and highlighted the role of “gut-lung axis” in the progression of COVID-19.

G (1-5)-NH2, G (1-7)-NH2, and G (1-9) are the active fragments of ghrelin. The aim of this study was to investigate the antinociceptive effects, their ability to cross the blood–brain barrier, and the receptor mechanism(s) of these fragments using the tail withdrawal test in male Kunming mice. The antinociceptive effects of these fragments (2, 6, 20, and 60 nmol/mouse) were tested at 5, 10, 20, 30, 40, 50, and 60 min after intravenous (i.v.) injection. These fragments induced dose- and time-related antinociceptive effects relative to saline. Using the near infrared fluorescence imaging experiments, our results showed that these fragments could cross the brain–blood barrier and enter the brain. The antinociceptive effects of these fragments were completely antagonized by naloxone (intracerebroventricular, i.c.v.); however, naloxone methiodide (intraperitoneal, i.p.), which is the peripheral restricted opioid receptor antagonist, did not antagonize these antinociceptive effects. Furthermore, the GHS-R1α antagonist [D-Lys3]-GHRP-6 (i.c.v.) completely antagonized these antinociceptive effects, too. These results suggested that these fragments induced antinociceptive effects through central opioid receptors and GHS-R1α. In conclusion, our studies indicated that these active fragments of ghrelin could cross the brain–blood barrier and enter the brain and induce antinociceptive effects through central opioid receptors and GHS-R1α after intravenous injection.