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Background In medical research and practice, the p -value is arguably the most often used statistic and yet it is widely misconstrued as the probability of the type I error, which comes with serious consequences. This misunderstanding can greatly affect the reproducibility in research, treatment selection in medical practice, and model specification in empirical analyses. By using plain language and concrete examples, this paper is intended to elucidate the p -value confusion from its root, to explicate the difference between significance and hypothesis testing, to illuminate the consequences of the confusion, and to present a viable alternative to the conventional p -value. Main text The confusion with p -values has plagued the research community and medical practitioners for decades. However, efforts to clarify it have been largely futile, in part, because intuitive yet mathematically rigorous educational materials are scarce. Additionally, the lack of a practical alternative to the p -value for guarding against randomness also plays a role. The p -value confusion is rooted in the misconception of significance and hypothesis testing. Most, including many statisticians, are unaware that p -values and significance testing formed by Fisher are incomparable to the hypothesis testing paradigm created by Neyman and Pearson. And most otherwise great statistics textbooks tend to cobble the two paradigms together and make no effort to elucidate the subtle but fundamental differences between them. The p -value is a practical tool gauging the “strength of evidence” against the null hypothesis. It informs investigators that a p -value of 0.001, for example, is stronger than 0.05. However, p -values produced in significance testing are not the probabilities of type I errors as commonly misconceived. For a p -value of 0.05, the chance a treatment does not work is not 5%; rather, it is at least 28.9%. Conclusions A long-overdue effort to understand p -values correctly is much needed. However, in medical research and practice, just banning significance testing and accepting uncertainty are not enough. Researchers, clinicians, and patients alike need to know the probability a treatment will or will not work. Thus, the calibrated p -values (the probability that a treatment does not work) should be reported in research papers.

Background Recent studies found associations between non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS), but the causal nature of this association is still uncertain. Methods We performed a bidirectional two-sample Mendelian randomization (MR) analysis to test for the causal association between NAFLD and PCOS using data from a large-scale biopsy-confirmed NAFLD genome-wide association study (GWAS) (1483 cases and 17,781 controls) and PCOS GWAS (10,074 cases and 103,164 controls) in European ancestries. Data from glycemic-related traits GWAS (in up to 200,622 individuals) and sex hormones GWAS (in 189,473 women) in the UK Biobank (UKB) were used in the MR mediation analysis to assess potential mediating roles of these molecules in the causal pathway between NAFLD and PCOS. Replication analysis was conducted using two independent datasets from NAFLD and PCOS GWASs in the UKB and a meta-analysis of data from FinnGen and the Estonian Biobank, respectively. A linkage disequilibrium score regression was conducted to assess genetic correlations between NAFLD, PCOS, glycemic-related traits, and sex hormones using full summary statistics. Results Individuals with higher genetic liability to NAFLD were more likely to develop PCOS (OR per one-unit log odds increase in NAFLD: 1.10, 95% CI: 1.02–1.18; P = 0.013). Indirect causal effects of NAFLD on PCOS via fasting insulin only (OR: 1.02, 95% CI: 1.01–1.03; P = 0.004) and further a suggestive indirect causal effect via fasting insulin in concert with androgen levels were revealed in MR mediation analyses. However, the conditional F statistics of NAFLD and fasting insulin were less than 10, suggesting likely weak instrument bias in the MVMR and MR mediation analyses. Conclusions Our study suggests that genetically predicted NAFLD was associated with a higher risk of developing PCOS but less evidence for vice versa. Fasting insulin and sex hormones might mediate the link between NAFLD and PCOS.

Non-alcoholic steatohepatitis (NASH) is an epidemic metabolic disease with limited therapeutic strategies. Cumulative data support the pivotal role of gut microbiota in NASH. Here, we investigated the hypothesis regarding whether fecal microbiota transplantation (FMT) is effective in attenuating high-fat diet (HFD)-induced steatohepatitis in mice. Mice were randomized into control, HFD and HFD + FMT groups. After an 8-week HFD, FMT treatment was initiated and carried out for 8 weeks. The gut microbiota structure, butyrate concentrations of the cecal content, liver pathology and intrahepatic lipid and cytokines were examined. Our results showed that after FMT, the gut microbiota disturbance was corrected in HFD-fed mice with elevated abundances of the beneficial bacteria Christensenellaceae and Lactobacillus . FMT also increased butyrate concentrations of the cecal content and the intestinal tight junction protein ZO-1, resulting in relief of endotoxima in HFD-fed mice. Steatohepatitis was alleviated after FMT, as indicated by a significant decrease in intrahepatic lipid accumulation (reduced Oli-red staining, decreased intrahepatic triglyceride and cholesterol), intrahepatic pro-inflammatory cytokines, and the NAS score. Accordingly, intrahepatic IFN-γ and IL-17 were decreased, but Foxp3, IL-4 and IL-22 were increased after FMT intervention. These data indicate that FMT attenuated HFD-induced steatohepatitis in mice via a beneficial effect on the gut microbiota.

Microbial metabolites have emerged as critical components that mediate the metabolic effects of the gut microbiota. Here, we show that indole-3-propionic acid (IPA), a tryptophan metabolite produced by gut bacteria, is a potent anti-non-alcoholic steatohepatitis (NASH) microbial metabolite. Here, we demonstrate that administration of IPA modulates the microbiota composition in the gut and inhibits microbial dysbiosis in rats fed a high-fat diet. IPA induces the expression of tight junction proteins, such as ZO-1 and Occludin, and maintains intestinal epithelium homeostasis, leading to a reduction in plasma endotoxin levels. Interestingly, IPA inhibits NF-κB signaling and reduces the levels of proinflammatory cytokines, such as TNFα, IL-1β, and IL-6, in response to endotoxin in macrophages to repress hepatic inflammation and liver injury. Moreover, IPA is sufficient to inhibit the expression of fibrogenic and collagen genes and attenuate diet-induced NASH phenotypes. The beneficial effects of IPA on the liver are likely mediated through inhibiting the production of endotoxin in the gut. These findings suggest a protective role of IPA in the control of metabolism and uncover the gut microbiome and liver cross-talk in regulating the intestinal microenvironment and liver pathology via a novel dietary nutrient metabolite. IPA may provide a new therapeutic strategy for treating NASH. Fatty liver disease: Bacterial metabolite protects liver by maintaining gut integrity A molecule made by beneficial microbes in the gut helps protect against a severe form of fatty liver disease by preventing bacterial toxins from leaking out of the intestines into the bloodstream. A research team in China led by Yu Li from the Shanghai Institute of Nutrition and Health (CAS) and Jian-Gao Fan from Xinhua Hospital (SJTU) showed in a rat model of non-alcoholic steatohepatitis that indole-3-propionic acid (IPA), a metabolite produced by gut bacteria, helps maintain the integrity of the intestinal inner lining. The more robust intestinal barrier ensures that bacterial toxins do not enter the bloodstream and eventually reach the liver, where they can trigger injury-inducing inflammation. The findings reveal an interaction between the gut microbiome and the liver, and suggest a role for IPA in the treatment of fatty liver disease.

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine. Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in murine models.

Insulin-induced gene (Insig) negatively regulates SREBP-mediated de novo fatty acid synthesis in the liver. However, the upstream regulation of Insig is incompletely understood. Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPK-dependent phosphorylation ablates Insig’s interaction with E3 ubiquitin ligase gp78 and represses its ubiquitination and degradation, whereas AMPK deficiency shows opposite effects. Interestingly, activation of AMPK by metformin causes an augmentation of Insig stability and reduction of lipogenic gene expression, and leads to the attenuation of hepatic steatosis in HFHS diet-fed mice. Moreover, hepatic overexpression of Insig-1 rescues hepatic steatosis in liver-specific AMPKα2 knockout mice fed with HFHS diet. These findings uncover a novel effector of AMPK. Targeting Insig may have the therapeutic potential for treating fatty liver disease and related disorders. Insulin-related gene (Insig) negatively regulates hepatic fatty acid synthesis, a process involved in development of non-alcoholic fatty liver disease (NAFLD). Here, the authors show that AMPK activation by metformin promotes Insig phosphorylation, stabilizing it and inhibiting lipogenic gene expression. This is protective against steatosis in diabetic mice.

The incidence and prevalence of non‐alcoholic fatty liver disease (NAFLD) have been steadily increasing worldwide, with a huge societal and economic burden. Recently, NAFLD and non‐alcoholic steatohepatitis have been renamed and redefined as metabolic dysfunction associated steatotic liver disease (MASLD) and steatohepatitis (Metabolic Dysfunction Associated Steatohepatitis (MASH)), which result from an imbalance between metabolic and inflammatory stress (mainly as a consequence of adipose tissue dysfunction and insulin resistance) and the defence and repair mechanisms of the steatotic liver. Once MASLD progresses to end‐stage of liver disease, treatment efficacy becomes limited and may require liver transplantation. Early detection and intervention are crucial. Lifestyle modification is consequently the cornerstone of its management. Timely consideration of bariatric surgeries should be given to patients meeting specific criteria. A multidisciplinary approach is warranted, starting from the concept that MASLD/MASH is at the centre of the cardiovascular‐liver‐metabolic syndrome. In some cases, pharmacological treatment can complement lifestyle modification. Several drugs used to treat the cardiometabolic co‐morbidities have some potential efficacy in slowing Down disease progression, and some have demonstrated efficacy on histological endpoints that are likely to translate into long‐term clinical benefits. Optimising the use of these drugs within their licenced indications is thus paramount for patients with MASLD. Several MASH‐specific drugs are on the horizon and are likely to enrich our therapeutic armamentarium in the near future, particularly in non‐cirrhotic stages of the disease. Much work still needs to be done to understand the specific features of MASH cirrhosis and develop efficacious treatments for this disease stage.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is increasingly identified in patients with inflammatory bowel disease (IBD), but there are few systematic reviews and meta-analyses of the studies of NAFLD in IBD patients. Methods MEDLINE, Web of Science, Cochrane Library, and Scopus were searched (until August 2018) to identify observational studies that reported the prevalence and risk factors for NAFLD in IBD patients. Pooled prevalence, odds ratios (OR), mean difference (MD), and 95% confidence intervals (95% CI) were calculated. Study quality was assessed using the modified Newcastle-Ottawa scale. Results Of the 662 citations evaluated, 19 studies (including 5620 subjects) reported the prevalence of NAFLD in IBD population and were included for the analysis. The overall pooled prevalence was 27.5% (95% CI, 20.7%–34.2%). The prevalence was higher in older patients (MD = 8.22; 95% CI, 6.22–10.22), type 2 diabetes (OR = 3.85; 95% CI, 2.49–5.95), hypertension (OR = 3.18; 95% CI, 2.36–4.28), obesity (OR = 2.79; 95% CI, 1.73–4.50), insulin resistance (OR = 6.66; 95% CI, 1.28–34.77), metabolic syndrome (OR = 4.96; 95% CI, 3.05–8.05), chronic kidney disease (OR = 4.83; 95% CI, 1.79–13.04), methotrexate use (OR = 1.76; 95% CI, 1.02–3.06), surgery for IBD (OR = 1.28; 95% CI, 1.02–1.62), and longer duration of IBD (MD = 5.60; 95% CI, 2.24–8.97). Conclusions We found that NAFLD was not uncommon in the IBD population. Older age, metabolic risk factors, methotrexate use, prior surgery, and longer duration of IBD are predictors for the presence of NAFLD in IBD. Screening of NAFLD might be recommended among IBD patients with the aforementioned factors.

A bstract We derive the chiral kinetic equation in 8 dimensional phase space in non- Abelian SU( N ) gauge field within the Wigner function formalism. By using the “covariant gradient expansion”, we disentangle the Wigner equations in four-vector space up to the first order and find that only the time-like component of the chiral Wigner function is independent while other components can be explicit derivative. After further decomposing the Wigner function or equations in color space, we present the non-Abelian covariant chiral kinetic equation for the color singlet and multiplet phase-space distribution functions. These phase-space distribution functions have non-trivial Lorentz transformation rules when we define them in different reference frames. The chiral anomaly from non-Abelian gauge field arises naturally from the Berry monopole in Euclidian momentum space in the vacuum or Dirac sea contribution. The anomalous currents as non-Abelian counterparts of chiral magnetic effect and chiral vortical effect have also been derived from the non-Abelian chiral kinetic equation.