With the rapid growth of biomedical literature, there is increasing need to make meaningful inferences from a comprehensive and complex body of evidence. Well-designed, single studies are often proposed to be the ultimate answer to a clinical question, and positive findings, particularly from interventional studies, are viewed very favorably by the research enterprise, including funders, fellow researchers, journals, and the lay media. However, it is important to recognize that early studies in a field tend to overestimate or inflate magnitude of benefits, due to study design features or overoptimistic sample size calculations, and can lead to “premature closure” bias.1Ioannidis J.P. Contradicted and initially stronger effects in highly cited clinical research.JAMA. 2005; 294: 218-228Crossref PubMed Scopus (1063) Google Scholar Subsequent, independent, similarly designed studies may fail to show the large effect estimates seen with the first study, and with time, the “truth wears off.”2Lehrer J. The truth wears off. The New Yorker, 2010https://www.newyorker.com/magazine/2010/12/13/the-truth-wears-offGoogle Scholar Hence, by examining the totality of evidence, rather than relying on individual studies, we can improve the translation of results to advance clinical practice and scientific research, by (1) calibrating confidence in the estimates based on consistency with other studies, (2) improving the precision of findings, (3) avoiding premature closure about the magnitude of effect before the estimate has moderated through repeated and independent evaluation, and (4) preventing premature closure of a potentially effective intervention owing to concerns for nonsignificant results.3Murad M.H. Montori V.M. Synthesizing evidence: shifting the focus from individual studies to the body of evidence.JAMA. 2013; 309: 2217-2218Crossref PubMed Scopus (68) Google Scholar One approach to understanding the body of evidence is through well-conducted systematic reviews with or without meta-analyses. In contrast to traditional, unstructured narrative reviews, which provide a broad overview of clinical and scientific developments in a particular field, systematic reviews address a focused clinical question in a structured and reproducible manner. It is often, but not always, accompanied by a meta-analysis, which is a statistical pooling of results from different studies to derive a single summary effect estimate, with more precision. At CGH, we have prioritized the publication of articles synthesizing this knowledge to provide our community a thorough, unbiased, scientific view on diverse aspects of gastroenterology and hepatology, ranging from epidemiology, natural history, diagnosis, prognosis, and treatment. In this Special Issue of CGH, we highlight some pivotal systematic reviews and/or meta-analyses on topics of high priority. Inflammatory bowel diseases (IBDs) are high-need, high-cost conditions with evolving global epidemiological patterns. In an elegant systematic review from the Global IBD Visualization of Epidemiology Studies in the 21st Century (GIVES-21) Research Group, Buie et al4Buie M.J. Quan J. Windsor J.W. et al.Global hospitalization trends for Crohn's disease and ulcerative colitis in the 21st century: a systematic review with temporal analyses.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar examined global trends in hospitalization for IBD from 84 studies from 42 countries/regions. They observed that countries where the incidence of IBD is stabilizing but prevalence is compounding, hospitalization rates for IBD are largely stabilizing, including those in North America and Northern Europe, suggesting that advances in the management of IBD are shifting the care of IBD from the hospital to the community. In contrast, hospitalization rates are increasing rapidly in newly industrialized countries with acceleration of IBD incidence, including those in Asia, Latin America, and the Middle East. This review offers insight into a differential health care burden that IBD may pose across the world in the coming decades. One potential benefit of meta-analysis is examining impact of therapies on rare adverse events. In a systematic review examining potential treatment side effects, Gubatan et al5Gubatan J. Barber G.E. Nielsen O.H. et al.Paternal medications in inflammatory bowel disease and male fertility and reproductive outcomes: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar examined the association between medication exposures in prospective fathers and its impact on male fertility and reproductive outcomes. In 10 studies, there was no association between exposure to IBD-directed immunosuppressive medications and semen parameters including sperm count, motility, or morphology. In 16 studies examining periconception paternal medication exposure and adverse pregnancy outcomes, they observed no association between biologic use, thiopurines and/or methotrexate, and adverse pregnancy outcomes including early pregnancy loss, preterm birth, or congenital malformations. In this situation, where individual studies may be underpowered to detect meaningful outcomes, a systematic review and meta-analysis offered reassurance to inform pregnancy counseling in men with IBD. Diet is intrinsically linked to several gastrointestinal and hepatic diseases, but individual studies are unable to examine overall impact of diverse dietary components on disease risk and outcomes. In a comprehensive review of 60 studies with 100,621 participants, Tsompanaki et al6Tsompanaki E. Thanapirom K. Papatheodoridi M. et al.Systematic review and meta-analysis: the role of diet in the development of nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar observed that total caloric intake, but not individual macronutrients impacted the development of nonalcoholic fatty liver disease (NAFLD); none of these components of diet were associated with progression to nonalcoholic steatohepatitis. Besides epidemiological links, there is increasing interest in food as medicine. In a robust synthesis, Limketkai et al7Limketkai B.N. Godoy-Brewer G. Parian A.M. et al.Dietary interventions for the treatment of inflammatory bowel diseases: an updated systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar examined randomized controlled trials of dietary interventions for treating IBD.7Limketkai B.N. Godoy-Brewer G. Parian A.M. et al.Dietary interventions for the treatment of inflammatory bowel diseases: an updated systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar In patients with Crohn’s disease (CD), they observed that low-refined carbohydrate diet and a symptoms-guided exclusion diet may promote clinical remission; a Mediterranean diet was comparable to specific carbohydrate diet in inducing remission in patients with CD. Among patients with CD in remission, there was no difference in the risk of relapse in patients with low vs high intake of red and processed meats, and in patients with intake of low-refined vs high-refined carbohydrates. No specific diet favorably altered the course of ulcerative colitis. Besides providing practical information for shared decision making with patients, this review highlighted paucity of high-quality evidence in this field, even though “what should I eat?” is the most frequently asked question in patients diagnosed with IBD. NAFLD is the most common chronic liver disease, affecting approximately 25%–33% of the world population and progressively becoming the leading cause of liver transplantation. While conventionally thought to be closely linked to obesity, several recent studies have focused on a unique phenotype of NAFLD: lean NAFLD. In a systematic review of 85 articles, Tang et al8Tang A. Ng C.H. Phang P.H. et al.Comparative burden of metabolic dysfunction in lean NAFLD vs non-lean NAFLD - a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar observed that approximately 13% lean adults have NAFLD; among all patients with NAFLD, approximately 1 in 4 patients was lean, increasing to 1 in 3 patients in Asia. Only 20% of patients with lean NAFLD were diabetic, compared with almost 50% obese patients with NAFLD; however, the prevalence of diabetes was approximately 5 times the prevalence observed in lean adults without NAFLD. Overall, lean NAFLD patients were less metabolically unhealthy compared with obese NAFLD patients. However, this does not necessarily portend a favorable prognosis. In a systematic review of 10 cohort studies, Ha et al9Ha J. Yim S.Y. Karagozian R. Mortality and liver-related events in lean versus non-lean nonalcoholic fatty liver disease: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar observed that patients with lean NAFLD had a 1.9 times higher risk of liver-related mortality compared with patients with nonlean NAFLD. There was no difference in the risk of all-cause mortality, cardiovascular mortality, and adverse liver events including decompensated cirrhosis and hepatocellular carcinoma (HCC) between lean and nonlean NAFLD. These studies highlight the need for future studies on the pathophysiology and genetic and ethnic variability, and risk factors and biomarkers for adverse outcomes, in the lean NAFLD phenotype. There is growing evidence supporting the role of gut-derived metabolites in the development and progression of NAFLD, but the relation of endotoxin levels with gut permeability and NAFLD stage remains unclear. In a systematic review of 43 studies, Soppert et al10Soppert J. Brandt E.F. Heussen N.M. et al.Blood endotoxin levels as biomarker of nonalcoholic fatty liver disease: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar examined the potential of blood endotoxin levels as diagnostic and prognostic biomarkers in NAFLD. In hypothesis-generating work, they observed that blood endotoxin levels are increased in patients with NAFLD compared with liver-healthy control subjects, after accounting for differences in body mass index, metabolic condition, and liver damage parameters. They also observed that blood endotoxin levels are higher in patients with nonalcoholic steatohepatitis, compared with isolated fatty liver. Future clinical trials incorporating blood endotoxin level, alone or with other noninvasive biomarkers, may help define the diagnostic and prognostic performance of endotoxin levels in patients with NAFLD. HCC is the second leading cause of cancer mortality, with hepatitis B and hepatitis C being leading causes. Oral direct-acting antiviral (DAA) therapies have transformed hepatitis C virus (HCV) management and can lead to decrease in fibrosis stage and decline in risk of HCC. Yet, societal guidelines emphasize the need for ongoing screening for HCC in patients with HCV based on pretreatment fibrosis stage. In a systematic review and meta-analysis, Kim et al11Kim N.J. Vutien P. Cleveland E. et al.Fibrosis stage-specific incidence of hepatocellular cancer after hepatitis C cure with direct-acting antivirals: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2022; Abstract Full Text Full Text PDF Scopus (4) Google Scholar estimated that the incidence of HCC is 2.99 per 100 person-years in patients with HCV cirrhosis after achieving sustained virologic response (SVR), though this risk progressively declines with increasing duration of follow-up after achieving SVR. In patients with F3 fibrosis or no documented cirrhosis, HCC incidence was 0.47–0.63 per 100 person-years, far below the threshold of >1.32 per 100 person-years considered to result in cost-effective HCC screening in patients with DAA-cured HCV, using current screening modalities. This review provides strong evidence that routine HCC screening may not be warranted in patients with HCV with F3 fibrosis or lower, after achieving SVR with DAA. In selected patients with HCC, liver transplantation can be performed in selected cases who are within the Milan criteria. To increase the access of liver transplantation for patients with HCC who may be outside the Milan criteria, several downstaging criteria have been introduced depending on patients’ response to locoregional therapy. In a systematic review and meta-analysis of 25 studies with ∼4000 patients with HCC in which downstaging was attempted, Tan et al12Tan D.J.H. Lim W.H. Yong J.N. et al.UNOS down-staging criteria for liver transplantation of hepatocellular carcinoma: systematic review and meta-analysis of 25 studies.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar observed that approximately 50% patients can be successfully down-staged to within the United Network for Organ Sharing Down-Staging criteria, but only one-third of all patients eventually received liver transplantation. However, these patients have excellent 1- and 5-year survival rates, and the risk of HCC recurrence was 16%. Alpha-fetoprotein >100 ng/mL at diagnosis and at transplant listing are associated with reduced odds of successful downstaging and poorer posttransplant survival, respectively. One of the most common indications for upper endoscopy in outpatients is dyspepsia. In a systematic review of 15 cross-sectional surveys of unselected community-based studies, Nasseri-Moghaddam et al13Nasseri-Moghaddam S. Mousavian A.H. Kasaeian A. et al.What is the prevalence of clinically significant endoscopic findings in subjects with dyspepsia? Updated systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar observed that 90% patients with dyspepsia had normal upper endoscopy. Erosive esophagitis and peptic ulcer disease were the most common findings in both Eastern and Western countries; <1 in 300 patients was noted to have a gastrointestinal malignancy. These findings provide reassurance that most patients with dyspepsia in the community may be treated empirically, and upper endoscopy should be considered only in patients with persistent symptoms despite these initial management strategies, or for those who present with alarm symptoms. Another common indication managed by gastroenterologists is gastroparesis, yet little is known about its epidemiology and impact on healthcare utilization. Dilmaghani et al14Dilmaghani S. Zheng T. Camilleri M. Epidemiology and healthcare utilization in patients with gastroparesis: a systematic review.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar conducted a systematic review of 13 studies and observed that the incidence and prevalence of definite gastroparesis (combination of symptoms and delayed gastric emptying) was 1.9–6.3 per 100,000 person-years and 13.8–267.7 per 100,000 adults, respectively. These patients with gastroparesis had 2- to 18-fold increased risk of hospitalization, and had higher risk of mortality, compared with the general population. However, most of these studies were based on administrative claims and at high risk of bias. The investigators’ main takeaway was that there is paucity of high-quality, demographically diverse, and population-based studies to accurately describe the epidemiology and risk factors of gastroparesis, particularly at the patient level. One of the leading causes for high rates of unplanned healthcare utilization in patients with gastroparesis is paucity of approved drug therapies, due in large part due to lack of well-designed clinical trials. As a first step toward modern drug development for gastroparesis, Wise et al15Wise J.L. Ingrosso M.R. Ianiro G. et al.Response and adverse event rates with placebo in gastroparesis: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar conducted a systematic review and meta-analysis examining placebo response and adverse events in 35 randomized controlled trials of gastroparesis. The overall placebo response rate was almost 30%, with higher rates in patients with idiopathic gastroparesis, trials not using a validated questionnaire, and short trial duration (<4 weeks). The adverse event rate in the placebo arms was 34%. Based on this review, investigators proposed key clinical trial design features for pharmacotherapy for gastroparesis: study duration longer than 8 weeks, separate diabetic from mixed or idiopathic gastroparesis, confirm delayed gastric emptying objectively prior to trial inclusion, and utilize validated questionnaires to assess symptoms throughout the course of clinical trials. Last, in this issue, we publish one of the most impactful reviews for scientific advancement in the field of health disparities. Liu et al16Liu J.J. DeCuir N. Kia L. et al.Tools to measure the impact of structural racism and discrimination on gastrointestinal and hepatology disease outcomes: a scoping review.Clin Gastroenterol Hepatol. 2023; (•••:•••–•••)Google Scholar conducted a scoping review of tools to measure the impact of structural racism and discrimination on gastrointestinal and hepatology disease outcomes. Based on 46 articles (19 studies using structural racism and discrimination measures and 27 studies of upstream interventions), the investigators’ observed that measures of residential racial segregation were most frequently reported. Structural racism and discrimination was associated with poorer health outcomes for racial and ethnic minority populations. While upstream intervention studies primarily focused on policies related to colon cancer screening and organ graft allocation, racial and ethnic disparities often persisted postintervention. They stressed an urgent need for research that goes beyond describing health disparities, to incorporating measures of structural racism and discrimination and implementing interventions that address this understudied determinant of health, to achieve health equity in gastroenterology and hepatology. This overview highlights the impact well-conducted systematic reviews and meta-analyses of diverse study types can have across field of gastroenterology and hepatology in informing clinical practice and advancing scientific research. We will continue to seek out and publish high-quality systematic reviews and meta-analyses.