Sushil Kumar Garg

Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis

Background and aims Acid-suppressive medications, particularly proton pump inhibitors (PPIs), may decrease the risk of oesophageal adenocarcinoma (OAC) in patients with Barretts oesophagus (BO). We performed a systematic review with meta-analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RAs)) and risk of OAC or high-grade dysplasia (BO-HGD) in patients with BO. Methods We performed a systematic search of multiple electronic databases and conference proceedings up to June 2013 to identify studies reporting the association between use of acid-suppressive medications and risk of OAC and/or BO-HGD in patients with BO. Summary ORs with 95% CIs were estimated. Results We identified seven observational studies (2813 patients with BO, 317 cases of OAC or BO-HGD, 84.4% PPI users). On meta-analysis, PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO (adjusted OR 0.29; 95% CI 0.12 to 0.79). There was a trend towards a dose–response relationship with PPI use for >2–3 years protective against OAC or BO-HGD (three studies; PPI use >2–3 years vs <2–3 years: OR 0.45 (95% CI 0.19 to 1.06) vs 1.09 (0.47 to 2.56)). Considerable heterogeneity was observed. Two studies reported the association between H2RA use and risk of OAC and/or BO-HGD (1352 patients with BO, 156 cases of OAC, 25.4% on H2RAs), and both studies did not show a significant effect. Conclusions Based on meta-analysis of observational studies, the use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC. PPI use should be considered in BO, and chemopreventive trials of PPIs in patients with BO are warranted.

C-Reactive Protein, Fecal Calprotectin, and Stool Lactoferrin for Detection of Endoscopic Activity in Symptomatic Inflammatory Bowel Disease Patients: A Systematic Review and Meta-Analysis.

Objectives:Persistent disease activity is associated with a poor prognosis in inflammatory bowel disease (IBD). Therefore, monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment concept. As endoscopic monitoring is invasive and resource intensive, identification of valid markers of disease activity is a priority. The objective was to evaluate the diagnostic accuracy of C-reactive protein (CRP), fecal calprotectin (FC), and stool lactoferrin (SL) for assessment of endoscopically defined disease activity in IBD.Methods:Databases were searched from inception to November 6, 2014 for relevant cohort and case-control studies that evaluated the diagnostic accuracy of CRP, FC, or SL and used endoscopy as a gold standard in patients with symptoms consistent with active IBD. Sensitivities and specificities were pooled to generate operating property estimates for each test using a bivariate diagnostic meta-analysis.Results:Nineteen studies (n=2499 patients) were eligible. The pooled sensitivity and specificity estimates for CRP, FC, and SL were 0.49 (95% confidence interval (CI) 0.34–0.64) and 0.92 (95% CI 0.72–0.96), 0.88 (95% CI 0.84–0.90) and 0.73 (95% CI 0.66–0.79), and 0.82 (95% CI 0.73–0.88) and 0.79 (95% CI 0.62–0.89), respectively. FC was more sensitive than CRP in both diseases and was more sensitive in ulcerative colitis than Crohn’s disease.Conclusions:Although CRP, FC, and SL are useful biomarkers, their value in managing individual patients must be considered in specific clinical contexts.

Dose Response Relationship Between Physical Activity and Risk of Heart Failure: A Meta-Analysis

Background— Prior studies have reported an inverse association between physical activity (PA) and risk of heart failure (HF). However, a comprehensive assessment of the quantitative dose–response association between PA and HF risk has not been reported previously. Methods and Results— Prospective cohort studies with participants >18 years of age that reported association of baseline PA levels and incident HF were included. Categorical dose–response relationships between PA and HF risk were assessed with random-effects models. Generalized least-squares regression models were used to assess the quantitative relationship between PA (metabolic equivalent [MET]–min/wk) and HF risk across studies reporting quantitative PA estimates. Twelve prospective cohort studies with 20 203 HF events among 370 460 participants (53.5% women; median follow-up, 13 years) were included. The highest levels of PA were associated with significantly reduced risk of HF (pooled hazard ratio for highest versus lowest PA, 0.70; 95% confidence interval, 0.67–0.73). Compared with participants reporting no leisure-time PA, those who engaged in guideline-recommended minimum levels of PA (500 MET-min/wk; 2008 US federal guidelines) had modest reductions in HF risk (pooled hazard ratio, 0.90; 95% confidence interval, 0.87–0.92). In contrast, a substantial risk reduction was observed among individuals who engaged in PA at twice (hazard ratio for 1000 MET-min/wk, 0.81; 95% confidence interval, 0.77–0.86) and 4 times (hazard ratio for 2000 MET-min/wk, 0.65; 95% confidence interval, 0.58–0.73) the minimum guideline-recommended levels. Conclusions— There is an inverse dose–response relationship between PA and HF risk. Doses of PA in excess of the guideline-recommended minimum PA levels may be required for more substantial reductions in HF risk.

Comparative Efficacy of Biologic Therapy in Biologic-Naïve Patients With Crohn Disease: A Systematic Review and Network Meta-analysis

OBJECTIVE To study the comparative efficacy of biologic therapy in the management of biologic-naïve patients with Crohn disease (CD). PATIENTS AND METHODS We conducted a systematic review of randomized controlled trials published from January 1, 1985, through September 30, 2013, comparing biologic agents (infliximab [IFX], adalimumab [ADA], certolizumab pegol, natalizumab, vedolizumab, and ustekinumab) with each other or placebo for inducing and maintaining clinical remission in adults with moderate to severe CD. To increase comparability across trials, we focused on a subset of biologic-naïve patients for the induction end point and on responders to induction therapy for the maintenance end point. We followed a Bayesian network meta-analysis approach. RESULTS We identified 17 randomized controlled trials of good methodological quality comparing 6 biologic agents with placebo, with no direct comparison of biologic agents. In network meta-analysis, we observed that IFX (relative risk [RR], 6.11; 95% credible interval [CrI], 2.49-18.29) and ADA (RR, 2.98; 95% CrI, 1.12-8.18), but not certolizumab pegol (RR, 1.48; 95% CrI, 0.76-2.93), natalizumab (RR, 1.36; 95% CrI, 0.69-2.86), vedolizumab (RR, 1.40; 95% CrI, 0.63-3.28), and ustekinumab (RR, 0.61; 95% CrI, 0.15-2.49), were more likely to induce remission than placebo. Similar results were observed for maintenance of remission. Infliximab had the highest probability of being ranked as the most efficacious agent for induction (86%) and ADA for maintenance of remission (48%). CONCLUSION On the basis of network meta-analysis, IFX may be most efficacious agent for inducing remission in CD in biologic-naïve patients. In the absence of head-to-head treatment comparison, the confidence in these estimates is low. Future comparative efficacy studies are warranted.

Extra-hepatic manifestations associated with hepatitis E virus infection: a comprehensive review of the literature

Background and aims: Hepatitis E virus (HEV) infection is a significant public health problem that afflicts almost 20 million individuals annually and causes acute liver injury in 3.5 million, with approximately 56 000 deaths. As with other viral hepatitides, extra-hepatic manifestations could represent an important aspect of this infection. The spectrum of these manifestations is still emerging. Acute pancreatitis and neurological, musculoskeletal, hematological, renal, and other immune-mediated manifestations have been described. The aim of this article is to comprehensively review the published literature of extra-hepatic manifestations associated with HEV infection. Data sources: We searched the PubMed database using the MeSH term “hepatitis E” and each of the extra-hepatic manifestations associated with HEV infection. No language or date restrictions were set in these searches. Searches retrieving articles with non-A, non-B hepatitis were excluded. Additional articles were identified through the reference lists of included articles. Results: Several extra-hepatic manifestations associated with HEV infection have been published. The temporal association between some extra-hepatic manifestations and HEV infection and the exclusion of other possible etiologies suggests that HEV infection could have caused some of them. According to the available data, HEV infection appears to be strongly associated with acute pancreatitis, neurological disorders (with primarily dominant peripheral nerve involvement, most commonly manifested as Guillain-Barré syndrome, followed by neuralgic amyotrophy), hematological diseases (hemolytic anemia due to glucose phosphate dehydrogenase deficiency, and severe thrombocytopenia), glomerulonephritis, and mixed cryoglobulinemia. More data are needed to clarify whether an association exists with musculoskeletal or other immune-mediated manifestations. Conclusions: HEV infection should be considered in patients with acute pancreatitis, Guillain-Barré syndrome, neuralgic amyotrophy, hemolytic anemia due to glucose phosphate dehydrogenase deficiency, severe thrombocytopenia, glomerulonephritis, and mixed cryoglobulinemia. Alternatively, signs and symptoms of these conditions should be sought in patients with acute or chronic HEV infection. More data are needed to confirm the role of HEV in other extra-hepatic disorders.

Comparative Efficacy of Pharmacologic Interventions in Preventing Relapse of Crohn’s Disease After Surgery: A Systematic Review and Network Meta-analysis

BACKGROUND & AIMS There are several drugs that might decrease the risk of relapse of Crohns disease (CD) after surgery, but it is unclear whether one is superior to others. We estimated the comparative efficacy of different pharmacologic interventions for postoperative prophylaxis of CD, through a network meta-analysis of randomized controlled trials. METHODS We conducted a systematic search of the literature through March 2014. We identified randomized controlled trials that compared the abilities of mesalamine, antibiotics, budesonide, immunomodulators, anti-tumor necrosis factor α (anti-TNF) (started within 3 months of surgery), and/or placebo or no intervention to prevent clinical and/or endoscopic relapse of CD in adults after surgical resection. We used Bayesian network meta-analysis to combine direct and indirect evidence and estimate the relative effects of treatment. RESULTS We identified 21 trials comprising 2006 participants comparing 7 treatment strategies. In a network meta-analysis, compared with placebo, mesalamine (relative risk [RR], 0.60; 95% credible interval [CrI], 0.37-0.88), antibiotics (RR, 0.26; 95% CrI, 0.08-0.61), immunomodulator monotherapy (RR, 0.36; 95% CrI, 0.17-0.63), immunomodulator with antibiotics (RR, 0.11; 95% CrI, 0.02-0.51), and anti-TNF monotherapy (RR, 0.04; 95% CrI, 0.00-0.14), but not budesonide (RR, 0.93; 95% CrI, 0.40-1.84), reduced the risk of clinical relapse. Likewise, compared with placebo, antibiotics (RR, 0.41; 95% CrI, 0.15-0.92), immunomodulator monotherapy (RR, 0.33; 95% CrI, 0.13-0.68), immunomodulator with antibiotics (RR, 0.16; 95% CrI, 0.04-0.48), and anti-TNF monotherapy (RR, 0.01; 95% CrI, 0.00-0.05), but neither mesalamine (RR, 0.67; 95% CrI, 0.39-1.08) nor budesonide (RR, 0.86; 95% CrI, 0.61-1.22), reduced the risk of endoscopic relapse. Anti-TNF monotherapy was the most effective pharmacologic intervention for postoperative prophylaxis, with large effect sizes relative to all other strategies (clinical relapse: RR, 0.02-0.20; endoscopic relapse: RR, 0.005-0.04). CONCLUSIONS Based on Bayesian network meta-analysis combining direct and indirect treatment comparisons, anti-TNF monotherapy appears to be the most effective strategy for postoperative prophylaxis for CD.

Endoplasmic reticulum stress is chronically activated in chronic pancreatitis.

Background: The nature of endoplasmic reticulum (ER) stress in chronic pancreatitis (CP) is not known. Results: ER stress is activated early, independently of trypsinogen activation, and remains sustained in CP. Conclusion: Pathologic ER stress activation may be a novel pathogenic mechanism of CP. Significance: ER stress is a key event independent of the traditional central event of pancreatitis-trypsinogen activation. The pathogenesis of chronic pancreatitis (CP) is poorly understood. Endoplasmic reticulum (ER) stress has now been recognized as a pathogenic event in many chronic diseases. However, ER stress has not been studied in CP, although pancreatic acinar cells seem to be especially vulnerable to ER dysfunction because of their dependence on high ER volume and functionality. Here, we aim to investigate ER stress in CP, study its pathogenesis in relation to trypsinogen activation (widely regarded as the key event of pancreatitis), and explore its mechanism, time course, and downstream consequences during pancreatic injury. CP was induced in mice by repeated episodes of acute pancreatitis (AP) based on caerulein hyperstimulation. ER stress leads to activation of unfolded protein response components that were measured in CP and AP. We show sustained up-regulation of unfolded protein response components ATF4, CHOP, GRP78, and XBP1 in CP. Overexpression of GRP78 and ATF4 in human CP confirmed the experimental findings. We used novel trypsinogen-7 knock-out mice (T−/−), which lack intra-acinar trypsinogen activation, to clarify the relationship of ER stress to intra-acinar trypsinogen activation in pancreatic injury. Comparable activation of ER stress was seen in wild type and T−/− mice. Induction of ER stress occurred through pathologic calcium signaling very early in the course of pancreatic injury. Our results establish that ER stress is chronically activated in CP and is induced early in pancreatic injury through pathologic calcium signaling independent of trypsinogen activation. ER stress may be an important pathogenic mechanism in pancreatitis that needs to be explored in future studies.

Similar Risk of Cardiopulmonary Adverse Events Between Propofol and Traditional Anesthesia for Gastrointestinal Endoscopy: A Systematic Review and Meta-analysis

BACKGROUND & AIMS: Even though propofol use for gastrointestinal endoscopic procedures has increased over the past decade, there is a perception that it causes a higher rate of cardiopulmonary adverse events. The aim of this study was to compare the sedation‐related adverse events associated with use of propofol vs nonpropofol agents for endoscopic procedures. We also wanted to determine the influence of duration or complexity of the procedures and endoscopist‐directed (gastroenterologist) vs non–gastroenterologist‐directed sedation on the outcomes. METHODS: A search was conducted using Medline, EMBASE, and the Cochrane controlled trials registry. The following cardiopulmonary adverse events were assessed: hypoxia, hypotension, and arrhythmias. The procedures were divided into 2 groups based on the procedure length: a nonadvanced endoscopic procedure group consisting of esophagogastroduodenoscopy, colonoscopy, and sigmoidoscopy, and an advanced endoscopic procedures group including endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, balloon enteroscopy, and endoscopic submucosal dissection. Pooled odds ratios for complications were calculated for all the procedures combined and then separately for the 2 groups. Random‐effects models were used for 2‐proportion comparisons. RESULTS: Of the 2117 citations identified, 27 original studies qualified for this meta‐analysis and included 2518 patients. Of these, 1324 received propofol, and 1194 received midazolam, meperidine, pethidine, remifentanil, and/or fentanyl. Most of the included studies were randomized trials of moderate quality and nonsignificant heterogeneity (Cochran Q, 26.07; P = .13). Compared with traditional sedative agents, the pooled odds ratio with the use of propofol for developing hypoxia for all the procedures combined was 0.82 (95% confidence interval [CI], 0.63–1.07), and for developing hypotension was 0.92 (95% CI, 0.64–1.32). In the nonadvanced endoscopic procedure group, those who received propofol were 39% less likely to develop complications than those receiving traditional sedative agents (odds ratio, 0.61; 95% CI, 0.38–0.99). There was no difference in the complication rate for the advanced endoscopic procedure group (odds ratio, 0.86; 95% CI, 0.56–1.34). A subgroup analysis did not show any difference in adverse events when propofol was administered by gastroenterologists or nongastroenterologists. CONCLUSIONS: Propofol sedation has a similar risk of cardiopulmonary adverse events compared with traditional agents for gastrointestinal endoscopic procedures. Propofol use in simple endoscopic procedures was associated with a decreased number of complications. When used for gastrointestinal endoscopic procedures of a complex nature and longer duration, propofol was not associated with increased rates of hypoxemia, hypotension, or arrhythmias. Administration of propofol by gastroenterologists does not appear to increase the complication rates.

Efficacy and Safety of Exercise Training in Chronic Pulmonary Hypertension Systematic Review and Meta-Analysis

Background—Exercise training has been shown to improve cardiorespiratory fitness, physical capacity, and quality of life in patients with cardiopulmonary conditions, such as heart failure and chronic obstructive pulmonary disease. However, its role in management of pulmonary hypertension is not well defined. In this study, we aim to evaluate the efficacy and safety of exercise training in patients with pulmonary hypertension. Methods and Results—We included all prospective intervention studies that evaluated the efficacy and safety of exercise training in patients with pulmonary hypertension. Primary outcome of this meta-analysis was a change in 6-minute walk distance. We also assessed the effect of exercise on peak oxygen uptake, resting pulmonary arterial systolic pressure, peak exercise heart rate, and quality of life. A total of 469 exercise-training participants enrolled in 16 separate training studies were included. In the pooled analysis, exercise training was associated with significant improvement in 6-minute walk distance (weighted mean difference, 53.3 m; 95% confidence interval, 39.5–67.2), peak oxygen uptake (weighted mean difference, 1.8 mL/kg per minute; 95% confidence interval, 1.4–2.3), pulmonary arterial systolic pressure (weighted mean difference, −3.7 mm Hg; 95% confidence interval, −5.4 to −1.9), peak exercise heart rate (weighted mean difference, 10 beats per min; 95% confidence interval, 6–15), and quality of life as measured on SF-36 questionnaire subscale scores. Furthermore, exercise training was well tolerated with a low dropout rate, and no major adverse events were related to exercise training. Conclusions—Exercise training in patients with pulmonary hypertension appears safe and is associated with a significant improvement in exercise capacity, pulmonary arterial pressure, and quality of life.

Continuous Dose-Response Association Between Sedentary Time and Risk for Cardiovascular Disease: A Meta-analysis

IMPORTANCE Prior studies suggest that higher sedentary time is associated with a greater risk for cardiovascular disease (CVD). However, the quantitative, dose-response association between sedentary time and CVD risk is not known. OBJECTIVE To determine the categorical and quantitative dose-response association between sedentary time and CVD risk. DATA SOURCES Two independent investigators searched the MEDLINE and EMBASE databases for all studies published before July 6, 2015, that evaluated the association between sedentary time and incident CVD. STUDY SELECTION Prospective cohort studies with participants 18 years or older that reported the association between sedentary time and incident CVD were included. DATA EXTRACTION AND SYNTHESIS Two independent investigators performed the data extraction and collection using a standardized form. The study quality was assessed using the Newcastle-Ottawa Scale. The categorical dose-response association was evaluated by comparing the pooled hazard ratio (HR) for incident CVD associated with different levels of sedentary time (vs lowest sedentary time) across studies. The continuous dose-response association was assessed using random-effects generalized least squares spline models. Data were collected from April 5 to July 6, 2015. MAIN OUTCOMES AND MEASURES Incident CVD (coronary heart disease, including nonfatal myocardial infarction, stroke, and cardiovascular mortality). RESULTS Nine prospective cohort studies with 720 425 unique participants (57.1% women; 42.9% men; mean age, 54.5 years) and 25 769 unique cardiovascular events and a median follow-up of 11 years were included. In categorical analyses, compared with the lowest sedentary time category (median, 2.5 h/d), participants in the highest sedentary time category (median, 12.5 h/d) had an increased risk for CVD (HR, 1.14; 95% CI, 1.09-1.19). However, no apparent risk associated with intermediate levels of sedentary time (HR for 7.5 h/d, 1.02; 95% CI, 0.96-1.08) was found. In continuous analyses, a nonlinear association between sedentary time and incident CVD was found (P for nonlinearity < .001), with an increased risk observed for more than 10 hours of sedentary time per day (pooled HR, 1.08; 95% CI, 1.00-1.14). CONCLUSIONS AND RELEVANCE The association between sedentary time and the risk for CVD is nonlinear with an increased risk only at very high levels. These findings could have implications for guideline recommendations regarding the risks related to sedentary behavior.