Two-stage deep learning model for fully automated pancreas segmentation on computed tomography: Comparison with intra-reader and inter-reader reliability at full and reduced radiation dose on an external dataset.

PURPOSE: To develop a two-stage three-dimensional (3D) convolutional neural networks (CNNs) for fully automated volumetric segmentation of pancreas on computed tomography (CT) and to further evaluate its performance in the context of intra-reader and inter-reader reliability at full dose and reduced radiation dose CTs on a public dataset. METHODS: A dataset of 1994 abdomen CT scans (portal venous phase, slice thickness ≤ 3.75-mm, multiple CT vendors) was curated by two radiologists (R1 and R2) to exclude cases with pancreatic pathology, suboptimal image quality, and image artifacts (n = 77). Remaining 1917 CTs were equally allocated between R1 and R2 for volumetric pancreas segmentation [ground truth (GT)]. This internal dataset was randomly divided into training (n = 1380), validation (n = 248), and test (n = 289) sets for the development of a two-stage 3D CNN model based on a modified U-net architecture for automated volumetric pancreas segmentation. Model's performance for pancreas segmentation and the differences in model-predicted pancreatic volumes vs GT volumes were compared on the test set. Subsequently, an external dataset from The Cancer Imaging Archive (TCIA) that had CT scans acquired at standard radiation dose and same scans reconstructed at a simulated 25% radiation dose was curated (n = 41). Volumetric pancreas segmentation was done on this TCIA dataset by R1 and R2 independently on the full dose and then at the reduced radiation dose CT images. Intra-reader and inter-reader reliability, model's segmentation performance, and reliability between model-predicted pancreatic volumes at full vs reduced dose were measured. Finally, model's performance was tested on the benchmarking National Institute of Health (NIH)-Pancreas CT (PCT) dataset. RESULTS: Three-dimensional CNN had mean (SD) Dice similarity coefficient (DSC): 0.91 (0.03) and average Hausdorff distance of 0.15 (0.09) mm on the test set. Model's performance was equivalent between males and females (P = 0.08) and across different CT slice thicknesses (P > 0.05) based on noninferiority statistical testing. There was no difference in model-predicted and GT pancreatic volumes [mean predicted volume 99 cc (31cc); GT volume 101 cc (33 cc), P = 0.33]. Mean pancreatic volume difference was -2.7 cc (percent difference: -2.4% of GT volume) with excellent correlation between model-predicted and GT volumes [concordance correlation coefficient (CCC)=0.97]. In the external TCIA dataset, the model had higher reliability than R1 and R2 on full vs reduced dose CT scans [model mean (SD) DSC: 0.96 (0.02), CCC = 0.995 vs R1 DSC: 0.83 (0.07), CCC = 0.89, and R2 DSC:0.87 (0.04), CCC = 0.97]. The DSC and volume concordance correlations for R1 vs R2 (inter-reader reliability) were 0.85 (0.07), CCC = 0.90 at full dose and 0.83 (0.07), CCC = 0.96 at reduced dose datasets. There was good reliability between model and R1 at both full and reduced dose CT [full dose: DSC: 0.81 (0.07), CCC = 0.83 and reduced dose DSC:0.81 (0.08), CCC = 0.87]. Likewise, there was good reliability between model and R2 at both full and reduced dose CT [full dose: DSC: 0.84 (0.05), CCC = 0.89 and reduced dose DSC:0.83(0.06), CCC = 0.89]. There was no difference in model-predicted and GT pancreatic volume in TCIA dataset (mean predicted volume 96 cc (33); GT pancreatic volume 89 cc (30), p = 0.31). Model had mean (SD) DSC: 0.89 (0.04) (minimum-maximum DSC: 0.79 -0.96) on the NIH-PCT dataset. CONCLUSION: A 3D CNN developed on the largest dataset of CTs is accurate for fully automated volumetric pancreas segmentation and is generalizable across a wide range of CT slice thicknesses, radiation dose, and patient gender. This 3D CNN offers a scalable tool to leverage biomarkers from pancreas morphometrics and radiomics for pancreatic diseases including for early pancreatic cancer detection.

Pancreatic ductal adenocarcinoma is associated with a unique endocrinopathy distinct from type 2 diabetes mellitus.

INTRODUCTION: The majority of patients with pancreatic ductal adenocarcinoma (PC) display either impaired fasting glucose/glucose intolerance or overt diabetes. However, the pathophysiologic basis of this association remains largely unexplained. METHODS: In this case-control study we aimed to study the morphological changes in the islets of patients with PC, compared to control patients with and without type 2 diabetes mellitus (T2DM). T2DM controls and PC cases had a lower ß-cell area and average islet size and density compared to non-T2DM controls (p < 0.05). RESULTS: Compared to both T2DM and non-T2DM controls, mean α-cell area was significantly lower and ß/α-ratio was higher in PC cases (p < 0.05). Furthermore, whereas islets in T2DM controls were characterized by disrupted islet architecture and presence of islet amyloid aggregates, islet composition in PC islets was not significantly different compared to non-T2DM controls (p > 0.05 vs. Control). CONCLUSIONS: Our data shows that PC is associated with a unique pattern of islet pathology characterized by preserved architecture, absence of amyloid aggregates, and relative α-cell loss indicating that distinct mechanisms are likely involved in the pathophysiology of islet failure in PC-induced DM. Insights into the mechanisms mediating ß-cell failure in PC can be important for our understanding of pathophysiology of PC.

Clostridium difficile Infection in the Emergency Department.

INTRODUCTION: Clostridioides difficile infection (CDI) is associated with substantial emergency department (ED) and inpatient burden. To date, few studies have evaluated the ED burden of CDI. Using the Nationwide Emergency Department Sample, we evaluated trends in ED use, ED and inpatient charges, admission and mortality rates, length of stay, and independent risk factors for hospital admission and mortality after an ED visit. METHODS: Using Nationwide Emergency Department Sample for 2006 through 2014, we identified all patients with the primary diagnosis of CDI (using diagnostic codes). We determined the trends in ED visits and used survey logistic regression analysis to identify factors associated with hospital admission. RESULTS: Overall, 909,236 ED visits for CDI resulted in 817,935 admissions (90%) to the hospital. The number of visits increased from 76,709 in 2006 to 106,869 in 2014, and the admission rate decreased from 92.4% to 84.4%. ED charges adjusted for inflation went up from US$1433.0 to 2900, a significant rise even accounting for inflation. The overall length of hospital stay decreased from 7 to 5.8 days. Independent predictors of admission after ED visits included smoking, use of alcohol, and presence of multiple comorbidities. Independent risk factors for mortality in admitted patients include increasing age and presence of comorbidities. CONCLUSIONS: Although ED use for CDI increased, rates of hospital admission decreased over 9 years. Identification of predictors of admission and in-hospital mortality will help guide policies and interventions to reduce the burden on health care resources.

Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD: JACC Review Topic of the Week.

Ticagrelor is a cornerstone of modern antithrombotic therapy alongside aspirin in patients with acute coronary syndrome and after percutaneous coronary intervention. Adverse effects such as bleeding and dyspnea have been associated with premature ticagrelor discontinuation, which may limit any potential advantage of ticagrelor over clopidogrel. The randomized trials of ticagrelor captured adverse events, offering the opportunity to more precisely quantify these effects across studies. Therefore, a meta-analysis of 4 randomized clinical trials of ticagrelor conducted between January 2007 and June 2017 was performed to quantify the incidence and causes of premature ticagrelor discontinuation. Among 66,870 patients followed for a median 18 months, premature ticagrelor discontinuation was seen in 25%; bleeding was the most common cause of discontinuation followed by dyspnea. Versus the comparators, the relative risk of dyspnea-related discontinuation during follow-up was 6.4-fold higher, the relative risk of bleeding was 3.2-fold higher, and the relative risk of discontinuation due to any adverse event was 59% higher for patients receiving ticagrelor. Understanding these potential barriers to adherence to ticagrelor is crucial for informed patient-physician decision making and can inform future efforts to improve ticagrelor adherence. This review discusses the incidence, causes, and biological mechanisms of ticagrelor-related adverse effects and offers strategies to improve adherence to ticagrelor.

Incidence and Risk Factors Associated With 30-Day Readmission for Alcoholic Hepatitis.

BACKGROUND: Alcohol abuse and liver disease are associated with high rates of 30-day hospital readmission, but factors linking alcoholic hepatitis (AH) to readmission are not well understood. We aimed to determine the incidence rate of 30-day readmission for patients with AH and to evaluate potential predictors of readmission. METHODS: We used the Nationwide Readmissions Database to determine the 30-day readmission rate for recurrent AH between 2010 and 2014 and examined trends in readmissions during the study period. We also identified the 20 most frequent reasons for readmission. Multivariate survey logistic regression analysis was used to identify factors associated with 30-day readmission. RESULTS: Of the 61,750 index admissions for AH, 23.9% were readmitted within 30-days. The rate of readmission did not change significantly during the study period. AH, alcoholic cirrhosis, and hepatic encephalopathy were the most frequent reasons for readmission. In multivariate analysis female sex, leaving against medical advice, higher Charlson comorbidity index, ascites, and history of bariatric surgery were associated with earlier readmissions, whereas older age, payer type (private or self-pay/other), and discharge to skilled nursing-facility reduced this risk. CONCLUSIONS: The 30-day readmission rate in patients with AH was high and stable during the study period. Factors associated with readmission may be helpful for development of consensus-based expert guidelines, treatment algorithms, and policy changes to help decrease readmission in AH.

Hospital Utilization in Patients With Gastric Cancer and Factors Affecting In-Hospital Mortality, Length of Stay, and Costs.

INTRODUCTION: Although gastric cancer (GC) rates have been declining in the United States, it continues to be a major cause of morbidity. This study examined trends in hospital admissions, in-hospital mortality, length of stay (LOS), and inpatient costs related to GC. In addition, various factors associated with in-hospital mortality, LOS, and inpatient costs were examined. METHODS: National inpatient sample-the largest publicly available all-payer inpatient care database-was interrogated to obtain information about various demographic and hospital-related factors (including those mentioned above) in patients who were primarily admitted for GC between the years 1998 to 2013. These trends were analyzed. Multivariate analysis was also performed to identify risk factors associated with LOS, costs, and mortality. RESULTS: A total of 679,330 hospital discharges with the principal diagnosis of GC were obtained. Hospital stays increased by approximately 340 stays per year (±110; P=0.00079). However, inpatient mortality rate and LOS declined by 0.36% per year (±0.024%; P<0.0001), and 0.11 days per year (±0.01; P<0.0001), respectively. The inpatient charges have increased at the rate of $3241 per year (±133.3; P<0.0001). Differences in mortality rate, LOS, and inpatient costs were affected by multiple factors. CONCLUSIONS: Despite the overall decline in GC incidence, the incidence of hospitalizations per 100,000 US population related to GC did not change significantly. Although LOS and mortality declined, inpatient charges increased over the study period.

Incidence, Admission Rates, and Predictors, and Economic Burden of Adult Emergency Visits for Acute Pancreatitis: Data From the National Emergency Department Sample, 2006 to 2012.

INTRODUCTION: Acute pancreatitis (AP) is the most common gastroenterology-related reason for hospital admission, and a major source of morbidity and mortality in the United States. This study examines the National Emergency Database Sample, a large national database, to analyze trends in emergency department (ED) utilization and costs, risk factors for hospital admission, and associated hospital costs and length of stay (LOS) in patients presenting with AP. METHODS: The National Emergency Database Sample (2006 to 2012) was evaluated for trends in ED visits, ED charges, hospitalization rates, hospital charges, and hospital LOS in patients with primary diagnosis of AP (further subcategorized by age and etiology). A survey logistic-regression model was used to determine factors predictive of hospitalization. RESULTS: A total of 2,193,830 ED visits were analyzed. There was a nonsignificant 5.5% (P=0.07) increase in incidence of ED visits for AP per 10,000 US adults from 2006 to 2012, largely driven by significant increases in ED visits for AP in the 18 to <45 age group (+9.2%; P=0.025), AP associated with alcohol (+15.9%; P=0.001), and AP associated with chronic pancreatitis (+59.5%; P=0.002). Visits for patients aged ≥65 decreased over the time period. Rates of admission and LOS decreased during the time period, while ED and inpatient costs increased (62.1%; P<0.001 and 7.9%; P=0.0011, respectively). Multiple factors were associated with increased risk of hospital admission from the ED, with the strongest predictors being morbid alcohol use [odds ratio (OR), 4.53; P<0.0001], advanced age (age>84 OR, 3.52; P<0.0001), and smoking (OR, 1.75; P<0.0001). CONCLUSIONS: Despite a relative stabilization in the overall incidence of ED visits for AP, continued increases in ED visits and associated costs appear to be driven by younger patients with alcohol-associated and acute on chronic pancreatitis. While rates of hospitalization and LOS are decreasing, associated inflation-adjusted costs are rising. In addition, identified risk factors for hospitalization, such as obesity, alcohol use, and increased age, should be explored in further study for potential use in predictive models and clinical improvement projects.

Incidence, Admission Rates, and Economic Burden of Adult Emergency Visits for Chronic Pancreatitis: Data From the National Emergency Department Sample, 2006 to 2012.

INTRODUCTION: Chronic pancreatitis (CP) is a common reason for emergency department (ED) visits, but little research has examined ED use by patients with CP. MATERIALS AND METHODS: The Nationwide Emergency Department Sample (2006 to 2012) was interrogated to evaluate trends in adult ED visits for a primary diagnosis of CP (International Classification of Disease, 9th revision, Clinical Modification code: 577.1), the rates of subsequent hospital admission, and total charges. A survey logistic regression model was used to determine factors associated with hospitalization from the ED. RESULTS: We identified 253,753 ED visits with a primary diagnosis of CP. No significant trends in annual incidence were noted. However, the ED-to-hospitalization rates decreased by 3% per year (P<0.001) and mean ED charges after adjusting for inflation increased by 11.8% per year (P<0.001). Higher Charlson comorbidity index, current smoker status, alcohol use, and biliary-related CP were associated with hospitalization. In hospitalized patients, length of stay decreased by 2.2% per year (P=0.003) and inpatient charges increased by 2.9% per year (P=0.004). CONCLUSIONS: Patient characteristics associated with higher risk of hospitalization from the ED deserve further attention.

Incidence and Predictors of 30-Day Readmission Among Patients Hospitalized for Chronic Pancreatitis.

OBJECTIVES: Chronic pancreatitis (CP) hospitalizations along with associated morbidity and costs are increasing. The goal of this study was to use the National Readmission Database to identify the incidence and risk factors for 30-day readmissions among patients with CP. METHODS: We performed a retrospective analysis of National Readmission Database from January 2013 to December 2013 to determine patient demographic and clinical characteristics predictive of 30-day hospital readmission for adult patients (aged >18 years) discharged with a principle diagnosis of CP. A survey logistic regression model was used to determine the predictive value of selected variables for 30-day readmission. RESULTS: In 2013, 12,545 admissions with primary diagnosis of CP were noted, and 30.4% were readmitted within 30 days. Cholecystectomy (odds ratio [OR], 0.53; P = 0.0024) or endoscopic retrograde cholangiopancreatography (OR, 0.70; P = 0.01) during index admission was associated with decreased all-cause readmissions. Pancreatectomy during index admission was associated with reduced (OR, 0.2; P = 0.0005) pancreatitis-related readmissions. CONCLUSIONS: Hospital readmissions for CP are frequent and pose a significant healthcare burden. Performing cholecystectomy, endoscopic retrograde cholangiopancreatography, or pancreatectomy during index admission was associated with reduced odds of readmission.

Clobazam monotherapy for focal or generalized seizures.

BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 10, 2014. There is a need to expand monotherapy options available to a clinician for the treatment of new focal or generalized seizures. A Cochrane systematic review for clobazam monotherapy is expected to define its place in the treatment of new-onset or untreated seizures and highlight gaps in evidence. OBJECTIVES: To evaluate the efficacy, effectiveness, tolerability and safety of clobazam as monotherapy in people with new-onset focal or generalized seizures. SEARCH METHODS: For the latest update we searched the following databases on 19 March 2018: the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946- ), BIOSIS Previews (1969- ), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). There were no language restrictions. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials comparing clobazam monotherapy versus placebo or other anti-seizure medication in people with two or more unprovoked seizures or single acute symptomatic seizure requiring short-term continuous anti-seizure medication, were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Primary outcome measure was time on allocated treatment (retention time), reflecting both efficacy and tolerability. Secondary outcomes included short- and long-term effectiveness measures, tolerability, quality of life, and tolerance measures. Two authors independently extracted the data. MAIN RESULTS: We identified three trials fulfilling the review criteria, which included 206 participants. None of the identified studies reported the preselected primary outcome measure. A meta-analysis was not possible. Lack of detail regarding allocation concealment and a high risk of performance and detection bias in two studies prompted us to downgrade the quality of evidence (by using the GRADE approach) for some of our results due to risk of bias.Regarding retention at 12 months, we detected no evidence of a statistically significant difference between clobazam and carbamazepine (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.61 to 1.12; low-quality evidence). There was low-quality evidence that clobazam led to better retention compared with phenytoin (RR 1.43, 95% CI 1.08 to 1.90). We could not determine whether participants receiving clobazam were found to be less likely to discontinue it due to adverse effects as compared to phenytoin (RR 0.10, 95% CI 0.01 to 1.65, low-quality evidence). AUTHORS' CONCLUSIONS: We found no advantage for clobazam over carbamazepine for retention at 12 months in drug-naive children and a slight advantage of clobazam over phenytoin for retention at six months in adolescents and adults with neurocysticercosis in a single clinical trial each. At present, the available evidence is insufficient to inform clinical practice.

Intestinal and Nonintestinal Cancer Risks for Patients with Crohn's Disease.

Crohn's disease (CD) is a chronic inflammatory disease that confers a higher risk of cancer than in the general population. New, large, population-based studies in the past decade show that patients with CD are at higher risk of colorectal, small bowel, melanoma, and cervical cancer. Patients who use thiopurines are at additional risk of development of lymphoma and nonmelanoma skin cancer. Preventive surveillance for cancers of the colorectum, skin, and uterine cervix is advised.

Early esophagogastroduodenoscopy is associated with better Outcomes in upper gastrointestinal bleeding: a nationwide study.

Background and study aims We analyzed NIS (National Inpatient Sample) database from 2007 - 2013 to determine if early esophagogastroduodenoscopy (EGD) (24 hours) for upper gastrointestinal bleeding improved the outcomes in terms of mortality, length of stay and costs. Patients and methods Patients were classified as having upper gastrointestinal hemorrhage by querying all diagnostic codes for the ICD-9-CM codes corresponding to upper gastrointestinal bleeding. For these patients, performance of EGD during admission was determined by querying all procedural codes for the ICD-9-CM codes corresponding to EGD; early EGD was defined as having EGD performed within 24 hours of admission and late EGD was defined as having EGD performed after 24 hours of admission. Results A total of 1,789,532 subjects with UGIH were identified. Subjects who had an early EGD were less likely to have hypovolemia, acute renal failure and acute respiratory failure. On multivariable analysis, we found that subjects without EGD were 3 times more likely to die during the admission than those with early EGD. In addition, those with late EGD had 50 % higher odds of dying than those with an early EGD. Also, after adjusting for all factors in the model, hospital stay was on average 3 and 3.7 days longer for subjects with no or late EGD, respectively, then for subjects with early EGD. Conclusion Early EGD (within 24 hours) is associated with lower in-hospital mortality, morbidity, shorter length of stay and lower total hospital costs.

Health Care Utilization and Costs Associated With Acute Pancreatitis.

OBJECTIVE: Acute pancreatitis is a common inpatient diagnosis among gastrointestinal disorders. The aim of this study was to evaluate the incidence of inpatient admissions, costs, and mortality rates associated with acute pancreatitis in the United States. METHODS: We analyzed the National Inpatient Sample for all patients in which acute pancreatitis (International Classification of Diseases, Ninth Revision code: 577.0) was the principal discharge diagnosis during the period 1997-2012. The statistical significance of the difference in the hospital discharges, length of stay, and costs over the study period was determined by utilization of regression analysis. RESULTS: In 1997, there were 164,776 admissions with a principal discharge diagnosis of acute pancreatitis as compared with 275,170 in 2012 (P < 0.001). The mean length of stay for acute pancreatitis decreased from 6.4 days in 1997 to 4.7 days in 2012 (P < 0.001). However, during this period, the mean hospital charges increased by 118.6% from $15,433 in 1997 to $33,744 in 2012 (P < 0.001). The in-hospital mortality rate decreased significantly from 1.9% in 1997 to 0.78% in 2012 (P < 0.001). CONCLUSIONS: Inpatient admissions for acute pancreatitis and associated costs have increased markedly over the last 16 years in the United States. However, the lengths of stay and mortality rates have decreased significantly.

Nationwide trends of hospital admissions for acute cholecystitis in the United States.

BACKGROUND AND AIMS: Acute cholecystitis is a fairly common inpatient diagnosis among the gastrointestinal disorders. The aim of this study was to use a national database of US hospitals to evaluate the incidence and costs of hospital admissions associated with acute cholecystitis. METHOD: We analyzed the National Inpatient Sample Database (NIS) for all patients in which acute cholecystitis (ICD-9 codes: 574.00, 574.01, 574.30, 574.31, 574.60, 574.61 or 575.0) was the principal discharge diagnosis from 1997 to 2012. The NIS is the largest all-payer inpatient database in the United States and contains data from approximately 8 million hospital stays each year. The statistical significance of the difference in the number of hospital discharges, lengths of stay and associated hospital costs over the study period was determined by using the Chi-square test for trends. RESULTS: In 1997, there were 149 661 hospital admissions with a principal discharge diagnosis of acute cholecystitis, which increased to 215 995 in 2012 ( P < 0.001). The mean length of stay for acute cholecystitis decreased by 17% between 1997 and 2012 (i.e. from 4.7 days to 3.9 days; (P < 0.05). During the same time period, however, mean hospital charges have increased by 195.4 % from US$14 608 per patient in 1997 to US$43 152 per patient in 2012 ( P < 0.001). CONCLUSION: The number of inpatient discharges related to acute cholecystitis has increased significantly in the United States over the last 16 years, along with a great increase in the associated hospital charges. However, there has been a gradual decline in the mean length of stay. Inpatient costs associated with acute cholecystitis contribute significantly to the total healthcare bill. Further research on cost-effective evaluation and management of acute cholecystitis is required.

Bilirubin in coronary artery disease: Cytotoxic or protective?

Bilirubin has traditionally been considered a cytotoxic waste product. However, recent studies have shown bilirubin to have anti-oxidant, anti-inflammatory, vasodilatory, anti-apoptotic and anti-proliferative functions. These properties potentially confer bilirubin a new role of protection especially in coronary artery disease (CAD), which is a low grade inflammatory process exacerbated by oxidative stress. In fact, recent literature reports an inverse relationship between serum concentration of bilirubin and the presence of CAD. In this article, we review the current literature exploring the association between levels of bilirubin and risk of CAD. We conclude that current evidence is inconclusive regarding the protective effect of bilirubin on CAD. A causal relationship between low serum bilirubin level and increased risk of CAD is not currently established.

Release of Cathepsin B in Cytosol Causes Cell Death in Acute Pancreatitis.

BACKGROUND & AIMS: Experimental studies in acute pancreatitis (AP) suggest a strong association of acinar cell injury with cathepsin B-dependent intracellular activation of trypsin. However, the molecular events subsequent to trypsin activation and their role, if any, in cell death is not clear. In this study, we have explored intra-acinar events downstream of trypsin activation that lead to acinar cell death. METHODS: Acinar cells prepared from the pancreas of rats or mice (wild-type, trypsinogen 7, or cathepsin B-deleted) were stimulated with supramaximal cerulein, and the cytosolic activity of cathepsin B and trypsin was evaluated. Permeabilized acini were used to understand the differential role of cytosolic trypsin vs cytosolic cathepsin B in activation of apoptosis. Cell death was evaluated by measuring specific markers for apoptosis and necrosis. RESULTS: Both in vitro and in vivo studies have suggested that during AP cathepsin B leaks into the cytosol from co-localized organelles, through a mechanism dependent on active trypsin. Cytosolic cathepsin B but not trypsin activates the intrinsic pathway of apoptosis through cleavage of bid and activation of bax. Finally, excessive release of cathepsin B into the cytosol can lead to cell death through necrosis. CONCLUSIONS: This report defines the role of trypsin in AP and shows that cytosolic cathepsin B but not trypsin activates cell death pathways. This report also suggests that trypsin is a requisite for AP only because it causes release of cathepsin B into the cytosol.

Risk of cancer in inflammatory bowel disease: going up, going down, or still the same?

PURPOSE OF REVIEW: There has been increasing use of immunosuppressive medications as well as better surveillance techniques in inflammatory bowel disease (IBD), which is associated with an increased risk of intestinal and extraintestinal malignancies. We assessed the temporal trends of cancer incidence in IBD patients by reviewing the biomedical literature, performing meta-regression of existing studies, and examining trends in hospitalizations for cancer in IBD patients using a national hospitalization database. RECENT FINDINGS: The overall risk of colorectal cancer in ulcerative colitis has decreased in the last 3 decades. The risk of small bowel cancer is significantly elevated among Crohn's disease patients, but there has been no change in incidence rates. The overall risk of non-Hodgkin lymphoma has increased over the last 16 years, and IBD patients on thiopurines and antitumor necrosis factor agents are at increased risk of non-Hodgkin lymphoma. The risk of melanoma in IBD patients is increased, with no significant change over time. The risk of nonmelanoma skin cancer is higher in patients using thiopurines compared with the non-IBD background population, with no significant change over time. SUMMARY: This study points toward a decrease in the incidence of colorectal cancer in ulcerative colitis patients, but an increase in the incidence of lymphoproliferative disorders and nonmelanoma skin cancers with the use of immunosuppressive medications in IBD.

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.

Laparoscopic fundoplication surgery versus medical management for gastro-oesophageal reflux disease (GORD) in adults.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is a common condition with 3% to 33% of people from different parts of the world suffering from GORD. There is considerable uncertainty about whether people with GORD should receive an operation or medical treatment for controlling the condition. OBJECTIVES: To assess the benefits and harms of laparoscopic fundoplication versus medical treatment for people with gastro-oesophageal reflux disease. SEARCH METHODS: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group (UGPD) Trials Register (June 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 6, 2015), Ovid MEDLINE (1966 to June 2015), and EMBASE (1980 to June 2015) to identify randomised controlled trials. We also searched the references of included trials to identify further trials. SELECTION CRITERIA: We considered only randomised controlled trials (RCT) comparing laparoscopic fundoplication with medical treatment in people with GORD irrespective of language, blinding, or publication status for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and independently extracted data. We calculated the risk ratio (RR) or standardised mean difference (SMD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models with RevMan 5 based on available case analysis. MAIN RESULTS: Four studies met the inclusion criteria for the review, and provided information on one or more outcomes for the review. A total of 1160 participants in the four RCTs were either randomly assigned to laparoscopic fundoplication (589 participants) or medical treatment with proton pump inhibitors (571 participants). All the trials included participants who had had reflux symptoms for at least six months and had received long-term acid suppressive therapy. All the trials included only participants who could undergo surgery if randomised to the surgery arm. All of the trials were at high risk of bias. The overall quality of evidence was low or very low. None of the trials reported long-term health-related quality of life (HRQoL) or GORD-specific quality of life (QoL).The difference between laparoscopic fundoplication and medical treatment was imprecise for overall short-term HRQOL (SMD 0.14, 95% CI -0.02 to 0.30; participants = 605; studies = 3), medium-term HRQOL (SMD 0.03, 95% CI -0.19 to 0.24; participants = 323; studies = 2), medium-term GORD-specific QoL (SMD 0.28, 95% CI -0.27 to 0.84; participants = 994; studies = 3), proportion of people with adverse events (surgery: 7/43 (adjusted proportion = 14.0%); medical: 0/40 (0.0%); RR 13.98, 95% CI 0.82 to 237.07; participants = 83; studies = 1), long-term dysphagia (surgery: 27/118 (adjusted proportion = 22.9%); medical: 28/110 (25.5%); RR 0.90, 95% CI 0.57 to 1.42; participants = 228; studies = 1), and long-term reflux symptoms (surgery: 29/118 (adjusted proportion = 24.6%); medical: 41/115 (35.7%); RR 0.69, 95% CI 0.46 to 1.03; participants = 233; studies = 1).The short-term GORD-specific QoL was better in the laparoscopic fundoplication group than in the medical treatment group (SMD 0.58, 95% CI 0.46 to 0.70; participants = 1160; studies = 4).The proportion of people with serious adverse events (surgery: 60/331 (adjusted proportion = 18.1%); medical: 38/306 (12.4%); RR 1.46, 95% CI 1.01 to 2.11; participants = 637; studies = 2), short-term dysphagia (surgery: 44/331 (adjusted proportion = 12.9%); medical: 11/306 (3.6%); RR 3.58, 95% CI 1.91 to 6.71; participants = 637; studies = 2), and medium-term dysphagia (surgery: 29/288 (adjusted proportion = 10.2%); medical: 5/266 (1.9%); RR 5.36, 95% CI 2.1 to 13.64; participants = 554; studies = 1) was higher in the laparoscopic fundoplication group than in the medical treatment group.The proportion of people with heartburn at short term (surgery: 29/288 (adjusted proportion = 10.0%); medical: 59/266 (22.2%); RR 0.45, 95% CI 0.30 to 0.69; participants = 554; studies = 1), medium term (surgery: 12/288 (adjusted proportion = 4.2%); medical: 59/266 (22.2%); RR 0.19, 95% CI 0.10 to 0.34; participants = 554; studies = 1), long term (surgery: 46/111 (adjusted proportion = 41.2%); medical: 78/106 (73.6%); RR 0.56, 95% CI 0.44 to 0.72); participants = 217; studies = 1) and those with reflux symptoms at short-term (surgery: 6/288 (adjusted proportion = 2.0%); medical: 53/266 (19.9%); RR 0.10, 95% CI 0.05 to 0.24; participants = 554; studies = 1) and medium term (surgery: 6/288 (adjusted proportion = 2.1%); medical: 37/266 (13.9%); RR 0.15, 95% CI 0.06 to 0.35; participants = 554; studies = 1) was less in the laparoscopic fundoplication group than in the medical treatment group. AUTHORS' CONCLUSIONS: There is considerable uncertainty in the balance of benefits versus harms of laparoscopic fundoplication compared to long-term medical treatment with proton pump inhibitors. Further RCTs of laparoscopic fundoplication versus medical management in patients with GORD should be conducted with outcome-assessor blinding and should include all participants in the analysis. Such trials should include long-term patient-orientated outcomes such as treatment-related adverse events (including severity), quality of life, and also report on the social and economic impact of the adverse events and symptoms.