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Patients with end-stage renal disease are more likely to suffer from gastrointestinal ( GI) problems, including bleeding from upper and lower sources. Peptic ulcer disease is the most common cause of upper GI bleeding, and although there is some debate in the literature regarding whether the frequency of ulcer disease is higher in patients with kidney disease, it is well established that outcomes are worse in patients with compromised renal function. Angioectasias can be found throughout the GI tract and are another common cause of bleeding; management can be divided into localized endoscopic therapy and systemic hormonal treatment, or surgery for refractory cases. The most frequent causes of lower GI bleeding in this population, in addition to angioectasias, are diverticulosis, hemorrhoids, and ischemic colitis. [ABSTRACT FROM AUTHOR]

Abstract: An in situ photopolymerization-coating technique was applied to wrap the pellets surface with a pH-sensitive hydrogel layer made from acrylic acid and hydrophobic acrylate monomers. Powdered cellulose (Elcema® P100) and poly(vinylpyrrolidone) (Kollidon® 30) pellets containing theophylline were prepared by extrusion–spheronization, sprayed with an ethanol:water 50:50v/v solution of the monomers, the cross-linker (N,N′-methylenebis(acrylamide)) and the initiator (Irgacure® 2959), and immediately irradiated at 366nm. The composition of coating mixture and the time of irradiation were optimized using oscillatory rheometry and analyzing the swelling and the drug release behaviour of the resultant hydrogels. When acrylic acid:lauryl acrylate 88:12 molar ratio was used, the coating did not significantly change the shape, size, or friability of the pellets, but remarkably modified theophylline release profiles. The thicker the coating layer, the better the pH-dependent control of drug release. [Copyright &y& Elsevier]

The usefulness of poly(N-isopropyl acrylamide), PNIPA, for preparing sustained release matrix or photopolymerization-coated cellulosic pellets was evaluated. Theophylline pellets and granules were prepared using powdered cellulose (PC), poly(vinylpyrrolidone) (PVP), and PNIPA of Mw ∼330 kDa, Mn ∼93 kDa and low critical solubility temperature ∼32°C. The low consistency of wet mass, evaluated by torsion rheometry, due to hydrophilic character of PNIPA at room temperature, favored extrusion-spheronization. Theophylline (20%) pellets prepared with 15% PNIPA, 20% PVP and 45% PC, and granules obtained using 40% PNIPA and 40% PC showed an enhanced, although limited, ability to sustain the release. This effect was notably promoted after compression (which provides slowly eroding tablets) or coating of individualized pellets. A new coating technique consisting in forming the polymer film by photo-polymerization/cross-linking of NIPA monomers on pellets surface, using a photoinitiator and UV-irradiation at 366 nm, was developed. The composition of coating mixture and the time of irradiation were optimized using oscillatory rheometry. Coating did not significantly change the shape, size, or friability of the pellets but remarkably decreased the porosity and sustained drug release for several hours. In situ formation and cross-linking of PNIPA on the pellet appears as a feasible way for controlling drug release. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:93–105, 2007 [ABSTRACT FROM AUTHOR]

Assesses the cost-effectiveness of empirical treatment in patients with noncardiac chest pain. Decision tree development; Probabilities and costs; Effectiveness of an initial treatment strategy versus an initial investigation strategy; Cost per case of chest pain successfully managed; Additional probability estimates for long-term model.

Nonalcoholic steatohepatitis (NASH) is a multifactorial disease involving different contributing mechanisms, with no approved therapies so far. Tropifexor (TXR), a farnesoid X receptor agonist, and cenicriviroc (CVC), a chemokine receptor types 2/5 antagonist, target the steatotic, inflammatory, and/or fibrotic pathways involved in NASH. TANDEM (CLJC242A2201J; NCT03517540) is a 48-week, phase 2b, randomized, double-blind, multicenter study in 200 adult patients with biopsy-proven NASH and liver fibrosis. Patients will be randomized in a 1:1:1:1 ratio to receive either TXR 140 μg once daily (qd), CVC 150 mg qd, TXR 140 μg + CVC 150 mg qd, or TXR 90 μg + CVC 150 mg qd. The study comprises a 48-week treatment period and 4 weeks of follow-up. The key inclusion criterion is presence of NASH with fibrosis stage F2/F3 as seen on screening liver biopsy or on historical liver biopsy performed within 6 months prior to screening. The primary objective is evaluation of the safety and tolerability of combination therapy compared with the monotherapies over 48 weeks. The secondary objective is to evaluate efficacy as assessed by ≥1-point improvement in liver fibrosis versus baseline or resolution of steatohepatitis after 48 weeks. TANDEM will evaluate the combination of TXR and CVC with respect to safety and efficacy outcomes related to improvement in fibrosis or resolution of steatohepatitis. Given the effects of TXR and CVC in multiple pathophysiological pathways associated with NASH, combination therapy is likely to show additional benefits compared with monotherapy. [ABSTRACT FROM AUTHOR]

The NASHmap model is a non-invasive tool using 14 variables (features) collected in standard clinical practice to classify patients as probable nonalcoholic steatohepatitis (NASH) or non-NASH, and here we have explored its performance and prediction accuracy. The National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) NAFLD Adult Database and the Optum Electronic Health Record (EHR) were used for patient data. Model performance metrics were calculated from correct and incorrect classifications for 281 NIDDK (biopsy-confirmed NASH and non-NASH, with and without stratification by type 2 diabetes status) and 1,016 Optum (biopsy-confirmed NASH) patients. NASHmap sensitivity in NIDDK is 81%, with a slightly higher sensitivity in T2DM patients (86%) than non-T2DM patients (77%). NIDDK patients misclassified by NASHmap had mean feature values distinct from correctly predicted patients, particularly for aspartate transaminase (AST; 75.88 U/L true positive vs 34.94 U/L false negative), and alanine transaminase (ALT; 104.09 U/L vs 47.99 U/L). Sensitivity was slightly lower in Optum at 72%. In an undiagnosed Optum cohort at risk for NASH (n = 2.9 M), NASHmap predicted 31% of patients as NASH. This predicted NASH group had AST and ALT mean levels above normal range of 0–35 U/L, and 87% had HbA1C levels > 5.7%. Overall, NASHmap demonstrates good sensitivity in predicting NASH status in both datasets, and NASH patients misclassified as non-NASH by NASHmap have clinical profiles closer to non-NASH patients. [ABSTRACT FROM AUTHOR]

Background & Aims Thrombocytopaenia and hypoalbuminaemia are surrogate markers for portal hypertension and hepatic synthetic dysfunction respectively. Patients infected with hepatitis C virus ( HCV) with these surrogates have reduced likelihood of sustained virologic response and increased risk for hepatic decompensation or death when treated with peginterferon/ribavirin plus either telaprevir or boceprevir. Methods We conducted a post-hoc analysis of the TURQUOISE- II clinical trial in patients with cirrhosis to examine the impact of these surrogates on efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. Results Of 380 genotype 1-infected patients in TURQUOISE- II, 104 had either a platelet count <100 × 109/L or albumin <3.5 g/dl. Sustained virologic response rates were 89 and 97% in patients with thrombocytopaenia, and 84 and 89% in patients with hypoalbuminaemia after 12 and 24 weeks of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin respectively. These rates were similar to those observed in the overall study population (92 and 97% for 12 and 24 weeks). HCV genotype 1a-infected patients with thrombocytopaenia or hypoalbuminaemia had higher response rates when treated for 24 weeks, whereas only 1 of 35 genotype 1b patients did not achieve a sustained virologic response. Adverse event rates and discontinuations because of adverse events were low. Conclusions The findings of these analyses support the use of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin in these subpopulations with cirrhosis. Genotype 1a-infected patients with indicators of portal hypertension may benefit from a 24-week treatment duration. [ABSTRACT FROM AUTHOR]

Background & Aims: Non-alcoholic steatohepatitis (NASH) is acknowledged as a severe disease that is associated with a significant burden on patients, payers, and society. However, limited evidence exists on the cost associated with NASH across different countries. This analysis aims to describe the cost associated with the routine care of patients with NASH in France, Germany, and the United States. Methods: Data was sourced from the Gesellschaft für Konsumforschung (now Ipsos) Disease Atlas Real- World Evidence program collected from July through November 2017 in France, Germany, and the United States. Country-level unit cost was estimated from national databases for diagnostic tests and procedures, prescription drugs, hospital stays, and outpatient visits in respective local currency based on 2017 values. These were combined to provide an estimate of the cost of management of confirmed NASH in this specific patient population and are presented as mean cost per patient per year for each country in local currency and as USD adjusted for purchasing power parity for comparison. Results: Annual mean ± standard deviation cost of non-alcoholic steatohepatitis ranged from purchasing power parity USD 1,049±2,461 in Germany to USD 1,723±2,988 in the United States. In all markets, the predominant contributor to cost is healthcare resource use represented by hospitalisation and outpatient visits. Conclusions: This study reveals that costs associated with NASH treatment and management vary across the three countries studied, in part due to differences in healthcare systems but also due to different approaches in managing this disease. Our analysis represents the costs for a specific cohort of patients and further studies are warranted to better understand the progressive impact of NASH on healthcare systems and society. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic hepatitis C genotype 1 (HCV-1) and difficult-to-treat characteristics respond poorly to pegylated interferon alfa and ribavirin (RBV), and could benefit from an interferon with increased activity (consensus interferon or CIFN), favorable viral kinetics from daily dosing, and a longer duration of therapy. The purpose of this pilot study was to determine the efficacy and safety of daily CIFN + RBV for initial treatment of patients with HCV-1 infection.Methods: Patients with difficult-to-treat characteristics (92% male, 33% African American, 78% Veterans Affairs [VA]; 67% high viral load, 59% stage 3-4 fibrosis, and mean weight of 204 lbs) were enrolled at seven VA and two community medical centers. They were randomized to daily CIFN (15 mcg/day SQ) and RBV (1-1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52-72 weeks (from time of viral response +48 weeks) (group B, n = 31).Results: Intention to treat analysis for treatment groups A and B demonstrated 33% (11/33) and 32% (10/31) sustained virologic response (SVR), respectively. Only 2/31 patients in group B received more than 52 weeks of treatment. The overall group demonstrated a 31% (20/64) rapid virologic response rate (RVR), 54% (34/64) end of treatment virologic response and a 33% (21/64) SVR. Patients with RVR at 4 weeks, early virologic response from 8-12 weeks, and late virologic response from 16-24 weeks demonstrated SVR of 75% (15/20), 31% (4/13), and 22% (2/9), respectively. Overall early non-protocol discontinuation occurred in 26/64 (40%) patients.Conclusion: Daily CIFN and ribavirin for initial treatment of HCV-1 patients has potential for achieving a relatively high RVR rate, but discontinuations are frequent and successful use of this regimen is highly dependent on adequate patient support to maintain adherence. [ABSTRACT FROM AUTHOR]

Background: The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. However, the cutpoints for stratifying laboratory variables in CTP have never been validated.Objective: The objective of this study was to identify evidence-based cutpoints for the CTP laboratory subscores to improve its predictive capacity for transplant-free survival.Design: Retrospective observational study.Data Source: Using a cohort of 30,897 cirrhotic US Veteran patients with at least 5 years of follow-up, we performed Cox proportional hazard survival model iterations varying the upper and lower cutpoints for INR, total bilirubin and albumin CTP subscores. Cutpoints yielding the highest Harrell's C-statistics for concordance with transplant-free survival were incorporated into a modified CTP (mCTP) score. Validation of the mCTP was performed at multiple time frames within the follow-up period of the cohort and within subsets defined by disease etiology.Results: Modification of CTP cutpoints increased the Harrell's C-statistic for age- and gender-adjusted Cox proportional hazard models from 0.701 ± 0.002 to 0.709 ± 0.002 and the risk ratio per unit change from 1.49 (1.48-1.50) to 1.53 (1.52-1.54). The modified cutpoints showed superiority in predicting 5-year transplant-free survival in various disease etiology subgroups. A mCTP substituting serum creatinine for INR performed superiorly for predicting 5-year transplant-free survival.Conclusion: We propose an evidence-based recalibration of CTP score cutpoints that optimizes this model's capacity to predict transplant-free survival in patients with cirrhosis. The CTP score remains the best predictor of 5-year overall and transplant-free survival in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Background: As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated.Aim: To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients.Methods: Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review.Results: A total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility.Conclusions: As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported. [ABSTRACT FROM AUTHOR]

BACKGROUND: Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment. METHODS: We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician. RESULTS: Overall, 32.2% (95% CI, 30.8–33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2–42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24–25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85–13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70–13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42–16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0–78.3%) agreed to be treated and multivariable analysis showed that persons ≥50 yr of age (OR = 1.37; 95% CI, 1.07–1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08–1.93) were more likely to decline treatment. CONCLUSIONS: The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population. (Am J Gastroenterol 2005;100:1–8) [ABSTRACT FROM AUTHOR]

Background: Phenotypic methods such as elevated liver tests and/or the presence of obesity or hypertension are often used to identify patients with T2DM at risk for NASH. Machine learning (ML) models allow the prediction of outcomes with many interacting features and may be superior to phenotype in the context of NASH and T2DM. Here we present an intergroup comparison between patients with T2DM predicted as positive or negative for NASH by NASHmap, a ML model showing high prediction performance in real-word datasets. Methods: We evaluated a subgroup of patients from a large T2DM clinical trial database (2002-2012) who had data for 14 NASHmap parameters. These include clinical observations and routine laboratory parameters but not HOMA-IR. We compared the profile of patients predicted by NASHmap (NASH positive or negative) using 17 parameters (14 NASHmap and 3 additional parameters). We compared HOMA-IR values between NASHmap positive and negative patients in the subgroup where the values were available. Results: The clinical database had 23038 metabolically compensated T2DM patients without chronic liver disease of other etiologies. Data for all 14 NASHmap parameters were available in 4336 patients. NASHmap positive patients were younger, had higher HbA1c, liver enzymes, triglycerides, WBC, body mass index, platelets, and a higher rate for hypertension. Data for HOMA-IR were available in 1208 patients. Median HOMA-IR value was 4.2 in NASHmap positive group vs. 2.6 in NASHmap negative group. Patients in both groups had a similar median duration of diabetes. Conclusion: Overall, the patients identified as at risk for NASH by NASHmap showed a metabolically unfavorable phenotype indicated by the higher HOMA-IR values in this group that the ML algorithm is also able to detect. ML models may be an important tool in effectively identifying patients at risk for NASH in electronic health records and clinical care. Disclosure: A. Tietz: Employee; Self; Novartis AG, Stock/Shareholder; Self; Novartis AG. G. Bader: Employee; Self; Novartis AG. M. Docherty: Employee; Self; ZS Associates. B. Reinhart: Employee; Self; ZS Associates. M. Balp: Employee; Self; Novartis AG. M. Pedrosa: Employee; Self; Novartis AG. S. K. Acharya: Employee; Self; Novartis Healthcare Pvt. Ltd., Employee; Spouse/Partner; Novartis Healthcare Pvt. Ltd. J. Loeffler: Employee; Self; Novartis AG, Stock/Shareholder; Self; Novartis AG. J. M. Schattenberg: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Boehringer Ingelheim, BMS, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Novo Nordisk, Nordic Bioscience, Pfizer, Roche, Sanofi, Siemens Healthcare GmbH, Zydus, Bristol-Myers Squibb Company. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) are under recognized due to low awareness and lack of specific symptoms. Machine learning techniques allow the creation of algorithms derived from large databases with many interacting features to predict outcomes of interest. The objective of this study was to estimate the patients who might have NASH in electronic health records (EHR) using a NASH machine learning model (NASHmap). Methods: NASHmap is a predictive extreme gradient boosting model built and validated in two databases in the USA. The model has a test area under the curve of 0.82 and 0.76 in the training and validation database, respectively. It uses 14 features, ranked by importance: HbA1c, AST, ALT, total protein, AST/ALT, BMI, triglycerides, height, platelets, WBC, hematocrit, albumin, hypertension, and gender. The model was applied to a cohort of patients in Optum EHR meeting predefined inclusion (e.g., common NASH comorbidities) and exclusion criteria (e.g., any other liver disease) and had the 14 features available. Results: Out of 86 million (M) patients in the Optum EHR, 14M met the inclusion and exclusion criteria and 3M had all 14 features. Among them ∼23,000 patients had a diagnosis of NASH or NAFLD based on ICD codes with 73% having type 2 diabetes (T2D), 65% female and 28% above 65 years. For the patients with no recorded NASH diagnoses, 56% had T2D, 54% were female and 46% were above 65 years. Among the 3M patients, NASHmap predicted ∼902,000 as potentially having NASH and among them 70% had T2D, 52% were female and 43% were above 65 years; median HbA1c was 7.1 for diabetics and 5.8 for nondiabetics. Conclusion: High-performing machine learning models can be used to alert on patients likely to have NASH. In clinical practice, this could help physicians to identify patients at risk and direct them to appropriate diagnostic and therapeutic interventions. Disclosure: M. Docherty: Consultant; Self; Novartis Pharmaceuticals Corporation. A. Tietz: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG. S.A. Regnier: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG. M. Balp: Employee; Self; Novartis AG. G. Capkun: Employee; Self; Novartis AG. J. Loeffler: Employee; Self; Novartis Pharmaceuticals Corporation. Stock/Shareholder; Self; Novartis Pharmaceuticals Corporation. M. Pedrosa: Employee; Self; Novartis AG. J.M. Schattenberg: Consultant; Self; GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Foundation. [ABSTRACT FROM AUTHOR]