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OBJECTIVE: To determine the efficacy of a zoster vaccine on herpes zoster (HR)-related interference with activities of daily living (ADLs) and health-related quality of life (HRQL). DESIGN: Randomized double-blind placebo controlled trial. SETTING: Twenty-two U.S. sites. PARTICIPANTS: Thirty eight thousand five hundred forty-six women and men aged 60 and olcer. MEASUREMENTS: HZ burden of interference with ADLs and HRQL using ratings from the Zoster Brief Pain Inventory (ZBPI) and Medical Outcomes Study 12-item Short Form Survey (SF-12) mental component summary (MCS) and physical component summary (PCS) scores. Vaccine efficacy was calculated for the modified-intention-to-treat trial population and solely in participants who developed HZ. RESULTS: For the modified-intention-to-treat population, the overall zoster vaccine efficacy was 66% (95% confidence interval (CI)=55DS74%) for ZBPI ADL burden of interference score and 55% (95% CI=48DS61%) for both the SF-12 MCS and PCS scores. Of participants who developed HZ, zoster vaccine reduced the ZBPI ADL burden of interference score by 31% (95% CI=12DS51%) and did not significantly reduce the effect on HRQL. CONCLUSIONS: Zoster vaccine reduced the burden of HZ-related interference with ADLs in the population of vaccinees and in vaccinees who developed HZ. Zoster vaccine reduced the effect of HZ on HRQL in the population of vaccinees but not in vaccinees who developed HZ. [ABSTRACT FROM AUTHOR]

Recurrent events are common in clinical studies and are often subject to terminal events. In pragmatic trials, participants are often nested in clinics and can be susceptible or structurally unsusceptible to the recurrent events. We develop a Bayesian shared random effects model to accommodate this complex data structure. To achieve robustness, we consider the Dirichlet processes to model the residual of the accelerated failure time model for the survival process as well as the cluster-specific shared frailty distribution, along with an efficient sampling algorithm for posterior inference. Our method is applied to a recent cluster randomized trial on fall injury prevention., Competing Interests: Conflict of interest: None declared., (© The Royal Statistical Society 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Inflammatory bowel disease (IBD) coexists in up to 80% of patients with primary sclerosing cholangitis (PSC). The aim of this study is to investigate the outcomes of immunomodulator (IMM)/advanced therapies for the treatment of PSC-IBD., Methods: This was a single-center, retrospective study of patients with PSC from 1 January 2012 to 1 April 2021. Adult patients (age ≥ 18 years) with PSC-IBD were included. Primary outcomes were rates and predictors of IMM/advanced therapies to treat PSC-IBD. Secondary outcomes included rates of cholangitis, PSC-IBD clinical remission, and endoscopic healing., Results: A total of 106 patients with PSC were reviewed and 72 (68%) with confirmed PSC-IBD were included in the study. The median age was 48 years (IQR, 33-59.5) and 69.4% were male. Overall, 28 patients (38.9%) required IMM/advanced therapies to treat PSC-IBD (22 biologic/small molecule therapy and six thiopurine monotherapy). Patients in the IMM/advanced therapies group were more likely to have small bowel involvement (32.1% vs. 4.6%; P = 0.002). In the IMM/advanced therapies group, clinical remission was achieved in 78.6% but endoscopic healing in only 50%. The rate of acute ascending cholangitis was 42.9% in the IMM/advanced therapies group compared with 31.8% in the non-IMM/advanced therapies group (P = 0.34)., Conclusion: In our cohort, up to a third of patients with PSC-IBD required IMM/advanced therapies with only 50% of these patients achieving endoscopic healing. The use of IMM/advanced therapies was not associated with a higher risk of cholangitis, but larger studies are needed to investigate the risk with different classes of advanced therapies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: The importance of the interaction between tumour cells and neutrophils has recently begun to emerge. However, the significance of tumour-infiltrating neutrophil (TIN) in colorectal carcinomas (CRCs) remains unclear. The aim of this study was to investigate the prognostic significance of TIN in CRCs., Methods: CRCs were evaluated for TIN and were classified as neutrophil-rich (NR), neutrophil-intermediate (NI) and neutrophil-poor (NP) based on the presence of >15, 5-15 and <5 TIN per 100 tumour cells, respectively. Various clinicopathological parameters were recorded in each case including age, gender, histological grade, tumour, node, metastasis (TNM) stage, tumour location and DNA mismatch repair (MMR) status., Results: Among the 348 CRC cases reviewed, 38 cases were NR, 43 cases were NI and 267 cases were NP. High TIN was associated with higher histological grade (p=0.0222), right-sided tumour location (p=0.0025), advanced TNM stage (p=0.0346) and higher rate of MMR-deficient CRCs (p=0.0027). Patients with NR CRCs had significantly poorer 5-year recurrence-free survival comparing to patients with NI or NP CRCs on Kaplan-Meier analysis (p=0.0001) and high TIN remained an independent risk factor with multivariate analysis (p=0.0137; HR: 1.930, 95% CI: 1.144 to 3.255). NR CRCs are more commonly seen in MMR-deficient than in MMR-proficient CRCs (p=0.0006). Patients with MMR-deficient NR CRCs showed similar 5-year recurrence-free survival compared with MMR-proficient NR CRCs., Conclusions: Our findings reveal that high TIN confers poorer patient prognosis in both MMR-proficient and MMR-deficient CRCs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Clinically significant portal hypertension (CSPH), defined as hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg, identifies patients with compensated cirrhosis at a high risk of decompensation. However, HVPG is an invasive and nuanced method. The ANTICIPATE models, which include liver stiffness measurements by transient elastography (TE) and platelet count ± body mass index, are robust noninvasive surrogates of CSPH but required external validation in patients with nonalcoholic steatohepatitis (NASH) cirrhosis. Additionally, TE is not widely available worldwide. The aims of the study were: (1) to externally validate the ANTICIPATE models using baseline data from patients with compensated NASH cirrhosis screened/enrolled in a multicenter international randomized controlled trial; and (2) to develop and externally validate a model using only laboratory values. Regarding aim 1, both ANTICIPATE models showed good calibration and discrimination (area under the curve [AUC] > 0.8) in our cohort (n = 222). Regarding aim 2, a new lab-based model using the Fibrosis-4 index (FIB-4 [age, aspartate aminotransferase, alanine aminotransferase, platelet count]) plus serum albumin was developed. The discrimination in the training cohort (n = 309) was good (AUC of 0.78 [95% confidence interval [CI]:0.72-0.83]). It was then externally validated in a separate cohort of 245 patients with compensated NASH cirrhosis (AUC of 0.8 [95% CI: 0.75-0.86]). Given the difference in the prevalence of CSPH between training (74%) and validation (39%) cohorts, the model required an update of the baseline risk to achieve a good calibration. The updated model was named FIB4+. In conclusion, both ANTICIPATE models performed well in predicting the presence of CSPH in NASH cirrhosis. A model using FIB-4 plus albumin (FIB4+) can be used to predict CSPH where TE is not available., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Introduction: Hepatocellular carcinoma (HCC) requires complex care coordination. Patient safety may be compromised with untimely follow-up of abnormal liver imaging. This study evaluated whether an electronic case-finding and tracking system improved timeliness of HCC care., Methods: An electronic medical record-linked abnormal imaging identification and tracking system was implemented at a Veterans Affairs Hospital. This system reviews all liver radiology reports, generates a queue of abnormal cases for review, and maintains a queue of cancer care events with due dates and automated reminders. This is a pre-/post-intervention cohort study to evaluate whether implementation of this tracking system reduced time between HCC diagnosis and treatment and time between first liver image suspicious for HCC, specialty care, diagnosis, and treatment at a Veterans Hospital. Patients diagnosed with HCC in the 37 months before tracking system implementation were compared to patients diagnosed with HCC in the 71 months after its implementation. Linear regression was used to calculate mean change in relevant intervals of care adjusted for age, race, ethnicity, BCLC stage, and indication for first suspicious image., Results: There were 60 patients pre-intervention and 127 post-intervention. In the post-intervention group, adjusted mean time from diagnosis to treatment was 36 days shorter (p = 0.007), time from imaging to diagnosis 51 days shorter (p = 0.21), and time from imaging to treatment 87 days shorter (p = 0.05). Patients whose imaging was performed for HCC screening had the greatest improvement in time from diagnosis to treatment (63 days, p = 0.02) and from first suspicious image to treatment (179 days, p = 0.03). The post-intervention group also had a greater proportion of HCC diagnosed at earlier BCLC stages (p<0.03)., Conclusions: The tracking system improved timeliness of HCC diagnosis and treatment and may be useful for improving HCC care delivery, including in health systems already implementing HCC screening., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Purpose: To assess the Liver Imaging Reporting and Data System (LI-RADS) and radiomic features in pretreatment magnetic resonance (MR) imaging for predicting progression-free survival (PFS) in patients with nodular hepatocellular carcinoma (HCC) treated with radiofrequency (RF) ablation., Material and Methods: Sixty-five therapy-naïve patients with 85 nodular HCC tumors <5 cm in size were included in this Health Insurance Portability and Accountability Act-compliant, institutional review board-approved, retrospective study. All patients underwent RF ablation as first-line treatment and demonstrated complete response on the first follow-up imaging. Gadolinium-enhanced MR imaging biomarkers were analyzed for LI-RADS features by 2 board-certified radiologists or by analysis of nodular and perinodular radiomic features from 3-dimensional segmentations. A radiomic signature was calculated with the most informative features of a least absolute shrinkage and selection operator Cox regression model using leave-one-out cross-validation. The association between both LI-RADS features and radiomic signatures with PFS was assessed via the Kaplan-Meier analysis and a weighted log-rank test., Results: The median PFS was 19 months (95% confidence interval, 16.1-19.4) for a follow-up period of 24 months. Multifocality (P = .033); the appearance of capsular continuity, compared with an absent or discontinuous capsule (P = .012); and a higher radiomic signature based on nodular and perinodular features (P = .030) were associated with poorer PFS in early-stage HCC. The observation size, presence of arterial hyperenhancement, nonperipheral washout, and appearance of an enhancing "capsule" were not associated with PFS (P > .05)., Conclusions: Although multifocal HCC clearly indicates a more aggressive phenotype even in early-stage disease, the continuity of an enhancing capsule and a higher radiomic signature may add value as MR imaging biomarkers for poor PFS in HCC treated with RF ablation., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Chronic opioid effects on the esophagus are poorly understood. We investigated whether opioids were associated with increased prevalence of esophageal motility disorders., Methods: A retrospective study of all patients undergoing high-resolution manometry (HREM) at the Yale Gastrointestinal Motility Lab between January 2014 and August 2019. Data were extracted from the electronic medical record after studies were reviewed by two motility specialists using the Chicago Classification v.3.0. We compared the manometric results of patients who use opioids to those who do not and adjusted for type and dose of opioids using a 24 h Morphine Milligram Equivalents (MME) scale to compare patients taking low or high amounts of opioids., Results: Four manometric abnormalities were significantly different between the opioid and non-opioid users. Achalasia type III, esophagogastric junction outflow obstruction (EGJOO), and distal esophageal spasm (DES) (p < 0.005, p < 0.01, and p < 0.005, respectively) were common among opioid users, whereas ineffective esophageal motility (IEM) was more common among non-opioid users (p < 0.01). The incidence of EGJOO was significantly higher in opioid users compared to non-opioid users (p < 0.001). Lastly, IRP, DCI, and distal latency were significantly different between the two groups. Patients in the high MME group had significantly greater IRP, DCI, and lower distal latency than non-opioids (p < 0.001). Also, achalasia type III and DES were more common in the high but not the low MME group., Conclusions: Opioid use is associated with multiple abnormalities on esophageal motility and these effects may be dose-dependent., (© 2021 John Wiley & Sons Ltd.)

Background & Aims: Psychological and life stressors may impact autoimmune hepatitis (AIH) disease activity and increase relapse risk. Mindfulness-based stress reduction (MBSR) is a validated course that reduces stress reactivity, and improves stress and emotion regulation. This single-arm exploratory pilot study of adult patients with AIH aimed to define the impact of an 8-week MBSR program on quality of life, disease activity, and cytokine mediators., Methods: The perceived stress survey-10 (PSS) and the brief self-control scale (BSCS) measured subjective distress and self-control. Serum alanine aminotransferase (ALT) and cytokine levels were measured, and immunosuppressant doses recorded., Results: Seventeen patients completed the MBSR program. Post-MBSR, 71% (n = 12) showed PSS score improvement at 8 weeks vs. baseline (median 15 vs. 21, p = 0.02). At 12 months, PSS improvement persisted vs. baseline (median 15 vs. 21, p = 0.02). Post-MBSR, 71% (n = 12) showed BSCS score improvement at 8 weeks vs. baseline (median 4.1 vs. 3.8, p = 0.03). At 12 months, the median BSCS score remained significant (3.9 vs. 3.8, p = 0.03). After the 8-week MBSR, the 35% of patients with ALT >34 U/L had a median ALT reduction (44.5 vs. 71.5 U/L, p = 0.06), whereas the 71% of patients on prednisone had significant dose reductions (5.75 vs. 10 mg, p = 0.02) which persisted at 12 months vs. baseline (3.75 vs. 10 mg, p = 0.02) without a compensatory increase in steroid-sparing dosing. Significant improvement was noted in peripheral blood cytokine levels (IL-6, IL-8, IL-10, IL-17, IL-23, and sCD74/MIF ratio) from baseline to 8 weeks., Conclusions: MBSR significantly improved perceived stress and self-control scores while decreasing ALT levels, steroid requirements, and inflammatory cytokine levels in this pilot study in adult AIH. Stress modification may impact quality of life and disease activity, and should be further evaluated as an intervention in AIH., Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT02950077)., Lay Summary: Autoimmune hepatitis can reduce quality of life and mental health, while stress may impact autoimmune hepatitis itself. We piloted mindfulness-based stress reduction as a strategy to reduce stress in adult patients with autoimmune hepatitis and found that the intervention reduced perceived stress and may have also impacted the disease by improving inflammation and medication needs. Stress reduction should be further studied to improve quality of life and possibly to impact disease activity in autoimmune hepatitis., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Objectives: The pathologic differences between hepatocellular carcinoma (HCC) arising in noncirrhotic and cirrhotic livers have not been well studied., Methods: We performed a retrospective analysis of 378 HCC cases (95 in noncirrhotic, 283 in cirrhotic livers) from pathology archives (2010-2017)., Results: Patients without cirrhosis were more likely to have hepatitis B (13.68% vs 2.83%, P < .001) or no known liver disease (30.53% vs 4.24%, P < .001), while hepatitis C was more common in patients with cirrhosis (65.72% vs 30.53%, P < .001). HCCs in noncirrhotic livers were larger in size (P < .001); were more likely to have a macrotrabecular histologic pattern (13.68% vs 4.95%, P < .01); were more likely to have fibrolamellar (3.16% vs 0%, P = .02), macrotrabecular-massive (13.68% vs 6.01%, P = .03), and clear cell (16.84% vs 6.71%, P < .01) subtypes; have a higher histologic grade (P < .01); be anaplastic tumor cells (P < .001); have a higher rate of vascular invasion (P < .01); and have a higher tumor stage (P = .04)., Conclusions: The findings indicate that HCCs in noncirrhotic livers demonstrate a larger tumor size; have a more macrotrabecular histologic pattern; have fibrolamellar, macrotrabecular-massive, and clear cell subtypes; have a higher tumor grade and stage; have a higher rate of vascular invasion; and have more anaplastic tumor cells compared with cirrhotic livers. Further studies to explore different pathways that promote oncogenesis in noncirrhotic livers are needed to better understand the pathogenesis of HCC., (© American Society for Clinical Pathology, 2021. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Background: Immune checkpoint inhibitors (ICIs) have transformed the management of advanced malignancies but are associated with diarrhea and colitis. The objective of our systematic review and meta-analysis was to determine the incidence and outcomes of ICI-associated diarrhea and colitis. Bibliographic databases were searched through August 13, 2019, for observational studies of ICI therapy reporting the incidence and/or treatment of diarrhea or colitis. The primary outcome was ICI-associated diarrhea and colitis. Meta-analyses were performed with random-effects models. Twenty-five studies (N=12,661) were included. All studies had a high risk of bias in at least 1 domain. The overall incidence of diarrhea/colitis was 12.8% [95% confidence interval (CI), 8.8-18.2, I2=96.5]. The incidence was lower in patients treated with anti-programmed cell death 1/programmed death-ligand 1 (4.1%, 95% CI, 2.6-6.5) than in those treated with anti-cytotoxic T-cell lymphocyte-associated antigen 4 (20.1%, 95% CI, 15.9-25.1). The remission of diarrhea and/or colitis was higher in patients treated with corticosteroids plus biologics (88.4%, 95% CI, 79.4-93.8) than in those treated with corticosteroids alone (58.3%, 95% CI, 49.3-66.7, Q=18.7, P<0.001). ICI were permanently discontinued in 48.1% of patients (95% CI, 17.8-79.1). ICI were restarted after temporary interruption in 48.6% of patients (95% CI, 18.2-79.4) of whom 17.0% (95% CI, 6.4-30.0) experienced recurrence. Real-world incidence of ICI-associated diarrhea/colitis exceeds 10%. These events lead to permanent ICI discontinuation in just over 50% of patients, while <20% have recurrence of symptoms if ICI are resumed. Further studies are needed to identify patients who would benefit from early treatment with biologics as well as appropriate patients to resume ICI therapy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Disturbed sleep is common among patients with cirrhosis. The extent to which this is associated with the different stages of compensated cirrhosis is unknown. This study examines whether the presence of portosystemic collaterals, an indicator of clinically significant portal hypertension, is associated with sleep disturbance in compensated cirrhosis. We conducted a cross-sectional study among patients with compensated cirrhosis, comparing sleep characteristics, sleep quality, and excessive daytime sleepiness between 21 patients without and 21 patients with portosystemic collaterals. Patients were assessed with wrist actigraphy, Pittsburgh Sleep Quality Index, and the Epworth Sleepiness Scale. Collateral presence was determined by imaging and esophagogastroduodenoscopy. Differences in sleep characteristics were analyzed using t tests and computed effect sizes. Multivariable linear regression analysis was used to evaluate the association between collaterals and sleep disturbance while controlling for possible confounders. The group of patients with collaterals had greater beta-blocker and tobacco use, lower albumin, and higher international normalized ratio compared to the group without collaterals. Patients with collaterals had more sleep fragmentation (Cohen's d  = -0.86), lower sleep efficiency (Cohen's d  = 0.59), and lower total sleep time (Cohen's d  = 0.75) than patients without collaterals. The presence of collaterals was independently associated with greater sleep fragmentation ( P  = 0.046) and greater daytime sleepiness ( P  = 0.030). Conclusion: Patients with compensated cirrhosis complicated by portosystemic collaterals experienced more sleep disturbance than those without collaterals., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background and Aims: Recent evidence suggests that acute kidney injury (AKI) is the main predictor of postparacentesis bleeding in patients with cirrhosis. To assess the factors responsible for bleeding tendency in AKI, we performed a prospective study comparing all three aspects of hemostasis (platelets, coagulation, and fibrinolysis) in patients with decompensated cirrhosis with and without AKI., Approach and Results: Primary hemostasis assessment included platelet aggregation and secretion (platelet function markers) and von Willebrand factor. Secondary hemostasis assessment included pro-coagulant (factor VIII and factor XIII) and anti-coagulant (protein C, protein S, and antithrombin) factors and thrombin generation. Tertiary hemostasis assessment included fibrinolytic factors and plasmin-antiplasmin complex. Eighty patients with decompensated cirrhosis were recruited (40 each with and without AKI). Severity of cirrhosis and platelet count were comparable between groups. Median serum creatinine was 1.8 mg/dL and 0.8 mg/dL in patients with and without AKI, respectively. At baseline, patients with cirrhosis and AKI had lower platelet aggregation and secretion, indicative of impaired platelet function (increased bleeding tendency), without differences in von Willebrand factor. Regarding coagulation factors, factor VIII was higher, whereas protein C, protein S, and antithrombin were all lower, which, together with increased thrombin generation, indicate hypercoagulability. In contrast, factor XIII was lower in AKI (increased bleeding tendency). Finally, while both hypofibrinolytic and hyperfibrinolytic changes were present in AKI, a higher plasmin-antiplasmin complex indicated a hyperfibrinolytic state. After AKI resolution (n = 23 of 40), platelet function and coagulation improved to levels observed in patients with cirrhosis patients without AKI; however, fibrinolysis remained hyperactivated., Conclusions: In patients with decompensated cirrhosis, AKI is associated with both hypocoagulable and hypercoagulable features that can potentially increase the risk of both bleeding and thrombosis., (© 2020 by the American Association for the Study of Liver Diseases.)

Platelet (PLT) count is included in non-invasive scores assessing liver fibrosis in patients with chronic liver disease. Improvement in fibrosis scores after antiviral treatment for hepatitis C virus (HCV) has been interpreted as indicative of an improvement in fibrosis. HCV itself can lower PLT and, therefore, an increase in PLT would be expected after viral elimination irrespective of pretreatment fibrosis stage. The aim of this study was to investigate this hypothesis by assessing changes in PLT after viral elimination in patients with chronic HCV stratified by the absence or presence of cirrhosis., Methods: Retrospective analysis of patients with chronic HCV infection treated with direct-acting antivirals (DAAs) who achieved viral elimination and in whom PLT were obtained prior to treatment, at first negative HCV-RNA, at treatment completion and at 6 months, and 1 year after treatment completion. Comparisons were made between patients with and without cirrhosis., Results: A total of 420 patients with chronic HCV were treated, of which 208 were excluded, leaving 212 patients eligible for analysis (142 without cirrhosis, 70 with cirrhosis). Overall, a significant increase in PLT was observed up to 1 year after antiviral treatment completion (P < .001). Changes in PLT between patients with and without cirrhosis were not significantly different at any of the time points., Conclusion: Platelet count increased significantly in patients with HCV who achieved viral elimination irrespective of the absence or presence of cirrhosis. This suggests that changes in PLT post-viral elimination should not be interpreted as being reflective of changes in liver fibrosis or portal hypertension., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.

Background: Portal vein thrombosis (PVT) develops in cirrhotic patients because of stagnation of blood flow. Transjugular intrahepatic portosystemic shunt (TIPS) creates a low-resistance conduit that restores portal venous patency and blood flow., Aim: The effect of PVT on transplant-free survival in cirrhotic patients undergoing TIPS creation was evaluated., Patients and Methods: A multicenter, retrospective cohort study of patients who underwent TIPS creation for cirrhotic portal hypertension was carried out. A Cox model with propensity score adjustment was developed to evaluate the effect of PVT on 90-day and 3-year transplant-free survival. A subgroup analysis examining mortality of those with superior and inferior PVT was also carried out., Results: A total of 252 consecutive TIPS creations were assessed, including 65 in patients with PVT. Survival of patients with high Model for End-stage Liver Disease scores (≥18) and PVT was not statistically different compared with patients with low Model for End-stage Liver Disease scores (<18) and no PVT at 90 days (P=0.46) and 3 years (P=0.42). Those with superior PVT had improved 90-day and 3-year survival both compared with patients with a inferior PVT and those without a PVT (P<0.01, all cases)., Conclusion: The presence of PVT does not impair the prognosis of patients following TIPS creation, particularly in patients with superior portal occlusion.

Rationale: Colorectal cancer (CRC) is preventable through screening, with colonoscopy and fecal occult blood testing comprising the two most commonly used screening tests. Given the differences in complexity, risk, and cost, it is important to understand these tests' comparative effectiveness., Study Design: The CONFIRM Study is a large, pragmatic, multicenter, randomized, parallel group trial to compare screening with colonoscopy vs. the annual fecal immunochemical test (FIT) in 50,000 average risk individuals. CONFIRM examines whether screening colonoscopy will be superior to a FIT-based screening program in the prevention of CRC mortality measured over 10 years. Eligible individuals 50-75 years of age and due for CRC screening are recruited from 46 Veterans Affairs (VA) medical centers. Participants are randomized to either colonoscopy or annual FIT. Results of colonoscopy are managed as per usual care and study participants are assessed for complications. Participants testing FIT positive are referred for colonoscopy. Participants are surveyed annually to determine if they have undergone colonoscopy or been diagnosed with CRC. The primary endpoint is CRC mortality. The secondary endpoints are (1) CRC incidence (2) complications of screening colonoscopy, and (3) the association between colonoscopists' characteristics and neoplasia detection, complications and post-colonoscopy CRC. CONFIRM leverages several key characteristics of the VA's integrated healthcare system, including a shared medical record with national databases, electronic CRC screening reminders, and a robust national research infrastructure with experience in conducting large-scale clinical trials. When completed, CONFIRM will be the largest intervention trial conducted within the VA (ClinicalTrials.gov identifier: NCT01239082).

Goals/background: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality., Study: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared., Results: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%., Conclusions: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.

Goals: To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC)., Background: PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders., Study: ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout., Results: Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline., Conclusions: In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

Objectives: Measurements of liver stiffness and spleen stiffness are useful noninvasive ways to assess fibrosis and portal hypertension in patients with chronic liver disease. One method for assessing stiffness is by point shear wave elastography via acoustic radiation force impulse imaging (ARFI). Its advantage is that sites where stiffness is measured are visualized sonographically. However, its reliability has not been well established, and all studies done to date evaluating the use of ARFI in chronic liver disease have been performed outside the United States. We aimed to characterize the intraobserver and interobserver variability of ARFI-measured liver and spleen stiffness., Methods: Two hepatologists evaluated unselected hepatology outpatients with ARFI. Exclusions were hepatocellular carcinoma, ascites, a surgical shunt or transjugular intrahepatic portosystemic shunt, portal thrombosis, and cholestatic disease. Each operator obtained 20 measurements from the right liver lobe and spleen. Intraclass correlation coefficients (ICC) were calculated., Results: A total of 177 patients were included: median age, 61 years; 85% male; and 43% obese. Intraobserver ICCs were the same for both observers for liver stiffness (0.89; 95% confidence interval [CI], 0.85-0.92) and spleen stiffness (0.72; 95% CI, 0.61-0.80). Interobserver agreement was excellent for liver stiffness (ICC, 0.85; 95% CI, 0.76-0.90) but not as good for spleen stiffness (ICC, 0.73; 95% CI, 0.60-0.83). A body mass index of 30 kg/m 2 or greater, waist circumference of greater than 105 cm, and skin-to-capsule distance of 2 cm or greater negatively affected the ICC for liver stiffness; small spleen size negatively affected the ICC for spleen stiffness., Conclusions: To our knowledge, this article is the first report of ARFI findings in a US population with chronic liver disease. Liver stiffness reproducibility was excellent, particularly in nonobese patients. Spleen stiffness reproducibility was excellent in those with larger spleens and therefore may be most useful in patients with cirrhosis and portal hypertension., (© 2016 by the American Institute of Ultrasound in Medicine.)

A subset of human regulatory T cells (Tregs) can secrete IFN-γ or IL-17, and thus share features of TH1 or TH17 effector cells and lose suppressive function. The main factors driving this differentiation of Tregs toward a proinflammatory phenotype include IL-12 for TH1-like and IL-6 for TH17-type Tregs. In this study we show that Tregs of patients with de novo autoimmune hepatitis (dAIH) display increased frequencies of proinflammatory IFN-γ and IL-17 cytokines. Irrespective of a fully demethylated FOXP3 locus, Tregs of subjects with dAIH are functionally impaired. In line with the observed Treg phenotype, we detected the presence of two dominant cytokines (IL-12 and IL-6) clustering with CD68(+) monocyte/macrophage cells in livers of subjects with dAIH, and isolated monocytes of subjects with dAIH secrete high levels of proinflammatory IL-12 and IL-6, suggesting that this inflammatory milieu is key for functional impairment of Tregs. Importantly, the blockade of IFN-γ partially restores suppressive function of Tregs of subjects with dAIH, indicating that monocyte/macrophage-derived triggers might play a central role in Treg dysfunction and pathogenesis of dAIH., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background: New treatments for hepatitis C (HCV) infection hold great promise for cure, but numerous challenges to diagnosing, establishing care, and receiving therapy exist. There are limited data on insurance authorization for these medications., Materials and Methods: We performed a retrospective chart review of patients receiving sofosbuvir/ledipasvir (SOF/LED) from October 11-December 31, 2014 to determine rates and timing of drug authorization. We also determined predictors of approval, and those factors associated with faster decision and approval times., Results: Of 174 patients prescribed HCV therapy during this period, 129 requests were made for SOF/LED, of whom 100 (77.5%) received initial approval, and an additional 17 patients (13.9%) ultimately received approval through the appeals process. Faster approval times were seen in patients with Child-Pugh Class B disease (14.4 vs. 24.7 days, p = 0.048). A higher proportion of patients were initially approved in those with Medicare/Medicaid coverage (92.2% vs. 71.4%, p = 0.002) and those with baseline viral load ≥ 6 million IU/mL (84.1% vs. 62.5%, p = 0.040). Linear regression modeling identified advanced fibrosis, high Model of End Stage Liver Disease (MELD) score, and female gender as significant predictors of shorter decision and approval times. On logistic regression, Medicare/Medicaid coverage (OR 5.96, 95% CI 1.66-21.48) and high viral load (OR 4.52, 95% CI 1.08-19.08) were significant predictors for initial approval., Conclusions: Early analysis of real-world drug authorization outcomes between October-December 2014 reveals that nearly one in four patients are initially denied access to SOF/LED upon initial prescription, although most patients are eventually approved through appeal, which delays treatment initiation. Having Medicare/Medicaid and advanced liver disease resulted in a higher likelihood of approval as well as earlier decision and approval times. More studies are needed to determine factors resulting in higher likelihood of denial and to evaluate approval rates and times after implementation of restrictive prior authorization guidelines.

Liver involvement in diabetes is well recognized in the form of steatohepatitis and glycogenic hepatopathy. More recently, sinusoidal fibrosis, even in the absence of steatosis, has also been suggested to be associated with diabetes (diabetic hepatosclerosis); however, case-control studies are lacking. In addition, microangiopathy (hyaline arteriolosclerosis), a well-known complication of diabetes, has not been well studied in liver. Therefore, we undertook a cross-sectional blinded study with the specific aim of evaluating the association between hepatic sinusoidal fibrosis and hepatic arteriolosclerosis (HA) with diabetes. Liver biopsy findings from 89 diabetic patients obtained between January 2006 and December 2009 were compared with those of 89 nondiabetic patients matched by age and hepatitis C virus infection status. Patients with cirrhosis, liver mass, right heart failure, significant alcohol use, or insufficient available clinical information were excluded. Medical records were reviewed for the presence of diabetes, body mass index, diabetes treatment, and comorbidities at the time of biopsy (eg, underlying liver disease, hypertension, dyslipidemia). Liver biopsies were evaluated blinded to all clinical data (including presence or absence of diabetes) for a variety of histologic features, especially patterns of fibrosis and HA. Diabetic patients had a higher average body mass index (33 vs. 30 m/kg, P=0.0039), prevalence of hypertension (78% vs. 33%, P<0.0001), and dyslipidemia (52% vs. 20%, P<0.0001). Among diabetic patients, 87% had type 2 diabetes, and 57% used insulin. Whereas sinusoidal fibrosis, with or without steatosis, was not significantly associated with the presence of diabetes, HA was significantly more prevalent among diabetic patients compared with controls: 45% versus 29% (P=0.0298). The presence of both diabetes and hypertension had a significant odds for HA: with an adjusted odds ratio of 2.632 (95% confidence interval, 1.178-5.878; P=0.0183). Biliary changes were associated with HA in some cases (10.6%).In this study, we describe the histopathologic entity of HA for the first time. It is a small-vessel complication (microangiopathy) of the liver observed mainly in patients with diabetes who also have arterial hypertension. The clinical and prognostic implications of this finding, particularly regarding liver injury, remain to be further investigated.

Aim: To investigate the relationship between upper esophageal sphincter abnormalities achalasia treatment, Methods: We performed a retrospective study of 41 consecutive patients referred for high resolution esophageal manometry with a final manometric diagnosis of achalasia. Patients were sub-divided by presence or absence of Upper esophageal sphincter (UES) abnormality, and clinical and manometric profiles were compared. Correlation between UES abnormality and sub-type (i.e., hypertensive, hypotensive or impaired relaxation) and a number of variables, including qualitative treatment response, achalasia sub-type, co-morbid medical illness, psychiatric illness, surgical history, dominant presenting symptom, treatment type, age and gender were also evaluated., Results: Among all 41 patients, 24 (58.54%) had a UES abnormality present. There were no significant differences between the groups in terms of age, gender or any other clinical or demographic profiles. Among those with UES abnormalities, the majority were either hypertensive (41.67%) or had impaired relaxation (37.5%) as compared to hypotensive (20.83%), although this did not reach statistical significance (P = 0.42). There was no specific association between treatment response and treatment type received; however, there was a significant association between UES abnormalities and treatment response. In patients with achalasia and concomitant UES abnormalities, 87.5% had poor treatment response, while only 12.5% had favorable response. In contrast, in patients with achalasia and no UES abnormalities, the majority (78.57%) had good treatment response, as compared to 21.43% with poor treatment response (P = 0.0001). After controlling for achalasia sub-type, those with UES abnormality had 26 times greater odds of poor treatment response than those with no UES abnormality (P = 0.009). Similarly, after controlling for treatment type, those with UES abnormality had 13.9 times greater odds of poor treatment response compared to those with no UES abnormality (P = 0.017)., Conclusion: The presence of UES abnormalities in patients with achalasia significantly predicted poorer treatment response as compared to those with normal UES function.

Background: The effect of carotid endarterectomy on cognitive function is not fully understood. This study aims to characterize changes in cerebral blood flow after carotid endarterectomy and to determine if patients with improvement in cerebral blood flow have improved cognitive function after endarterectomy., Methods: Cerebral blood flow was measured preoperatively and 1 month postoperatively using phase contrast magnetic resonance angiography. Preoperative flow impairment was defined as ipsilateral flow at least 20% less than contralateral flow. Improvement in flow was defined as an absolute increase of at least 0.10 in flow ratio from pre- to postoperative assessments. Patients underwent cognitive testing preoperatively and at 1, 6, and 12 months postoperatively., Results: Twenty-four patients with unilateral carotid stenosis were enrolled from 3 sites. Preoperative internal carotid artery (ICA) and middle cerebral artery (MCA) flow impairment was observed in 50% and 22% of patients, respectively. Patients with preoperative flow impairment had an average of 0.25 and 0.16 absolute improvement in flow ratio in the ICA and MCA vessels, respectively; this was statistically significant for patients with baseline ICA flow impairment (P < .01). One hundred percent of patients with improvement in MCA flow had a significant improvement in attention compared to 56% of patients without MCA flow improvement (P = .06). Clinically significant improvements in all 4 cognitive domains were observed at 1 year (P < .01)., Conclusions: Patients with baseline impairment of MCA blood flow were more likely to experience improvement in flow after revascularization. Improvement in MCA blood flow was associated with greater cognitive improvement in attention and executive functioning., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: México is one of the world's centers of species diversity (richness) for Opuntia cacti. Yet, in spite of their economic and ecological importance, Opuntia species remain poorly studied and protected in México. Many of the species are sparsely but widely distributed across the landscape and are subject to a variety of human uses, so devising implementable conservation plans for them presents formidable difficulties. Multi-criteria analysis can be used to design a spatially coherent conservation area network while permitting sustainable human usage., Methods and Findings: Species distribution models were created for 60 Opuntia species using MaxEnt. Targets of representation within conservation area networks were assigned at 100% for the geographically rarest species and 10% for the most common ones. Three different conservation plans were developed to represent the species within these networks using total area, shape, and connectivity as relevant criteria. Multi-criteria analysis and a metaheuristic adaptive tabu search algorithm were used to search for optimal solutions. The plans were built on the existing protected areas of México and prioritized additional areas for management for the persistence of Opuntia species. All plans required around one-third of México's total area to be prioritized for attention for Opuntia conservation, underscoring the implausibility of Opuntia conservation through traditional land reservation. Tabu search turned out to be both computationally tractable and easily implementable for search problems of this kind., Conclusions: Opuntia conservation in México require the management of large areas of land for multiple uses. The multi-criteria analyses identified priority areas and organized them in large contiguous blocks that can be effectively managed. A high level of connectivity was established among the prioritized areas resulting in the enhancement of possible modes of plant dispersal as well as only a small number of blocks that would be recommended for conservation management.

To identify risk factors that account for the difference in anal sphincter tear (AST) among midwife, private obstetrician, and resident deliveries. We performed a retrospective review of our obstetrical database and used logistic regression analysis to identify risk factors for AST. The relationship between delivery technique and AST was evaluated by comparing AST increase between vaginal deliveries without and with an episiotomy among the three categories of providers. After adjusting for risk factors, private obstetricians (OR: 1.81, 95% CI: 1.27-2.56) and residents (OR: 1.60, 95% CI: 1.20-2.15) had a higher rate of AST during vaginal delivery than midwives. Episiotomy increased the odds of AST by four-fold for midwives, two-fold for private obstetricians, and eight-fold for residents. Although midwife and resident's delivery methods were associated with more AST, neither experienced this complication more frequently than private obstetricians. This suggests that midwives and residents probably misdiagnosed some AST.