FXR mediates T cell-intrinsic responses to reduced feeding during infection.

Reduced nutrient intake is a widely conserved manifestation of sickness behavior with poorly characterized effects on adaptive immune responses. During infectious challenges, naive T cells encountering their cognate antigen become activated and differentiate into highly proliferative effector T cells. Despite their evident metabolic shift upon activation, it remains unclear how effector T cells respond to changes in nutrient availability in vivo. Here, we show that spontaneous or imposed feeding reduction during infection decreases the numbers of splenic lymphocytes. Effector T cells showed cell-intrinsic responses dependent on the nuclear receptor Farnesoid X Receptor (FXR). Deletion of FXR in T cells prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions, but imparted greater weight loss to the host. FXR deficiency increased the contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. Provision of glucose during anorexia of infection rescued effector T cells, suggesting that this sugar is a limiting nutrient for activated lymphocytes and that alternative fuel usage may affect cell survival in starved animals. Altogether, we identified a mechanism by which the host scales immune responses according to food intake, featuring FXR as a T cell-intrinsic sensor.

Cannabis use may reduce healthcare utilization and improve hospital outcomes in patients with cirrhosis.

INTRODUCTION AND OBJECTIVES: Previous studies reveal conflicting data on the effect of cannabis use in patients with cirrhosis. This research evaluates the impact of cannabis on hepatic decompensation, health care utilization, and mortality in patients with cirrhosis. MATERIAL AND METHODS: A retrospective analysis of the State Inpatient Database (SID) was performed evaluating patients from Colorado and Washington in 2011 to represent pre-cannabis legalization and 2015 to represent post-cannabis legalization. Multivariable analysis was performed to study the impact of cannabis on the rate of admissions with hepatic decompensations, healthcare utilization, and mortality in patients with cirrhosis. RESULTS: Cannabis use was detected in 370 (2.1%) of 17,520 cirrhotics admitted in 2011 and in 1162 (5.3%) of 21,917 cirrhotics in 2015 (p-value <0.001). On multivariable analysis, cirrhotics utilizing cannabis after its legalization experienced a decreased rate of admissions related to hepatorenal syndrome (Odds Ratio (OR): 0.51; 95% Confidence Interval (CI): 0.34-0.78) and ascites (OR: 0.73; 95% CI: 0.63-0.84). Cirrhotics with an etiology of disease other than alcohol and hepatitis C had a higher risk of admission for hepatic encephalopathy if they utilized cannabis [OR: 1.57; 95% CI: 1.16-2.13]. Decreased length of stay (-1.15 days; 95% CI: -1.62, -0.68), total charges (-$15,852; 95% CI: -$21,009, -$10,694), and inpatient mortality (OR: 0.68; 95% CI: 0.51-0.91) were also observed in cirrhotics utilizing cannabis after legalization compared to cirrhotics not utilizing cannabis or utilizing cannabis prior to legalization. CONCLUSION: Cannabis use in patients with cirrhosis resulted in mixed outcomes regarding hospital admissions with hepatic decompensation. A trend towards decreased hospital utilization and mortality was noted in cannabis users after legalization. These observations need to be confirmed with a longitudinal randomized study.

Outcomes of hepatitis C virus seropositive donors to hepatitis C virus seronegative liver recipients: A large single center analysis.

INTRODUCTION AND OBJECTIVES: The success of direct-acting antivirals (DAA) has transformed the management of hepatitis C virus (HCV) infection and has led to the expansion of the deceased donor organ pool for liver transplantation. MATERIAL AND METHODS: We present a single center retrospective review of liver transplantations performed on HCV-seronegative recipients from HCV-seropositive organs from 11/2017 to 05/2020. HCV nucleic acid testing (NAT) was performed on HCV-seropositive donors to assess active HCV infection. RESULTS: 42 HCV-seronegative recipients underwent a liver transplant from a HCV-seropositive donor, including 21 NAT negative (20 liver, 1 simultaneous liver kidney transplant) and 21 NAT positive liver transplants. Two (9.5%) HCV antibody positive/NAT negative recipients developed HCV viremia and achieved sustained virologic response with DAA therapy. The remaining patients with available data (19 patients) remained polymerase chain reaction (PCR) negative at 6 months. 20 (95%) of HCV antibody positive/NAT positive recipients had a confirmed HCV viremia. 100% of patients with available data (15 patients) achieved SVR. Observed events include 1 mortality and graft loss and equivalent rates of post-transplant complications between NAT positive and NAT negative recipients. CONCLUSIONS: HCV-seropositive organs can be safely transplanted into HCV-seronegative patients with minimal complications post-transplant.

Anti-CD40 antibody 2C10 binds to a conformational epitope at the CD40-CD154 interface that is conserved among primate species.

The antagonistic anti-CD40 antibody, 2C10, and its recombinant primate derivative, 2C10R4, are potent immunosuppressive antibodies whose utility in allo- and xenotransplantation have been demonstrated in nonhuman primate studies. In this study, we defined the 2C10 binding epitope and found only slight differences in affinity of 2C10 for CD40 derived from four primate species. Staining of truncation mutants mapped the 2C10 binding epitope to the N-terminal portion of CD40. Alanine scanning mutagenesis of the first 60 residues in the CD40 ectodomain highlighted key amino acids important for binding of 2C10 and for binding of the noncross-blocking anti-CD40 antibodies 3A8 and 5D12. All four 2C10-binding residues defined by mutagenesis clustered near the membrane-distal tip of CD40 and partially overlap the CD154 binding surface. In contrast, the overlapping 3A8 and 5D12 epitopes map to an opposing surface away from the CD154 binding domain. This biochemical characterization of 2C10 confirms the validity of nonhuman primate studies in the translation of this therapeutic antibody and provides insight its mechanism of action.

Validation of Risk Score in Predicting Early Readmissions in Decompensated Cirrhotic Patients: A Model Based on the Administrative Database.

Early readmission in patients with decompensated liver cirrhosis leads to an enormous burden on health care use. A retrospective cohort study using the 2013 and 2014 Nationwide Readmission Database (NRD) was conducted. Patients with a diagnoses of cirrhosis and at least one feature of decompensation were included. The primary outcome was to develop a validated risk model for early readmission. Secondary outcomes were to study the 30-day all-cause readmission rate and the most common reasons for readmission. A multivariable logistic regression model was fit to identify predictors of readmissions. Finally, a risk model, the Mumtaz readmission risk score, was developed for prediction of 30-day readmission based on the 2013 NRD and validated on the 2014 NRD. A total of 123,011 patients were included. The 30-day readmission rate was 27%, with 79.6% of patients readmitted with liver-related diagnoses. Age <65 years; Medicare or Medicaid insurance; nonalcoholic etiology of cirrhosis; ≥3 Elixhauser score; presence of hepatic encephalopathy, ascites, variceal bleeding, hepatocellular carcinoma, paracentesis, or hemodialysis; and discharge against medical advice were independent predictors of 30-day readmission. This validated model enabled patients with decompensated cirrhosis to be stratified into groups with low (<20%), medium, (20%-30%), and high (>30%) risk of 30-day readmissions. Conclusion: One third of patients with decompensated cirrhosis are readmitted within 30 days of discharge. The use of a simple risk scoring model with high generalizability, based on demographics, clinical features, and interventions, can bring refinement to the prediction of 30-day readmission in high-risk patients; the Mumtaz readmission risk score highlights the need for targeted interventions in order to decrease rates of readmission within this population.

A validated risk model for prediction of early readmission in patients with hepatic encephalopathy.

INTRODUCTION AND AIM: Hepatic encephalopathy (HE) is a common complication in cirrhotics and is associated with an increased healthcare burden. Our aim was to study independent predictors of 30-day readmission and develop a readmission risk model in patients with HE. Secondary aims included studying readmission rates, cost, and the impact of readmission on mortality. MATERIALS AND METHODS: We utilized the 2013 Nationwide Readmission Database (NRD) for hospitalized patients with HE. A risk assessment model based on index hospitalization variables for predicting 30-day readmission was developed using multivariate logistic regression and validated with the 2014 NRD. Patients were stratified into Low Risk and High Risk groups. Cox regression models were fit to identify predictors of calendar-year mortality. RESULTS: Of 24,473 cirrhosis patients hospitalized with HE, 32.4% were readmitted within 30 days. Predictors of readmission included presence of ascites (OR: 1.19; 95% CI: 1.06-1.33), receiving paracentesis (OR: 1.43; 95% CI: 1.26-1.62) and acute kidney injury (OR: 1.11; 95% CI: 1.00-1.22). Our validated model stratified patients into Low Risk and High Risk of 30-day readmissions (29% and 40%, respectively). The cost of the first readmission was higher than index admission in the 30-day readmission cohort ($14,198 vs. $10,386; p-value <0.001). Thirty-day readmission was the strongest predictor of calendar-year mortality (HR: 4.03; 95% CI: 3.49-4.65). CONCLUSIONS: Nearly one-third of patients with HE were readmitted within 30 days, and early readmission adversely impacted healthcare utilization and calendar-year mortality. With our proposed simple risk assessment model, patients at high risk for early readmissions can be identified to potentially avert poor outcomes.

Rotational Thromboelastometry or Conventional Coagulation Tests in Liver Transplantation: Comparing Blood Loss, Transfusions, and Cost.

INTRODUCTION: Orthotopic liver transplantation (OLT) can be associated with significant bleeding requiring multiple blood product transfusions. Rotational thromboelastometry (ROTEM) is a point-of-care device that has been used to monitor coagulation during OLT. Whether it reduces blood loss/transfusions during OLT remains controversial. MATERIALS AND METHODS: We aim to compare ROTEM with conventional coagulation tests (aPTT, PT, INR, platelet count, fibrinogen) to guide transfusion of platelets, cryoprecipitate, and fresh frozen plasma (FFP) during OLT over 3 years. Thirty-four patients who had transfusions guided by ROTEM were compared to 34 controls who received transfusions guided by conventional coagulation tests (CCT). Intraoperative blood loss, type/ amount of blood products transfused, and direct costs were compared between the two groups. RESULTS: The ROTEM group had significantly less intra-operative blood loss (2.0 vs. 3.0 L, p = 0.04) and fresh frozen plasma (FFP) transfusion (4 units vs. 6.5 units, p = 0.015) compared to the CCT group (2.0L vs. 3.0L, p = 0.04). However, total number of patients transfused cryoprecipitate was increased in ROTEM (n = 25;73%) as compared to CCT (n = 19; 56%), p = 0.033. The direct cost of blood products plus testing was reduced in the ROTEM group ($113,142.89 vs. $127,814.77). CONCLUSION: In conclusion implementation of a ROTEM-guided transfusion algorithm resulted in a reduction in intra-operative blood loss, FFP transfusion and a decrease in direct cost during OLT. ROTEM is a useful and safe point of care device in OLT setting.

An indeterminate nodule in the cirrhotic liver discovered by surveillance imaging is a prelude to malignancy.

BACKGROUND: Surveillance imaging often shows indeterminate lesions in the cirrhotic liver, which may represent early hepatocellular carcinoma (HCC), dysplastic or regenerative nodules, or vascular shunts. The risk of HCC after identification of an indeterminate nodule is not well described. METHODS: We identified 252 patients with cirrhosis and at least one indeterminate nodule discovered on surveillance imaging over a 4-year period. The incidence of HCC development within 2 years of nodule identification was measured along with baseline risk factors associated with developing HCC. RESULTS: The incidence of HCC in this population was 21% (53 of 252), and risk factors associated with HCC included chronic viral hepatitis, male gender, and low platelet count. The median time from identification of an indeterminate nodule to diagnosis of HCC was 2.7 months. Patients with indeterminate nodules who developed HCC were more likely have to have an indeterminate nodule with arterial enhancement. CONCLUSIONS: The 2-year incidence of HCC in the setting of cirrhosis and an indeterminate nodule discovered by surveillance imaging may be as high as one in five persons. Early follow-up imaging, biopsy, or empiric treatment should be considered for those at higher risk. Further, this population is well suited for early detection biomarker and chemoprevention studies.

Inflammatory markers are associated with outcome in patients with unresectable hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND: The serum neutrophil-lymphocyte ratio (NLR) is associated with outcomes in several solid organ cancers, including hepatocellular carcinoma (HCC). METHODS: We reviewed our experience in patients with HCC who underwent transarterial chemoembolization (TACE) as the initial treatment. Serum complete blood counts were used to calculate the NLR before and after TACE. The Kaplan-Meier method was used to determine survival and significant differences between groups by the log-rank test. RESULTS: There were 103 patients identified who underwent TACE for HCC. The median age was 60.5 years. Median overall survival was 12.6 (95% confidence interval 8.3-17) months. Median survival in patients with a high preprocedural NLR was 4.2 months compared to 15 months in those with a normal NLR (p = 0.021). In those whose NLR either rose 1 month after treatment or remained elevated, survival was worse compared to those who normalized or remained normal (18.6 vs. 10.6 months, p = 0.026). The same was true at 6 months (21.3 vs. 9.5 months, p = 0.002). An unresponsive NLR was associated with very poor outcome (median survival 3.7 months). Multivariate analysis of clinicopathologic factors showed that presence of extrahepatic disease and high NLR were independent factors associated with worse survival. CONCLUSIONS: Our study demonstrates that periprocedural trends of serum NLR are associated with outcome in unresectable HCC undergoing TACE. Serum NLR is easy to calculate from a routine complete blood count with differential. Along with liver function, serum NLR may be helpful to clinicians in providing prognostic information and monitoring response to therapy.

Hepatic preservation injury: severity of hepatitis C recurrence and survival after liver transplantation.

BACKGROUND: Preservation injury in the HCV liver transplant population has been reported to correlate with poorer survival outcomes compared to preservation injury in the non-HCV liver transplant population. However, determinants of progression to cirrhosis in HCV infection remain poorly defined in this population. AIM: This study aimed to determine if the presence and severity of preservation injury impact the acceleration of HCV recurrence and survival after liver transplant. METHODS: We retrospectively reviewed liver transplant HCV patients over a 10-year period. Biopsies from postoperative day 7 were assessed for preservation injury and 4- and 12-month biopsies were assessed for fibrosis. Patients with Ishak fibrosis >0.8 Units/year were considered rapid fibrosers. RESULTS: Our study group consisted of 255 patients. The mean age was 49.3 years old, 180 (70.6 %) were male, and 221 (86.7 %) were Caucasian. The incidence of preservation injury on the 7-day biopsy was 69.0 %. A strong correlation between postoperative peak AST within the first week and preservation injury was found. The overall prevalence of rapid fibrosers at 4 months, 1 and 2 years was 47.4, 75.2, and 58.9 %, respectively. The prevalence of rapid fibrosers at 4 months, 1 and 2 years between patients with or without preservation injury was not statistically significant (p = 0.39, p = 0.46, and p = 0.53, respectively). No differences were seen between patients with and without PI in terms of patient and graft survival. CONCLUSION: In this study, the presence and severity of preservation injury were not associated with development of rapid HCV recurrence or worsening in survival.

Nuclear receptor LXRß controls fitness and functionality of activated T cells.

T cells increase cholesterol biosynthesis upon activation to generate substrates for cellular growth and proliferation. The ubiquitously expressed liver X receptor ß (LXRß) encoded by the Nr1h2 gene is a critical regulator of cholesterol homeostasis in mammalian cells; however, its cell-intrinsic role in T cell biology remains poorly understood. We report that ablation of LXRß in T cells leads to spontaneous T cell activation and T lymphocytopenia. Unexpectedly, analysis of mixed bone marrow chimeric mice revealed a cell-autonomous survival defect that reduced the fitness of LXRß-deficient effector T cells, suggesting that the heightened immune activation in mice harboring LXRß-deficient T cells was due to impaired regulatory T (T reg) cell functionality. Indeed, we found that single-copy deletion of Nr1h2 in T reg cells disrupted activated T reg cell metabolism and fitness and resulted in early-onset fatal autoimmune disease. Our study demonstrated an indispensable requirement for T reg cell-intrinsic LXRß function in immune homeostasis and provides a basis for immunological therapies through targeting of this receptor.

Temporal dynamics of persistent germinal centers and memory B cell differentiation following respiratory virus infection.

Following infection or immunization, memory B cells (MBCs) and long-lived plasma cells provide humoral immunity that can last for decades. Most principles of MBC biology have been determined with hapten-protein carrier models or fluorescent protein immunizations. Here, we examine the temporal dynamics of the germinal center (GC) B cell and MBC response following mouse influenza A virus infection. We find that antiviral B cell responses within the lung-draining mediastinal lymph node (mLN) and the spleen are distinct in regard to duration, enrichment for antigen-binding cells, and class switching dynamics. While splenic GCs dissolve after 6 weeks post-infection, mLN hemagglutinin-specific (HA+) GCs can persist for 22 weeks. Persistent GCs continuously differentiate MBCs, with "peak" and "late" GCs contributing equal numbers of HA+ MBCs to the long-lived compartment. Our findings highlight critical aspects of persistent GC responses and MBC differentiation following respiratory virus infection with direct implications for developing effective vaccination strategies.

Assembly of a spatial circuit of T-bet-expressing T and B lymphocytes is required for antiviral humoral immunity.

Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes on the basis of their dynamic colocalization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GCs) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of TH1 cells at the T-B boundary. The encounter of B and TH1 cells at the T-B boundary enables IFN-γ produced by the latter to induce IgG2c class switching. Within GCs, T-bet+ TFH cells represent a specialized stable sublineage required for GC growth but dispensable for IgG2c class switching. Our studies show that during respiratory viral infection, T-bet-expressing T and B lymphocytes form a circuit assembled in a spatiotemporally controlled manner that acts as a functional unit enabling a robust and coherent humoral response tailored for optimal antiviral immunity.

New therapies in the management of hepatitis C virus.

PURPOSE OF REVIEW: The present review discusses recent developments in drug discovery for hepatitis C. We are on the verge of a new era with the introduction of direct acting oral agents that will transform the treatment landscape. Both healthcare providers and patients need to stay abreast of these changes that will influence decisions to treat. This article will discuss the most promising up-to-date hepatitis C virus antiviral therapies in clinical investigation as well as the associated clinical trial results. RECENT FINDINGS: First generation protease inhibitors will offer higher sustained viral response rates for both naive (70-80%) and treatment-experienced (40-50%) populations when added to standard pegylated interferon and ribavirin. However, these dramatic gains will be partially offset by new challenges with viral resistance and increased adverse events. SUMMARY: There are currently a number of drugs under investigation that target the enzymes involved in hepatitis C virus replication. Year 2011 should bring the approval of the first generation of protease inhibitors that will offer higher cure rates for genotype 1 patients and open the door for the eventual testing of interferon-free regimens.

Thirty-day readmission rates, trends and its impact on liver transplantation recipients: a national analysis.

Reduction of early hospital readmissions is a declared goal in the United States economic and quality improvement agenda. A retrospective study was performed using the Nationwide Readmissions Database from 2010 to 2014. Our primary aim was to study the rate of early readmissions and its predictors in liver transplant recipients (LTRs). Our secondary aims were to determine the trends of LT, reasons for readmission, costs and predictors of calendar year mortality. Multivariable logistic regression and Cox proportional hazards models were utilized. The 30-day readmission rate was 30.6% among a total of 25,054 LTRs. Trends of LT were observed to be increased in patients > 65 years (11.7-17.8%, p < 0.001) and decreased in 40-64 years (78.0-73.5%, p = 0.001) during study period. The majority of 30-day readmissions were due to post transplant complications, with packed red blood cell transfusions being the most common intervention during readmission. Medicaid or Medicare insurance, surgery at low and medium volume centers, infections, hemodialysis, liver biopsy, and length of stay > 10 days were the predictors of 30-day readmission. Moreover, number of early readmission, age > 64 years, non-alcoholic cirrhosis, and length of stay > 10 days were significant predictor of calendar year mortality in LTRs. Approximately one third of patients require early admission after LT. Early readmission not only increases burden on healthcare, but is also associated with calendar year mortality. Strategies should be implemented to reduce readmission in patients with high risk of readmission identified in our study.

Paracentesis in cirrhotics is associated with increased risk of 30-day readmission.

AIM: To determine the readmission rate, its reasons, predictors, and cost of 30-d readmission in patients with cirrhosis and ascites. METHODS: A retrospective analysis of the nationwide readmission database (NRD) was performed during the calendar year 2013. All adults cirrhotics with a diagnosis of ascites, spontaneous bacterial peritonitis, or hepatic encephalopathy were identified by ICD-9 codes. Multivariate analysis was performed to assess predictors of 30-d readmission and cost of readmission. RESULTS: Of the 59597 patients included in this study, 18319 (31%) were readmitted within 30 d. Majority (58%) of readmissions were for liver related reasons. Paracentesis was performed in 29832 (50%) patients on index admission. Independent predictors of 30-d readmission included age < 40 (OR: 1.39; CI: 1.19-1.64), age 40-64 (OR: 1.19; CI: 1.09-1.30), Medicaid (OR: 1.21; CI: 1.04-1.41) and Medicare coverage (OR: 1.13; CI: 1.02-1.26), > 3 Elixhauser comorbidity (OR: 1.13; CI: 1.05-1.22), nonalcoholic cirrhosis (OR: 1.16; CI: 1.10-1.23), paracentesis on index admission (OR: 1.28; CI: 1.21-1.36) and having hepatocellular carcinoma (OR: 1.21; CI: 1.05; 1.39). Cost of index admission was similar in patients readmitted and not readmitted (P-value: 0.34); however cost of care was significantly more on 30 d readmission ($30959 ± 762) as compared to index admission ($12403 ± 378), P-value: < 0.001. CONCLUSION: Cirrhotic patients with ascites have a 33% chance of readmission within 30-d. Younger patients, with public insurance, nonalcoholic cirrhosis and increased comorbidity who underwent paracentesis are at increased risk of readmission. Risk factors for unplanned readmission should be targeted given these patients have higher healthcare utilization.

Effect of transplant center volume on post-transplant survival in patients listed for simultaneous liver and kidney transplantation.

AIM: To examine the effect of center size on survival differences between simultaneous liver kidney transplantation (SLKT) and liver transplantation alone (LTA) in SLKT-listed patients. METHODS: The United Network of Organ Sharing database was queried for patients ≥ 18 years of age listed for SLKT between February 2002 and December 2015. Post-transplant survival was evaluated using stratified Cox regression with interaction between transplant type (LTA vs SLKT) and center volume. RESULTS: During the study period, 393 of 4580 patients (9%) listed for SLKT underwent a LTA. Overall mortality was higher among LTA recipients (180/393, 46%) than SLKT recipients (1107/4187, 26%). The Cox model predicted a significant survival disadvantage for patients receiving LTA vs SLKT [hazard ratio, hazard ratio (HR) = 2.85; 95%CI: 2.21, 3.66; P < 0.001] in centers performing 30 SLKT over the study period. This disadvantage was modestly attenuated as center SLKT volume increased, with a 3% reduction (HR = 0.97; 95%CI: 0.95, 0.99; P = 0.010) for every 10 SLKs performed. CONCLUSION: In conclusion, LTA is associated with increased mortality among patients listed for SLKT. This difference is modestly attenuated at more experienced centers and may explain inconsistencies between smaller-center and larger registry-wide studies comparing SLKT and LTA outcomes.

Endoscopic ultrasonography guided celiac plexus neurolysis and celiac plexus block in the management of pain due to pancreatic cancer and chronic pancreatitis.

Pain is a common symptom of pancreatic disease and is frequently difficult to manage. Pain relief provided by narcotics is often suboptimal and is associated with significant side effects. An alternative approach to pain management in pancreatic disease is the use of celiac plexus block (CPB) or neurolysis (CPN). Originally performed by anesthesiologists and radiologists via a posterior approach, recent advances in endoscopic ultrasonography (EUS) have made this technique an attractive alternative. EUS guided celiac plexus block/neurolysis is simple to perform and avoids serious complications such as paraplegia or pneumothorax that are associated with the posterior approach. EUS guided CPN should be considered first line therapy in patients with pain due to pancreatic cancer. It provides superior pain control compared to traditional management with narcotics. A trend for improved survival in pancreatic cancer patients treated with CPN has been reported, but larger studies are needed to confirm this finding. At this time, the use of EUS guided CPB cannot be recommended as routine therapy for pain in chronic pancreatitis since only one-half of the patients experience pain reduction and the beneficial effect tends to be short lived. EUS guided CPB and CPN should be used as part of a multidisciplinary team approach for pain management.

Depletion of Gut-Resident CCR5+ Cells for HIV Cure Strategies.

The HIV reservoir forming at the earliest stages of infection is likely composed of CCR5+ cells, because these cells are the targets of transmissible virus. Restriction of the CCR5+ reservoir, particularly in the gut, may be needed for subsequent cure attempts. Strategies for killing or depleting CCR5+ cells have been described, but none have been tested in vivo in nonhuman primates, and the extent of achievable depletion from tissues is not known. In this study we investigate the efficacy of two novel cytotoxic treatments for targeting and eliminating CCR5+ cells in young rhesus macaques. The first, an immunotoxin consisting of the endogenous CCR5 ligand RANTES fused with Pseudomonas exotoxin (RANTES-PE38), killed CCR5+ lamina propria lymphocytes (LPLs) ex vivo, but had no detectable effect on CCR5+ LPLs in vivo. The second, a primatized bispecific antibody for CCR5 and CD3, depleted all CCR5+ cells from blood and the vast majority of such cells from the colonic mucosa (up to 96% of CD4+CCR5+). Absence of CCR5-expressing cells from blood endured for at least 1 week, while CCR5+ cells in colon were substantially replenished over the same time span. These data open an avenue to investigation of combined early ART treatment and CCR5+ reservoir depletion for cure of HIV-infected infants.

Impact of transjugular intrahepatic porto-systemic shunt on post liver transplantation outcomes: Study based on the United Network for Organ Sharing database.

AIM: To determine the impact of transjugular intrahepatic porto-systemic shunt (TIPS) on post liver transplantation (LT) outcomes. METHODS: Utilizing the United Network for Organ Sharing (UNOS) database, we compared patients who underwent LT from 2002 to 2013 who had underwent TIPS to those without TIPS for the management of ascites while on the LT waitlist. The impact of TIPS on 30-d mortality, length of stay (LOS), and need for re-LT were studied. For evaluation of mean differences between baseline characteristics for patients with and without TIPS, we used unpaired t-tests for continuous measures and χ2 tests for categorical measures. We estimated the impact of TIPS on each of the outcome measures. Multivariate analyses were conducted on the study population to explore the effect of TIPS on 30-d mortality post-LT, need for re-LT and LOS. All covariates were included in logistic regression analysis. RESULTS: We included adult patients (age ≥ 18 years) who underwent LT from May 2002 to September 2013. Only those undergoing TIPS after listing and before liver transplant were included in the TIPS group. We excluded patients with variceal bleeding within two weeks of listing for LT and those listed for acute liver failure or hepatocellular carcinoma. Of 114770 LT in the UNOS database, 32783 (28.5%) met inclusion criteria. Of these 1366 (4.2%) had TIPS between the time of listing and LT. We found that TIPS increased the days on waitlist (408 ± 553 d) as compared to those without TIPS (183 ± 330 d), P < 0.001. Multivariate analysis showed that TIPS had no effect on 30-d post LT mortality (OR = 1.26; 95%CI: 0.91-1.76) and re-LT (OR = 0.61; 95%CI: 0.36-1.05). Pre-transplant hepatic encephalopathy added 3.46 d (95%CI: 2.37-4.55, P < 0.001), followed by 2.16 d (95%CI: 0.92-3.38, P = 0.001) by TIPS to LOS. CONCLUSION: TIPS did increase time on waitlist for LT. More importantly, TIPS was not associated with 30-d mortality and re-LT, but it did lengthen hospital LOS after transplantation.