Association between sustained virological response and clinical outcomes in patients with hepatitis C infection and hepatocellular carcinoma.

BACKGROUND: Sustained viral response (SVR) improves survival for patients with hepatitis C (HCV) and hepatocellular carcinoma (HCC) after curative treatment; however, the benefit of SVR in those with active HCC with a significant competing risk of mortality is unknown. This study aimed to evaluate the association between SVR and outcomes in patients with active HCC. METHODS: The authors performed a multicenter, retrospective cohort study including consecutive adults with HCV cirrhosis and treatment-naive HCC diagnosed between 2014 and 2018. Patients were stratified into two groups: active viremia (n = 431) and SVR before HCC diagnosis (n = 135). All patients underwent nonsurgical therapy as their initial treatment and were followed until liver transplantation, last follow-up, or death. The primary outcome was incident or worsening hepatic decompensation within 6 months and the secondary outcome was overall survival. All analyses used inverse probability of treatment weights (IPTW) to account for differences between the nonrandomized cohorts. RESULTS: Post-SVR patients had significantly lower odds of hepatic decompensation compared to viremic patients (odds ratio [OR], 0.18; 95% confidence interval [CI], 0.06-0.59). Results were consistent among subgroups of patients with Child Pugh A cirrhosis (OR, 0.22; 95% CI, 0.04-0.77), Barcelona Clinic Liver Cancer stage B/C HCC (OR, 0.20; 95% CI, 0.04-0.65), and those receiving nonablative HCC therapies (OR, 0.21; 95% CI, 0.07-0.67). However, in IPTW multivariable Cox regression, SVR was not associated with improved survival (hazard ratio, 0.79; 95% CI, 0.56-1.12). CONCLUSIONS: Patients with HCV-related HCC and SVR are less likely to experience hepatic decompensation than viremic patients, suggesting patients with HCC who are undergoing nonsurgical therapies may benefit from DAA treatment.

A Clinical Predictive Model for One-year Colectomy in Adults Hospitalized for Severe Ulcerative Colitis.

Background: Models to predict colectomy in ulcerative colitis (UC) are valuable for identification, clinical management, and follow-up of high-risk patients. Our aim was to develop a clinical predictive model based on admission data for one-year colectomy in adults hospitalized for severe UC. Methods: We performed a retrospective analysis of patients hospitalized at a tertiary academic center for management of severe UC from 1/2013 to 4/2018. Multivariate regression was performed to identify individual predictors of one-year colectomy. Outcome probabilities of colectomy based on the prognostic score were estimated using a bootstrapping technique. Results: Two hundred twenty-nine individuals were included in the final analytic cohort. Four independent variables were associated with one-year colectomy which were incorporated into a point scoring system: (+) 1 for single class biologic exposure prior to admission; (+) 2 for multiple classes of biologic exposure; (+) 1 for inpatient salvage therapy with cyclosporine or a TNF-alpha inhibitor; (+) 1 for age <40. The risk probabilities of colectomy within one year in patients assigned scores 1, 2, 3, and 4 were 9.4% (95% CI, 1.7-17.2), 33.7% (95% CI, 23.9-43.5), 58.5% (95% CI, 42.9-74.1), 75.0% (95% CI, 50.5-99.5). An assigned score of zero was a perfect predictor of no colectomy. Conclusion: Risk factors most associated with one-year colectomy for severe UC included: prior biologic exposure, need for inpatient salvage therapy, and younger age. We developed a simple scoring system using these variables to identify and stratify patients during their index hospitalization.

Epigenetic regulation of arginine vasopressin receptor 2 expression by PAX2 and Pax transcription interacting protein.

Renal arginine vasopressin receptor 2 (AVPR2) plays a crucial role in osmoregulation. Engagement of ligand with AVPR2 results in aquaporin 2 movement to the apical membrane and water reabsorption from the urinary filtrate. Despite this essential role, little is known about transcriptional regulation of Avpr2. Here, we identify novel roles for PAX2, a transcription factor crucial for kidney development, and its adaptor protein, Pax transcription interacting protein (PTIP), for epigenetic regulation of Avpr2 and thus body water balance. Chromatin immunoprecipitation (ChIP) from murine inner medulla cells (IMCD-3) identified the minimal DNA-binding region of PAX2 on the Avpr2 promoter. Regulation of Avpr2 by PAX2 was confirmed using a heterologous DNA expression system. PAX2 recruits the adaptor protein PTIP and its associated histone methyltransferase (HMT) complex to Avpr2 promoter, imposing epigenetic marks on this region and throughout the coding sequence that modulate Avpr2 gene transcription. Reduction of PAX2 or PTIP protein levels by siRNA prevented histone lysine methylation and expression of Avpr2. ChIP using mouse or human kidneys determined that PAX2 is highly enriched in the AVPR2 promoter alongside PTIP and HMT proteins, leading to high levels of histone H3 lysine trimethylation within the promoter and throughout the gene. In conclusion, PAX2 provides locus specificity for PTIP, allowing the HMT complex to impart epigenetic changes at the Avpr2 locus and regulate Avpr2 transcription. These finding have major implications for understanding regulation of body water balance.NEW & NOTEWORTHY The transcription factor PAX2 plays an indispensable role in kidney development. In the adult kidney, we identified the first described protein this protein regulates. PAX2 and its interacting partner Pax transcription interacting protein recruit a histone methyltransferase complex to the promoter and epigentically regulate the expression of arginine vasopressin receptor 2, a protein that plays a crucial role in osmoregulation in the distal tubule.

Inpatient Therapy With Calcineurin Inhibitors in Severe Ulcerative Colitis.

BACKGROUND: Inpatient management of severe ulcerative colitis is complicated by the use of prior immunosuppressant therapies. Our aim was to determine the rate of 1-year colectomy among individuals receiving inpatient calcineurin inhibitor (CNI)-based therapy stratified by prior biologic therapy. METHODS: A retrospective cohort study was performed between January 1, 2013 and April 1, 2018. Only individuals requiring inpatient administration of intravenous cyclosporine or oral tacrolimus were included in the analysis. Individuals were stratified according to prior biologic therapy exposure. The primary outcome of interest was 1-year risk of colectomy. Kaplan-Meier curves were generated for time-to-event data, and regression models were performed to examine the effects of covariates on the clinical endpoint. RESULTS: Sixty-nine (62.3% male) patients were treated with an inpatient CNI-based therapy and were included in the analysis. Fifteen (21.7%) patients were biologic-naïve, 42 (60.9%) patients had prior exposure to 1 class of biologic therapy, and 12 (17.4%) patients had prior exposure to 2 classes of biologic therapy (third-line CNI therapy). Third-line CNI therapy showed a greater risk of 1-year colectomy risk when compared with the risk for patients who were biologic-naïve (hazard ratio, 3.63; 95% confidence interval, 1.17-13.45; P = 0.025). In a multivariate proportional hazards model, third-line CNI therapy remained significantly associated with 1-year colectomy risk (hazard ratio, 7.94; 95% confidence interval, 1.97-39.76; P = 0.003). CONCLUSIONS: The use of CNI-based therapy in individuals exposed to multiple classes of prior biologic therapies leads to a significantly increased risk of 1-year colectomy. Future studies will be required to compare inpatient management strategies with the expanding novel therapies in UC.

Fecal Microbiota Transplantation for the Management of Clostridium difficile Infection.

The clinical burden of Clostridium difficile infection (CDI) continues to grow. Despite the multitude of treatment options that have been developed and tested to combat the morbidity and death associated with CDI, recurrence remains common. As such, treatment modalities such as fecal microbiota transplantation (FMT) have become studied increasingly; FMT serves to transplant stool from carefully selected healthy subjects into C. difficile positive patients through a variety of delivery routes. In doing so, FMT is hypothesized to correct dysbiosis of the recipient gut microbiome addressing the root cause of the pathogenesis of C. difficile infection. A growing body of evidence shows FMT to be efficacious in this setting, and the study of FMT accordingly continues to evolve to identify novel indications for its utilization.

Psoas muscle size as a frailty measure for open and transcatheter aortic valve replacement.

OBJECTIVE: To evaluate the use of sarcopenia as a frailty assessment tool for patients with aortic stenosis undergoing surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). METHODS: The study cohort comprised 295 patients who underwent either SAVR (n = 156) or TAVR (n = 139). The mean preoperative Society of Thoracic Surgeons mortality risk score was 4.7%. Preoperative computed tomography (CT) scans were used to calculate gender-standardized total psoas area (TPA), as a validated measure of sarcopenia. RESULTS: For the entire cohort, independent predictors of a composite measure of 30-day death, stroke, renal failure, prolonged ventilation, and deep wound infection included preoperative STS major morbidity and mortality risk score (odds ratio [OR], 91.1; P = .02) and TPA (OR, 0.5; P = .024). Two-year survival was 85.7% in patients with sarcopenia, compared with 93.8% in patients without sarcopenia (P = .02). Independent predictors of late survival included TPA (hazard ratio, 0.47; P = .02). Male sex (OR, 0.52; P = .04) and TPA (OR, 0.6; P = .001) were predictive of high resource utilization. A separate analysis by treatment group found that TPA predicted high resource utilization after SAVR (OR, 0.4; P < .001), but not after TAVR (P = .66). CONCLUSIONS: CT scan-derived measurement of TPA as an objective frailty assessment tool predicts early morbidity and mortality, high resource utilization, and late survival after treatment for aortic stenosis. The correlation observed between sarcopenia and resource utilization after SAVR versus TAVR suggests that this simple and reproducible risk assessment tool also may help identify those patients who will derive optimal benefit from catheter-based therapy.

The Groucho-associated phosphatase PPM1B displaces Pax transactivation domain interacting protein (PTIP) to switch the transcription factor Pax2 from a transcriptional activator to a repressor.

Pax genes encode developmental regulatory proteins that specify cell lineages and tissues in metazoans. Upon binding to DNA through the conserved paired domain, Pax proteins can recruit both activating and repressing complexes that imprint distinct patterns of histone methylation associated with either gene activation or silencing. How the switch from Pax-mediated activation to repression is regulated remains poorly understood. In this report, we identify the phosphatase PPM1B as an essential component of the Groucho4 repressor complex that is recruited by Pax2 to chromatin. PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation. Loss of PPM1B prevents Groucho-mediated gene repression. Thus, PPM1B helps switch Pax2 from a transcriptional activator to a repressor protein. This can have profound implications for developmental regulation by Pax proteins and suggests a model for imprinting specific epigenetic marks depending on the availability of co-factors.

Epigenetic mechanisms of Groucho/Grg/TLE mediated transcriptional repression.

The repression of transcription, through the concerted actions of tissue specific DNA binding proteins, Polycomb repressor complexes, and DNA methylation, is essential for maintaining stem cell pluripotency and for cell fate specification in development. In this report, we show that recruitment of the co-repressor protein Grg4 to a Pax DNA-binding site displaces the adaptor protein PTIP and a histone H3K4me complex. Grg4 recruits the arginine methyltransferase PRMT5 to chromatin resulting in symmetric H4R3 dimethylation. PRMT5 is essential for recruiting Polycomb proteins, in a Pax2/Grg4 dependent manner, which results in H3K27 methylation. These data define the early epigenetic events in response to Pax/Grg mediated gene repression and demonstrate that a single DNA binding protein can recruit either an activator or a repressor complex depending on the availability of Grg4. These data suggest a model for understanding the initiation of Groucho/Grg/TLE mediated gene silencing.