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Background Patients with primary sclerosing cholangitis (PSC) are at increased risk of developing acute cholangitis. The majority of patients with PSC have comorbid inflammatory bowel disease, and many take immunosuppressive medications. The epidemiological risks for the development of acute cholangitis in patients with PSC, including the impact of immunosuppressive therapy, are unknown. Methods We conducted a 2-center, retrospective cohort study using data from 228 patients at Stanford University Medical Center and Santa Clara Valley Medical Center (CA), a county health care system. Patient demographics, medications, PSC disease severity, and inflammatory bowel disease status were extracted. Using stepwise variable selection, we included demographic and covariate predictors in the multiple logistic regression model assessing risk factors for cholangitis. Time-to-event analysis was performed to evaluate specific immunosuppressive medications and development of cholangitis. Results Thirty-one percent of patients had at least 1 episode of acute cholangitis (n = 72). Anti-tumor necrosis factor (TNF) therapy was associated with increased odds of acute cholangitis (odds ratio, 7.29; 95% confidence interval, 2.63-12.43), but immunomodulator use was protective against acute cholangitis (odds ratio, 0.23; 95% confidence interval, 0.05-0.76). Anti-TNF therapy was associated with decreased time-to-cholangitis, with a median time of 28.4 months; in contrast, only 11.1% of patients who were prescribed immunomodulators developed cholangitis over the same time period (P < 0.001). Conclusions Our observations suggest that classes of immunosuppressive medications differentially modify the odds of acute cholangitis. Biologic therapy, ie, anti-TNF therapy, was shown to have significantly higher odds for patients developing acute cholangitis whereas immunomodulator therapy was shown to have a potential protective effect. These findings may help guide physicians in decision-making for determining appropriate immunosuppressive therapy.

BackgroundMost research manuscripts are not accepted for publication on first submission. A major part of the resubmission process is reformatting to another journal's specific requirements, a process separate from revising the scientific content. There has been little research to understand the magnitude of the burden imposed by the current resubmission process.MethodsWe analyzed original research article submission requirements from twelve randomly selected journals in each of eight scientific and clinical focus areas from the InCites Journal Citation Reports database. From the 96 journals selected, we randomly identified three recently published manuscripts and sent surveys to those first and/or corresponding authors (288 total) to solicit information on time spent reformatting resubmissions and opinions on the process.FindingsThere was significant variation in manuscript submission requirements for journals within the same scientific focus and only 4% of journals offered a fully format-free initial submission. Of 203 authors responding (71.5% response rate), only 11.8% expressed satisfaction with the resubmission process and 91% desired reforming the current system. Time spent on reformatting delays most publications by at least two weeks and by over three months in about 20% of manuscripts. The effort to comply with submission requirements has significant global economic burden, estimated at over $1.1 billion dollars annually when accounting for a research team's time.InterpretationWe demonstrate that there is significant resource utilization associated with resubmitting manuscripts, heretofore not properly quantified. The vast majority of authors are not satisfied with the current process. Addressing these issues by reconciling reformatting requirements among journals or adopting a universal format-free initial submission policy would help resolve a major subject for the scientific research community and provide more efficient dissemination of findings.

Background Patients with inflammatory bowel disease are using online community forums (OCFs) to seek emotional support. The impact of OCFs on well-being and their emotional content are unknown. Methods We used an unsupervised machine learning algorithm to identify the thematic content of 51,591 public, online posts from the Crohn’s & Colitis Foundation Community Forum. Results We identified 10,702 (20.8%) posts expressing: gratitude (40%), anxiety/fear (20.8%), empathy (18.2%), anger/frustration (13.4%), hope (13.2%), happiness (10.0%), sadness/depression (5.8%), shame/guilt (2.5%), and/or loneliness (2.5%). A common subtheme was the importance of fostering social support. Conclusions High-throughput, machine learning-directed analysis of OCFs may help identify psychosocial impacts of inflammatory bowel disease on patients and their caregivers.

Vascular and haematopoietic cells organize into specialized tissues during early embryogenesis to supply essential nutrients to all organs and thus play critical roles in development and disease. At the top of the haemato-vascular specification cascade lies cloche, a gene that when mutated in zebrafish leads to the striking phenotype of loss of most endothelial and haematopoietic cells and a significant increase in cardiomyocyte numbers. Although this mutant has been analysed extensively to investigate mesoderm diversification and differentiation and continues to be broadly used as a unique avascular model, the isolation of the cloche gene has been challenging due to its telomeric location. Here we used a deletion allele of cloche to identify several new cloche candidate genes within this genomic region, and systematically genome-edited each candidate. Through this comprehensive interrogation, we succeeded in isolating the cloche gene and discovered that it encodes a PAS-domain-containing bHLH transcription factor, and that it is expressed in a highly specific spatiotemporal pattern starting during late gastrulation. Gain-of-function experiments show that it can potently induce endothelial gene expression. Epistasis experiments reveal that it functions upstream of etv2 and tal1, the earliest expressed endothelial and haematopoietic transcription factor genes identified to date. A mammalian cloche orthologue can also rescue blood vessel formation in zebrafish cloche mutants, indicating a highly conserved role in vertebrate vasculogenesis and haematopoiesis. The identification of this master regulator of endothelial and haematopoietic fate enhances our understanding of early mesoderm diversification and may lead to improved protocols for the generation of endothelial and haematopoietic cells in vivo and in vitro.

Background Despite the increasing annual incidence of hepatocellular carcinoma (HCC) in the USA, now estimated at 2.7 cases per 100 000 population, only a small proportion of patients receive treatment and 5-year survival rates range from 9% to 17%. Objectives The present study examines the effects of multimodal treatment on survival in a mixed-stage HCC cohort, focusing on the impact of radical therapy in patients with Barcelona Clinic Liver Cancer (BCLC) stage B disease. Methods A retrospective review of the medical records of 254 patients considered for HCC treatment between 2003 and 2011 at a large tertiary referral centre was conducted. Results A total of 195 (76.8%) patients were treated with a median of two liver-directed interventions. Median survival time was 16 months. In proportional hazards analysis, radiofrequency ablation (RFA) and resection were associated with significantly improved 1- and 5-year survival among patients with BCLC stage 0-A disease. In patients with BCLC stage B disease, RFA conferred a survival benefit at 1 year and resection was associated with significantly improved survival at 5 years. Conclusions As one of few studies to track the complete course of sequential HCC therapies, the findings of the present study suggest that HCC patients with intermediate-stage (BCLC stage B) disease may benefit from aggressive interventions not currently included in societal guidelines. © 2014 International Hepato-Pancreato- Biliary Association.

Background and aims Transjugular intrahepatic portosystemic shunt (TIPS) placement is an effective treatment for complications of portal hypertension. We aimed to describe post-TIPS mortality and its predictors in the modern era of covered stents. Patients and methods We identified patients with cirrhosis who underwent TIPS insertion at Veterans Affairs Healthcare facilities nationally from 2004 to 2014 (n=703), most of which (95%) were performed as elective procedures. We followed patients until the date of death, transplantation, or the end of the observation period. Results TIPS recipients had a mean age of 59.3 years (SD 8) and 97% were men. The mean Model for End Stage Liver Disease (MELD) score was 13 (SD 4.8); 47% had hepatitis C virus (HCV) infection, 48% had variceal hemorrhage, and 40% had ascites. During a mean follow-up of 1.72 years (SD 1.9), 57.5% of TIPS recipients died (n=404) and only 5.3% underwent liver transplantation (n=37). The median survival after TIPS was 1.74 years (interquartile range 0.3-4.7). Thirty-day mortality after TIPS was 11.6% [95% confidence interval (CI) 9.4-14.2], 1-year mortality was 40.3% (95% CI 36.7-44.2), and 3-year mortality was 61.9% (95% CI 57.9-66.0). Independent predictors of post-TIPS mortality included medical comorbidity burden, low albumin, HCV infection, and high MELD score (or high international normalized ratio and bilirubin when the components of the MELD score were analyzed individually). TIPS revision was performed at least once in 27.3% of TIPS recipients. Conclusion TIPS should not be considered simply as a bridge to transplantation. Burden of extra-hepatic comorbidities, HCV infection, and low serum albumin strongly predict post-TIPS mortality in addition to the MELD score.

Nature 535, 294–298 (2016); doi:10.1038/nature18614 In the Author Information section of this Letter, LT571435 from the SRA was provided as the accession number for the PacBio whole-genome sequencing data. Immediately after publication, we noted that LT571435 is instead the GenBank entry for the assembled genomic sequence of the cloche locus and this information is now included in the legend of Extended Data Fig. 2.

HURP is a spindle-associated protein that mediates Ran-GTP-dependent assembly of the bipolar spindle and promotes chromosome congression and interkinetochore tension during mitosis. We report here a biochemical mechanism of HURP regulation by Aurora A, a key mitotic kinase that controls the assembly and function of the spindle. We found that HURP binds to microtubules through its N-terminal domain that hyperstabilizes spindle microtubules. Ectopic expression of this domain generates defects in spindle morphology and function that reduce the level of tension across sister kinetochores and activate the spindle checkpoint. Interestingly, the microtubule binding activity of this N-terminal domain is regulated by the C-terminal region of HURP: in its hypophosphorylated state, C-terminal HURP associates with the microtubule-binding domain, abrogating its affinity for microtubules. However, when the C-terminal domain is phosphorylated by Aurora A, it no longer binds to N-terminal HURP, thereby releasing the inhibition on its microtubule binding and stabilizing activity. In fact, ectopic expression of this C-terminal domain depletes endogenous HURP from the mitotic spindle in HeLa cells in trans, suggesting the physiological importance for this mode of regulation. We concluded that phosphorylation of HURP by Aurora A provides a regulatory mechanism for the control of spindle assembly and function.

Background & Aims A transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment of refractory ascites and variceal bleeding. However, it is unclear whether a TIPS affects long-term survival. We investigated whether a TIPS is associated with survival in patients with cirrhosis awaiting liver transplantation. Methods By using the United Network for Organ Sharing registries from 2002 to 2013, we followed up a cohort of transplant-naive adults with cirrhosis (N = 97,063) from the time of transplant listing until the time of death or transplantation. We used Cox proportional hazards and competing-risks analyses to compare these primary outcomes between patients with a TIPS (n = 7475; 7.7%) and without a TIPS (n = 89,588; 92.3%) at the time of listing, adjusting for baseline characteristics. Results During an average follow-up period of 1.61 years, 23,305 (24%) patients died before undergoing transplantation, 47,563 (49%) underwent transplantation, and the remaining 26,195 (27%) still were alive without having received a liver transplant. Compared with patients without a TIPS, patients with a TIPS had a lower risk of death (adjusted subhazard ratio, 0.95; 95% confidence interval, 0.9–0.99), transplantation (adjusted subhazard ratio, 0.92, 95% confidence interval, 0.88–0.95), or the combined outcome of death or transplantation (adjusted hazard ratio, 0.85; 95% confidence interval, 0.83–0.88). Conclusions Among patients with cirrhosis awaiting liver transplantation, patients with a TIPS had a lower mortality rate than patients without a TIPS.

Background The long-term consequences of unsuccessful interferon-α based hepatitis C treatment on liver disease progression and survival have not been fully explored. Methods and Findings We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-α based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR = 2.35, CI 1.18–4.69, mean follow-up 10 years, and University Hospital HR = 5.90, CI 1.50–23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients. Conclusion These unexpected findings suggest that patients who receive interferon-α based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients.

Introduction Social isolation in the context of social anxiety disorder has not been closely examined. This study aimed to describe the role and measurement of social isolation in those with social anxiety disorder. Method A systematic review and meta-analyses were conducted using a prospectively prepared protocol for search strategy, selection criteria, and data extraction. DerSimonian–Laird random effects models were used to calculate pooled estimates of effect. Results Thirty-four studies, containing 20 formal instruments and four other measures of social isolation, were included. Most formal instruments were utilized in single studies, whereas simple structural measures (e.g., living alone) were used most frequently. The pooled score was 38.1 on the Loneliness and Social Dissatisfaction Questionnaire, 33.1 on the Liebowitz Social Anxiety Scale (avoidance subscale), and 21.1 on the Social Avoidance and Distress Scale. Conclusions Social isolation is common in social anxiety disorder but assessed by a heterogeneous mix of measures.

Background: Over the past decade, the U.S. Department of Veterans Affairs (VA) has seen a more than 6-fold increased prevalence in hepatcocellular carcinoma (HCC). However, the treatment outcome of HCC in this population is not well characterized. Aim:Using intentionto-treat analysis to compare overall survival among patients with HCC treated by different modalities at a single VA center. Methods: 127 consecutive HCC patients, referred for consideration of therapy at the San Francisco VA between 4/2003 to 9/2007 were included, and their outcomes were reviewed in 10/2011. Based on their “intention-to-treat”, these patients were grouped into four categories: surgical resection, transplantation, curative radiofrequency ablation (RFA), and palliative treatment (palliative RFA, transarterial embolization, percutaneous ethanol injection, or none). Baseline patient characteristics, disease stage, and survival outcome using Cox proportional hazard models stratified by BCLC stages were compared. Results: The median age was 58 at initial presentation; 4% were at BCLC stage 0, 25% stage A, 54% stage B, 15% stage C, and 2% stage D. Median MELD score was 10 (range 6 to 30). Initial treatment plans were: 32 (25%) resection, 19 (15%) transplantation, 15 (12%) RFA, and 61 (48%) palliation. In this cohort, 28/32 (88%) of the resection group actually underwent resection and 12/19 (63%) of the transplant group were actually transplanted. At study end, 22 (19%) patients (10 transplant, 11 resections, 1 RFA) were alive, and 94 (80%) had died, and 1 was lost to follow-up. Mean follow-up was 29.8 months, but varied from 56.5 months in the transplant group to 16.3 months in the palliative group (p