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Objectives Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early‐onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD‐ and schizophrenia (SCZ)‐associated risk variants is associated with an earlier AAO in BD patients. Methods A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn‐Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD‐ and SCZ‐PRSs and AAO were evaluated with regression models. Results BD‐ and SCZ‐PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

BACKGROUND Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double‐blind, placebo‐controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second‐line treatment for metastatic colorectal cancer. METHODS Patients with metastatic colorectal cancer who progressed on first‐line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28‐day cycle. Crossover was not allowed. The primary endpoint was progression‐free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1‐sided α value of .1. RESULTS One hundred eighty‐one patients were randomized (120 to regorafenib‐FOLFIRI and 61 to placebo‐FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib‐FOLFIRI than placebo‐FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53‐1.01; log‐rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71‐1.44). The response rate was higher with regorafenib‐FOLFIRI (34%; 95% CI, 25%‐44%) than placebo‐FOLFIRI (21%; 95% CI, 11%‐33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. CONCLUSIONS The addition of regorafenib to FOLFIRI as second‐line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society .

Abstract This Consensus Document is the first of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The first document appraises the role of intracoronary imaging to guide percutaneous coronary interventions (PCIs) in clinical practice. Current evidence regarding the impact of intracoronary imaging guidance on cardiovascular outcomes is summarized, and patients or lesions most likely to derive clinical benefit from an imaging-guided intervention are identified. The relevance of the use of IVUS or OCT prior to PCI for optimizing stent sizing (stent length and diameter) and planning the procedural strategy is discussed. Regarding post-implantation imaging, the consensus group recommends key parameters that characterize an optimal PCI result and provides cut-offs to guide corrective measures and optimize the stenting result. Moreover, routine performance of intracoronary imaging in patients with stent failure (restenosis or stent thrombosis) is recommended. Finally, strengths and limitations of IVUS and OCT for guiding PCI and assessing stent failures and areas that warrant further research are critically discussed.

Background/Aims. The aim of this study was to evaluate the association of fluid balance with outcomes in patients hospitalized with acute pancreatitis (AP).Methods. This was a retrospective study of patients hospitalized between May 2008 and June 2016 with AP and a clinical order for strict recording of intake and output. Data collected included various types of fluid intake and output at 24 and 48 hours after admission. The primary outcome was length of stay (LOS). Analysis was performed using single-variable and multivariable negative binomial regression models.Results. Of 1256 patients hospitalized for AP during the study period, only 71 patients (5.6%) had a clinical order for strict recording of intake and output. Increased urine output was associated with a decreased LOS at 24 and 48 hours in univariable analysis. An increasingly positive fluid balance (total intake minus urine output) at 24 hours was associated with a longer LOS in multivariable analysis.Conclusions. Few patients hospitalized for AP had a documented order for strict monitoring of fluid intake and output, despite the importance of monitoring fluid balance in these patients. Our study suggests an association between urine output and fluid balance with LOS in AP.

Significance Much of the inherited susceptibility to pancreatic cancer remains unexplained. Germline variants that cause protein misfolding and impaired secretion of pancreatic enzymes such as CPA1 (encoding carboxypeptidase A1) can cause pancreatic acinar cell endoplasmic reticulum (ER) stress. We investigated the hypothesis that pancreatic cancer could arise from germline variants in genes encoding pancreatic secretory enzymes that induce pancreatic acinar cell stress. We find ∼1% of 1,579 patients with pancreatic cancer vs. 1 of 2,012 controls have germline variants in the genes encoding CPA1 and CPB1 (carboxypeptidase B1) that impair secretion of its protein product and induce ER stress. These findings implicate pancreatic acinar cell stress as a mechanism of pancreatic cancer susceptibility.