Search

Background and Aims: Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival.Approach and Results: A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 109/L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation [P Conclusions: In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.

GOALS AND BACKGROUND Using natural language processing to create a nonalcoholic fatty liver disease (NAFLD) cohort in primary care, we assessed advanced fibrosis risk with the Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Score (NFS) and evaluated risk score agreement. MATERIALS AND METHODS In this retrospective study of adults with radiographic evidence of hepatic steatosis, we calculated patient-level FIB-4 and NFS scores and categorized them by fibrosis risk. Risk category and risk score agreement was analyzed using weighted κ, Pearson correlation, and Bland-Altman analysis. A multinomial logistic regression model evaluated associations between clinical variables and discrepant FIB-4 and NFS results. RESULTS Of the 767 patient cohorts, 71% had a FIB-4 or NFS score in the indeterminate-risk or high-risk category for fibrosis. Risk categories disagreed in 43%, and scores would have resulted in different clinical decisions in 30% of the sample. The weighted κ statistic for risk category agreement was 0.41 [95% confidence interval (CI): 0.36-0.46] and the Pearson correlation coefficient for log FIB-4 and NFS was 0.66 (95% CI: 0.62-0.70). The multinomial logistic regression analysis identified black race (odds ratio=2.64, 95% CI: 1.84-3.78) and hemoglobin A1c (odds ratio=1.37, 95% CI: 1.23-1.52) with higher odds of having an NFS risk category exceeding FIB-4. CONCLUSIONS In a primary care NAFLD cohort, many patients had elevated FIB-4 and NFS risk scores and these risk categories were often in disagreement. The choice between FIB-4 and NFS for fibrosis risk assessment can impact clinical decision-making and may contribute to disparities of care.

The Fibrosis-4 index (FIB-4) can reliably assess fibrosis risk in patients with chronic liver disease, and advanced fibrosis is associated with severe liver disease (SLD) outcomes. However, CLD is underdiagnosed in primary care. We examined the association between FIB-4 risk strata and the incidence of SLD preceding a CLD diagnosis while considering incident CLD diagnoses as competing risks.Using primary care clinic data between 2007 and 2018, we identified patients with two FIB-4 scores and no liver disease diagnoses preceding the index FIB-4. Patients were followed from index FIB-4 until an incident SLD (a composite of cirrhosis, hepatocellular carcinoma or liver transplantation), CLD or were censored. Hazard ratios were computed using a Fine-Gray competing risk model.Of 20 556 patients, there were 54.8% in the low, 34.8% in the indeterminate, 6.6% in the high and 3.8% in the persistently high-risk FIB-4 strata. During a mean 8.2 years of follow-up, 837 (4.1%) patients experienced an SLD outcome and 11.5% of the sample received a CLD diagnosis. Of patients with an SLD event, 49% received no preceding CLD diagnosis. In the adjusted Fine-Gray model, the indeterminate (HR 1.41, 95% CI 1.17-1.71), high (HR 4.65, 95% CI 3.76-5.76) and persistently high-risk (HR 7.60, 95% CI 6.04-9.57) FIB-4 risk strata were associated with a higher incidence of SLD compared to the low-risk stratum.FIB-4 scores with indeterminate- and high-risk values are associated with an increased incidence of SLD in primary care patients without known CLD.

Background/objective Assessing prognosis for acetaminophen-induced acute liver failure (APAP-ALF) patients during the first week of hospitalization often presents significant challenges. Current models such as the King's College Criteria (KCC) and the Acute Liver Failure Study Group (ALFSG) Prognostic Index are developed to predict outcome using only a single time point on hospital admission. Models using longitudinal data are not currently available for APAP-ALF patients. We aim to develop and compare performance of prediction models for outcomes during the first week of hospitalization for APAP-ALF patients. Methods Models are developed for the ALFSG registry data to predict longitudinal outcomes for 1042 APAP-ALF patients enrolled 01/1998–02/2016. The primary outcome is defined as daily low versus high coma grade. Accuracy in prediction of outcome (AC), sensitivity (SN), specificity (SP) and area under the receiver operating curve (AUC) are compared between the following models: classification and regression tree, random forest, frequentist generalized linear mixed model (GLMM), Bayesian GLMM, BiMM tree, and BiMM forest using original and imputed datasets. Results BiMM tree offers predictive (test set) 63% AC, 72% SP and 53% SN for the original dataset, whereas BiMM forest offers predictive (test set) 69% AC, 63% SP and 74% SN for the imputed dataset. BiMM tree has the highest AUC for the original testing dataset (0.697), whereas BiMM forest and standard random forest have the highest AUC for the imputed testing dataset (0.749). The three most important predictors of daily outcome for the BiMM tree are pressor use, bilirubin and creatinine. The BiMM forest model identifies lactate, ammonia and ALT as the three most important predictors of outcome. Conclusions BiMM tree offers a prognostic tool for APAP-ALF patients, which has good accuracy and simple interpretation of predictors which are consistent with clinical observations. BiMM tree and forest models are developed using the first week of in-patient data and are appropriate for predicting outcome over time. While the BiMM forest has slightly higher predictive AC, the BiMM tree model is simpler to use at the bedside.

Clustered binary outcomes and datasets with many predictor variables are frequently encountered in clinical research (e.g. longitudinal studies). Generalized linear mixed models (GLMMs) typically employed for clustered endpoints have challenges for some scenarios, particularly for complex datasets which contain many interactions among predictors and nonlinear predictors of outcome. We propose a new method called Binary Mixed Model (BiMM) forest, which combines random forest and GLMM methodology. BiMM forest offers a flexible and stable method which naturally models interactions among predictors and can be employed in the setting of clustered data. Simulation studies show that BiMM forest achieves similar or superior prediction accuracy compared to standard random forest, GLMMs and its tree counterpart (BiMM tree) for clustered binary outcomes. The method is applied to a real dataset from the Acute Liver Failure Study Group. BiMM forest offers an alternative method for modeling clustered binary outcomes which may be applied in myriad research settings.

Background: The Fibrosis-4 Index (FIB-4) non-invasively assesses fibrosis risk in chronic liver disease, but underdiagnosis limits FIB-4’s application in primary care. This study evaluates the association of FIB-4 risk with severe liver outcomes in primary care patients with and without diagnosed chronic liver disease. Methods: This retrospective cohort study of primary care data from 2007 to 2018 Included adult patients with qualifying aminotransferase and platelet count results. A single FIB-4 score was calculated for each patient using the first of these values. Patients with a chronic liver disease diagnosis or outcome prior to their FIB-4 score were excluded. FIB-4 advanced fibrosis risk categorization (low, indeterminate, and high) was the primary predictor variable. Patients were followed from FIB-4 score to a severe liver outcome, a composite of cirrhosis, liver transplantation, and hepatocellular carcinoma. We analyzed the association of FIB-4 with hazard risk of a severe liver outcome using stratified Cox regression models, stratifying patients by known chronic liver disease. Findings: 20,556 patients were followed for a mean 2,978 days (8·2 years; SD 1,201 days), and 4% of patients experienced a severe liver outcome. Of patients with low, indeterminate, and high risk FIB-4 scores, 2%, 4%, and 20% suffered a severe liver outcome, respectively. In the overall adjusted model, high risk FIB-4 scores were associated with hazard of severe liver disease (HR 6·54; 95% CI 5·49-7·77). High risk FIB-4 scores were associated with severe liver outcomes for patients with known NAFLD (HR 7·71; 95% CI 3·62-16·45), other liver disease (HR 11·12; 95% CI 8·33-14·82), and no known chronic liver disease (HR 4·04; 95% CI 3·10-5·28). Interpretation: High risk FIB-4 scores were strongly associated with risk of severe liver outcomes in patients with and without known chronic liver disease. Comprehensive FIB-4 application in primary care may signal silently advancing liver fibrosis. Funding Information: National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDKK23DK118200 PI: Schreiner). Declaration of Interests: All authors report no conflicts of interest with this work. Ethics Approval Statement: The Institutional Review Board at the Medical University of South Carolina (MUSC) approved this study.

Clustered binary outcomes are frequently encountered in clinical research (e.g. longitudinal studies). Generalized linear mixed models (GLMMs) for clustered endpoints have challenges for some scenarios (e.g. data with multi-way interactions and nonlinear predictors unknown a priori). We develop an alternative, data-driven method called Binary Mixed Model (BiMM) tree, which combines decision tree and GLMM within a unified framework. Simulation studies show that BiMM tree achieves slightly higher or similar accuracy compared to standard methods. The method is applied to a real dataset from the Acute Liver Failure Study Group.

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] μg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting.OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).

Background & Aims: Acetaminophen-related acute liver injury and liver failure (ALF) result from ingestion of supratherapeutic quantities of this analgesic, frequently in association with other forms of substance abuse including alcohol, opioids, and cocaine. Thus, overdosing represents a unique high-risk behavior associated with other forms of drug use disorder. Methods: We examined a series of 21 single nucleotide polymorphisms (SNPs) in 9 genes related to impulsivity and/or stress responsivity that may modify response to stress. Study subjects were 229 white patients admitted to tertiary care liver centers for ALF that was determined to be due to acetaminophen toxicity after careful review of historical and biochemical data. Identification of relevant SNPs used Sanger sequencing, TaqMan, or custom microarray. Association tests were carried out to compare genotype frequencies between patients and healthy white controls. Results: The mean age was 37 years, and 75.6% were female, with similar numbers classified as intentional overdose or unintentional (without suicidal intent, occurring for a period of several days, usually due to pain). There was concomitant alcohol abuse in 30%, opioid use in 33.6%, and use of other drugs of abuse in 30.6%. The genotype frequencies of 2 SNPs were found to be significantly different between the cases and controls, specifically SNP rs2282018 in the arginine vasopressin gene (AVP, odds ratio 1.64) and SNP rs11174811 in the AVP receptor 1A gene (AVPR1A, odds ratio 1.89), both of which have been previously linked to a drug use disorder diagnosis. Conclusions: Patients who develop acetaminophen-related ALF have increased frequency of gene variants that may cause altered stress responsivity, which has been shown to be associated with other unrelated substance use disorders. Keywords: Impulsivity, Stress Responsivity, Pituitary-Adrenal Axis, Overdose

Identification in econometric models maps prior assumptions and the data to information about a parameter of interest. However, there are two important features characterize duration data. The first feature is that the data may be censored, and the second characteristic of duration data is that exogenous determinants of the event times characterizing the data may change during the event spell. The two features induce some well-known identification issues for the duration models. Following the recent literature in partial identification, we provide the conditions when the duration models could be identified and provide several suggestions for the confidence bounds of partial identifications.

The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar-arterial oxygen gradient (AaPO2 ) at 3 months in patients with HPS. We performed a randomized, double-blind, placebo-controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, -3.8 to 7.0 mm Hg) and those allocated to placebo (-2.4 mm Hg; IQR, -4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2-expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.

We present occurrence rates for rocky planets in the habitable zones (HZ) of main-sequence dwarf stars based on the Kepler DR25 planet candidate catalog and Gaia-based stellar properties. We provide the first analysis in terms of star-dependent instellation flux, which allows us to track HZ planets. We define $\eta_\oplus$ as the HZ occurrence of planets with radius between 0.5 and 1.5 $R_\oplus$ orbiting stars with effective temperatures between 4800 K and 6300 K. We find that $\eta_\oplus$ for the conservative HZ is between $0.37^{+0.48}_{-0.21}$ (errors reflect 68\% credible intervals) and $0.60^{+0.90}_{-0.36}$ planets per star, while the optimistic HZ occurrence is between $0.58^{+0.73}_{-0.33}$ and $0.88^{+1.28}_{-0.51}$ planets per star. These bounds reflect two extreme assumptions about the extrapolation of completeness beyond orbital periods where DR25 completeness data are available. The large uncertainties are due to the small number of detected small HZ planets. We find similar occurrence rates using both a Poisson likelihood Bayesian analysis and Approximate Bayesian Computation. Our results are corrected for catalog completeness and reliability. Both completeness and the planet occurrence rate are dependent on stellar effective temperature. We also present occurrence rates for various stellar populations and planet size ranges. We estimate with $95\%$ confidence that, on average, the nearest HZ planet around G and K dwarfs is about 6 pc away, and there are about 4 HZ rocky planets around G and K dwarfs within 10 pc of the Sun., Comment: To appear in The Astronomical Journal

NASA's Kepler Mission (Fig. 1) has been wildly successful in discovering exoplanets. This paper summarizes the mission goals, briefly explains the transit method of finding exoplanets and design of the mission, provides some key findings, and describes useful education materials available at the Kepler website.

Gastric antral vascular ectasia (GAVE) commonly presents as linear striped (“watermelon stomach”) or punctate phenotypes, to which a newly discovered nodular form was recently added. We performed a retrospective cohort study to detail and compare the clinical and histological characteristics of major GAVE phenotypes. In 136 GAVE patients (tertiary care ambulatory and inpatient, median age 61.3 years, 73 men, and 63 women), clinical and laboratory results were recorded, with comorbidities, endoscopy indications, and complications of cirrhosis. In 74 patients, GAVE histopathology was cataloged by a pathologist masked to endoscopy results. Median age 61.3 years, 73 men, and 63 women. GAVE phenotypes were: linear striped—62 (46%), punctate—32 (24%), and nodular—41 (30%). Endoscopy was commonly performed for variceal screening in linear striped (45%) and nodular (34%) GAVE and for gastrointestinal bleeding in punctate (41%) and nodular (29%) GAVE, respectively. Of 89 cirrhotic patients, 37.5% each had linear striped or nodular GAVE, 24.7% had punctate forms (p = 0.03). Child–Turcotte–Pugh and Model for End-Stage Liver Disease scores were similar among phenotypes. Histologically, reactive epithelial hyperplasia and vascular ectasia were universal; smooth muscle proliferation was more common and consistent (78–86%) than microvascular thrombi (27–59%) and fibrohyalinosis (18–53%), which each varied with phenotype. Nodular GAVE is a gastric mucosal abnormality that is similar to the linear striped and punctate phenotypes, yet has distinct clinical and histological features. Increased awareness of nodular GAVE by endoscopists is needed to avoid its misdiagnosis as nonspecific antral nodules.

The most critical factor in econometric estimations is parameter identification. Identification in econometric models formalizes prior assumptions and the data to information about a parameter of interest. However, there are two important features characterize duration data. The first one is that the data may be censored, and the second feature of duration data is that exogenous determinants of the event times characterizing the data may change during the event spell. The two characteristics lead some famous identification problems for the duration models. Following the recent literature in partial identification, we show the conditions when the duration models could be identified and provide several suggestions for the confidence bounds of partial identifications.

Context Little systematic research has been conducted to understand pain among persons with end-stage liver disease, especially among liver transplant candidates. Appropriate pain assessment and management are important areas of consideration as treatment options are limited. Objective To describe the nature of chronic pain in patients with end-stage liver disease, the extent to which pain affects daily level of functioning, and the variety and effectiveness of current treatments. Design Retrospective chart review. Setting Academic medical center in the Southeastern United States. Patients Data were collected from 108 consecutive adult liver transplant candidates. Results Most (77%) reported having experienced moderate levels of bodily pain within the past 24 hours. Patients with only alcoholic cirrhosis reported less pain than patients with cirrhosis due to other causes (alcoholism and hepatitis C, nonalcoholic steatohepatitis, only hepatitis C). Pain interfered significantly across all 10 functional domains assessed. Although 90% reported being prescribed a variety of analgesic agents (most commonly short-acting opioids), patients reported experiencing only 33% pain relief. Conclusions Pain is a significant problem among liver transplant candidates, and current pain treatments are perceived to be relatively ineffective. Increased understanding is needed to safely and effectively evaluate and treat such medically complicated patients.

Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death.386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure.Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death.A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Purpose of review This article discusses the most recent studies regarding the management of gastric varices. Recent findings New case series and meta-analyses have increased our understanding of the endoscopic and endovascular treatment options for patients with gastric varices, including the use of cyanoacrylates, the potential increased utility of endoscopic ultrasound over conventional endoscopy and the emerging role of balloon-occluded retrograde transvenous obliteration. Summary The management of gastric varices remains poorly defined. However, our increasing experience with endoscopic and endovascular treatment methods provides clinicians with therapeutic options to better manage this patient population.

We present a method to confirm the planetary nature of objects in systems with multiple transiting exoplanet candidates. This method involves a Fourier-Domain analysis of the deviations in the transit times from a constant period that result from dynamical interactions within the system. The combination of observed anti-correlations in the transit times and mass constraints from dynamical stability allow us to claim the discovery of four planetary systems Kepler-25, Kepler-26, Kepler-27, and Kepler-28, containing eight planets and one additional planet candidate.

Most Sun-like stars in the Galaxy reside in gravitationally bound pairs of stars (binaries). Although long anticipated, the existence of a 'circumbinary planet' orbiting such a pair of normal stars was not definitively established until the discovery of the planet transiting (that is, passing in front of) Kepler-16. Questions remained, however, about the prevalence of circumbinary planets and their range of orbital and physical properties. Here we report two additional transiting circumbinary planets: Kepler-34 (AB)b and Kepler-35 (AB)b, referred to here as Kepler-34 b and Kepler-35 b, respectively. Each is a low-density gas-giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 b orbits two Sun-like stars every 289 days, whereas Kepler-35 b orbits a pair of smaller stars (89% and 81% of the Sun's mass) every 131 days. The planets experience large multi-periodic variations in incident stellar radiation arising from the orbital motion of the stars. The observed rate of circumbinary planets in our sample implies that more than ∼1% of close binary stars have giant planets in nearly coplanar orbits, yielding a Galactic population of at least several million.

The Kepler spacecraft has been monitoring the light from 150,000 stars in its primary quest to detect transiting exoplanets. Here we report on the detection of an eclipsing stellar hierarchical triple, identified in the Kepler photometry. KOI-126 (A,(B, C)), is composed of a low-mass binary (masses M_B = 0.2413+/-0.0030 M_Sun, M_C = 0.2127+/-0.0026 M_Sun; radii R_B = 0.2543+/-0.0014 R_Sun, R_C = 0.2318+/-0.0013 R_Sun; orbital period P_1 = 1.76713+/-0.00019 days) on an eccentric orbit about a third star (mass M_A = 1.347+/-0.032 M_Sun; radius R_A = 2.0254+/-0.0098 R_Sun; period of orbit around the low-mass binary P_2 = 33.9214+/-0.0013 days; eccentricity of that orbit e_2 = 0.3043+/-0.0024). The low-mass pair probe the poorly sampled fully-convective stellar domain offering a crucial benchmark for theoretical stellar models., Comment: To be published in Science on 2/4/2011. Announced at Jan. 2011 AAS meeting and made available on Science Express. Includes Supporting Online Material

Through the observational study of stellar pulsations, the internal structure of stars can be probed and theoretical models can be tested. The main sequence -γ Doradus (Dor) and δ Scuti (Sct) stars with masses 1.2–2.5 M⊙ are particularly interesting for asteroseismic study. The -γ Dor stars pulsate in high-order gravity (g) modes, with pulsational periods of order of one day. The δ Sct stars, on the other hand, show low-order g and pressure (p) modes with periods of order of 2 hours. Theory predicts the existence of ‘hybrid’ stars, i.e. stars pulsating in both types of modes, in an overlap region between the instability strips of -γ Dor and δ Sct stars in the Hertzsprung-Russell diagram. Hybrid stars are particularly interesting as the two types of modes probe different regions of the stellar interior and hence provide complementary model constraints. Before the advent of Kepler, only a few hybrid stars had been confirmed. The Kepler satellite is providing a true revolution in the study of and search for hybrid stars. Analysis of the first 50 days of Kepler data of hundreds of -γ Dor and δ Sct candidates reveals extremely rich frequency spectra, with most stars showing frequencies in both the δ Sct and -γ Dor frequency range. As these results show that there are practically no pure δ Sct or -γ Dor pulsators, a new observational classification scheme is proposed by Grigahcene et al. (2010). We present their results and characterize 234 stars in terms of δ Sct, -γ Dor, δ Sct/-γ Dor or -γ Dor/δ Sct hybrids (© 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Kepler is a NASA mission designed to detect exoplanets and characterize the properties of exoplanetary systems. Kepler also includes an asteroseismic programme which is being conducted through the Kepler Asteroseismic Science Consortium (KASC), whose 400 members are organized into 13 working groups by type of variable star. So far data have been available from the first 7 month of the mission containing a total of 2937 targets observed at a 1-min. cadence for periods between 10 days and 7 months. The goals of the asteroseismic part of the Kepler project is to perform detailed studies of stellar interiors. The first results of the asteroseismic analysis are orders of magnitude better than seen before, and this bodes well for how the future analysis of Kepler data for many types of stars will impact our general understanding of stellar structure and evolution., Proc. HELAS IV Conference, Lanzarote, January 2010. Eds T. Roca Cort\'es, P. Pall\'e and S. Jim\'enez Reyes. To appear in Astron. Nachr

We report spectroscopic observations for 19 $\delta$\,Sct candidates observed by the {\it Kepler} satellite both in long and short cadence mode. For all these stars, by using spectral synthesis, we derive the effective temperature, the surface gravity and the projected rotational velocity. An equivalent spectral type classification has been also performed for all stars in the sample. These determinations are fundamental for modelling the frequency spectra that will be extracted from the {\it Kepler} data for asteroseismic inference. For all the 19 stars, we present also periodograms obtained from {\it Kepler} data. We find that all stars show peaks in both low- ($\gamma$\,Dor; g mode) and high-frequency ($\delta$\,Sct; p mode) regions. Using the amplitudes and considering 5\,c/d as a boundary frequency, we classified 3 stars as pure $\gamma$\,Dor, 4 as $\gamma$\,Dor\,-\,$\delta$\ hybrid, Sct, 5 as $\delta$\,Sct\,-\,$\gamma$\,Dor hybrid, and 6 as pure $\delta$\,Sct. The only exception is the star KIC\,05296877 which we suggest could be a binary.

We present the discovery of nonradial pulsations in a hot subdwarf B star based on 30.5 days of nearly continuous time-series photometry using the \emph{Kepler} spacecraft. KIC 010139564 is found to be a short-period pulsator of the V361 Hya (EC 14026) class with more than 10 independent pulsation modes whose periods range from 130 to 190 seconds. It also shows one periodicity at a period of 3165 seconds. If this periodicity is a high order g-mode, then this star may be the hottest member of the hybrid DW Lyn stars. In addition to the resolved pulsation frequencies, additional periodic variations in the light curve suggest that a significant number of additional pulsation frequencies may be present. The long duration of the run, the extremely high duty cycle, and the well-behaved noise properties allow us to explore the stability of the periodic variations, and to place strong constraints on how many of them are independent stellar oscillation modes. We find that most of the identified periodicities are indeed stable in phase and amplitude, suggesting a rotation period of 2-3 weeks for this star, but further observations are needed to confirm this suspicion.

We present the discovery of nonradial pulsations in five hot subdwarf B (sdB) stars based on 27 days of nearly continuous time-series photometry using the Kepler spacecraft. We find that every sdB star cooler than $\approx 27\,500\,$K that Kepler has observed (seven so far) is a long-period pulsator of the V1093~Her (PG~1716) class or a hybrid star with both short and long periods. The apparently non-binary long-period and hybrid pulsators are described here. The V1093~Her periods range from one to 4.5~h and are associated with $g-$mode pulsations. Three stars also exhibit short periods indicative of $p-$modes with periods of 2 to 5~m and in addition, these stars exhibit periodicities between both classes from 15 to 45~m. We detect the coolest and longest-period V1093~Her-type pulsator to date, KIC010670103 ($T_eff\approx 20\,900\,$K, $P_max\approx 4.5$~h) as well as a suspected hybrid pulsator, KIC002697388 which is extremely cool ($T_{\rm eff}\approx 23\,900\,$K) and for the first time hybrid pulsators which have larger $g-$mode amplitudes than $p-$mode ones. All of these pulsators are quite rich with many frequencies and we are able to apply asymptotic relationships to associate periodicities with modes for KIC010670103. Kepler data are particularly well-suited for these studies as they are long-duration, extremely high duty cycle observations with well-behaved noise properties.

The survey phase of the Kepler Mission includes a number of hot subdwarf B (sdB) stars to search for nonradial pulsations. We present our analysis of two sdB stars that are found to be g-mode pulsators of the V1093 Her class. These two stars also display the distinct irradiation effect typical of sdB stars with a close M-dwarf companion with orbital periods of less than half a day. Because the orbital period is so short, the stars should be in synchronous rotation, and if so, the rotation period should imprint itself on the multiplet structure of the pulsations. However, we do not find clear evidence for such rotational splitting. Though the stars do show some frequency spacings that are consistent with synchronous rotation, they also display multiplets with splittings that are much smaller. Longer-duration time series photometry will be needed to determine if those small splittings are in fact rotational splitting, or caused by slow amplitude or phase modulation. Further data should also improve the signal-to-noise, perhaps revealing lower amplitude periodicities that could confirm the expectation of synchronous rotation. The pulsation periods seen in these stars show period spacings that are suggestive of high-overtone g-mode pulsations.

Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overre-presentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End-Stage Liver Disease scores. Conclusion DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival.

During the first 33.5 days of science-mode operation of the Kepler Mission, the stellar flux of 156,000 stars were observed continuously. The data show the presence of more than 1800 eclipsing binary stars, over 700 stars with planetary candidates, and variable stars of amazing variety. Analyses of the commissioning data also show transits, occultations and light emitted from the known exoplanet HAT-P7b. The depth of the occultation is similar in amplitude to that expected from a transiting Earth-size planet and demonstrates that the Mission has the precision necessary to detect such planets. On 15 June 2010, the Kepler Mission released most of the data from the first quarter of observations. At the time of this data release, 706 stars from this first data set have exoplanet candidates with sizes from as small as that of the Earth to larger than that of Jupiter. More than half the candidates on the released list have radii less than half that of Jupiter. Five candidates are present in and near the habitable zone; two near super-Earth size, one similar in size to Neptune, and two bracketing the size of Jupiter. The released data also include five possible multi-planet systems. One of these has two Neptune-size (2.3 and 2.5 Earth-radius) candidates with near-resonant periods as well as a super-Earth-size planet in a very short period orbit.

The first detection of the period doubling phenomenon is reported in the Kepler RR Lyrae stars RR Lyr, V808 Cyg and V355 Lyr. Interestingly, all these pulsating stars show Blazhko modulation. The period doubling manifests itself as alternating maxima and minima of the pulsational cycles in the light curve, as well as through the appearance of half-integer frequencies located halfway between the main pulsation period and its harmonics in the frequency spectrum. The effect was found to be stronger during certain phases of the modulation cycle. We were able to reproduce the period doubling bifurcation in our nonlinear RR Lyrae models computed by the Florida-Budapest hydrocode. This enabled us to trace the origin of this instability in RR Lyrae stars to a resonance, namely a 9:2 resonance between the fundamental mode and a high-order (9th) radial overtone showing strange-mode characteristics. We discuss the connection of this new type of variation to the mysterious Blazhko effect and argue that it may give us fresh insights to solve this century-old enigma.

We present the Kepler Object of Interest (KOI) catalog of transiting exoplanets based on searching four years of Kepler time series photometry (Data Release 25, Q1-Q17). The catalog contains 8054 KOIs of which 4034 are planet candidates with periods between 0.25 and 632 days. Of these candidates, 219 are new and include two in multi-planet systems (KOI-82.06 and KOI-2926.05), and ten high-reliability, terrestrial-size, habitable zone candidates. This catalog was created using a tool called the Robovetter which automatically vets the DR25 Threshold Crossing Events (TCEs, Twicken et al. 2016). The Robovetter also vetted simulated data sets and measured how well it was able to separate TCEs caused by noise from those caused by low signal-to-noise transits. We discusses the Robovetter and the metrics it uses to sort TCEs. For orbital periods less than 100 days the Robovetter completeness (the fraction of simulated transits that are determined to be planet candidates) across all observed stars is greater than 85%. For the same period range, the catalog reliability (the fraction of candidates that are not due to instrumental or stellar noise) is greater than 98%. However, for low signal-to-noise candidates between 200 and 500 days around FGK dwarf stars, the Robovetter is 76.7% complete and the catalog is 50.5% reliable. The KOI catalog, the transit fits and all of the simulated data used to characterize this catalog are available at the NASA Exoplanet Archive., 61 pages, 23 Figures, 9 Tables, Accepted to The Astrophysical Journal Supplement Series

We announce the discovery of Kepler-6b, a transiting hot Jupiter orbiting a star with unusually high metallicity, [Fe/H] = +0.34 +/- 0.04. The planet's mass is about 2/3 that of Jupiter, Mp = 0.67 Mj, and the radius is thirty percent larger than that of Jupiter, Rp = 1.32 Rj, resulting in a density of 0.35 g/cc, a fairly typical value for such a planet. The orbital period is P = 3.235 days. The host star is both more massive than the Sun, Mstar = 1.21 Msun, and larger than the Sun, Rstar = 1.39 Rsun.

Ten days of commissioning data (Quarter 0) and thirty-three days of science data (Quarter 1) yield instrumental flux timeseries of ~150,000 stars that were combed for transit events, termed Threshold Crossing Events (TCE), each having a total detection statistic above 7.1-sigma. TCE light curves are modeled as star+planet systems. Those returning a companion radius smaller than 2R_J are assigned a KOI (Kepler Object of Interest) number. The raw flux, pixel flux, and flux-weighted centroids of every KOI are scrutinized to assess the likelihood of being an astrophysical false-positive versus the likelihood of a being a planetary companion. This vetting using Kepler data is referred to as data validation. Herein, we describe the data validation metrics and graphics used to identify viable planet candidates amongst the KOIs. Light curve modeling tests for a) the difference in depth of the odd- versus even-numbered transits, b) evidence of ellipsoidal variations, and c) evidence of a secondary eclipse event at phase=0.5. Flux-weighted centroids are used to test for signals correlated with transit events with a magnitude and direction indicative of a background eclipsing binary. Centroid timeseries are complimented by analysis of images taken in-transit versus out-of-transit, the difference often revealing the pixel contributing the most to the flux change during transit. Examples are shown to illustrate each test. Candidates passing data validation are submitted to ground-based observers for further false-positive elimination or confirmation/characterization., submitted to Astrophysical Journal Letters

Aims: The goal of this preliminary study was to evaluate the relationship between blood phosphatidylethanol (PEth) and recent drinking in patients with liver disease and hypertension. Methods: Twenty-one patients with liver disease and 21 patients with essential hypertension were recruited at an academic medical center. Alcohol consumption was estimated using validated self-report methods, and blood PEth was measured by HPLC-MS/MS at a contracted laboratory. Nonparametric comparisons were made between abstainers/light drinkers, moderate drinkers consuming between 1 and 3 drinks per day, and those drinking above this level. Regression methods were used to estimate the effects of liver disease, gender, and age on the relationship between PEth and alcohol use, and to estimate the strength of the linear relationship between PEth and drinking. Results: PEth differed significantly between the three drinking groups ( P < 0.001). The relationship between PEth and alcohol did not differ between hypertension and liver disease patients ( P = 0.696), nor by gender and age. While there was substantial variability between subjects in the PEth concentration given a similar level of reported drinking, the amount of ethanol consumed was strongly associated with the PEth concentration ( P < 0.001). Conclusion: Results support PEth measurement by HPLC-MS/MS as a promising marker of past 1- to 2-week moderate to heavy alcohol consumption in patients with and without liver disease. PEth appears useful for differentiating abstinence or light drinking from moderate to heavy consumption, but may have limited utility for differentiating moderate from heavy alcohol use.

TheKepler Missionis a space-based mission whose primary goal is to determine the frequency of Earth-size and larger planets in the habitable zone of solar-like stars. The mission will monitor more than 100,000 stars for patterns of transits with a differential photometric precision of 20 ppm at V = 12 for a 6.5 hour transit. It will also provide asteroseismic results on several thousand dwarf stars. It is specifically designed to continuously observe a single field of view of greater than 100 square degrees for 3.5 or more years.This paper provides a short overview of the mission, a brief history of the mission development, expected results, new investigations by the recently chosen Participating Scientists, and the plans for the Guest Observer and Astrophysical Data Programs.

TheKepler Missionis a space-based mission whose primary goal is to detect Earth-size and smaller planets in the habitable zone of solar-like stars. The mission will monitor more than 100,000 stars for transits with a differential photometric precision of 20 ppm at V=12 for a 6.5 hour transit. It will also provide asteroseismic results on several thousand dwarf stars. It is specifically designed to continuously observe a single field of view of greater than 100 square degrees for 3.5 or more years.This overview describes the mission design, its goals and capabilities, the measured performance for those photometer components that have now been tested, the Kepler Input Catalog, an overview of the analysis pipeline, the plans for the Follow-up Observing Program to validate the detections and characterize the parent stars, and finally, the plans for the Guest Observer and Astrophysical Data Program.

Variceal hemorrhage (VH) is a lethal complication of portal hypertension. Aspiration occurring during endoscopic intervention for acute VH is a concern; however, few data exist regarding the efficacy of prophylactic intubation to prevent aspiration pneumonia. We reviewed all endoscopic procedures for acute VH from January 1995 to December 2002; only patients with the absence of hepatic encephalopathy greater than stage II and normal chest x-ray at admission were included. The use of prophylactic intubation, post-procedure chest x-ray, and mortality were recorded. Sixty-two patients (69 bleeding episodes) were identified. Elective intubation was performed in 42 patients (47 episodes); pulmonary infiltrates developed in 7 of 42 (17%), with an overall mortality rate of 9 of 42 (21%). Twenty patients (22 episodes) were not intubated. None developed pulmonary infiltrates, and the overall mortality rate was 1 in 20 (5%). We conclude that in patients with suspected variceal bleeding, elective intubation is associated with a substantial risk of aspiration pneumonia.

The Kepler Mission is a photometric space mission that will continuously observe a single 100 square degree field of view (FOV) of the sky of more than 100,000 stars in the Cygnus-Lyra region for four or more years with a precision of 14 parts per million (ppm) for a 6.5 hour integration including shot noise for a twelfth magnitude star. The primary goal of the mission is to detect Earth-size planets in the habitable zone of solar-like stars. In the process, many eclipsing binaries (EB) will also be detected. Prior to launch, the stellar characteristics will have been determined for all the stars in the FOV with K < 14.5. As part of the verification process, stars with transits (about 5%) will need to have follow-up radial velocity observations performed to determine the component masses and thereby separate grazing eclipses caused by stellar companions from transits caused by planets. The result will be a rich database on EBs. The community will have access to the archive for uses such as for EB modeling of the high-precision light curves. A guest observer program is also planned for objects not already on the target list.

The Kepler Mission is a NASA Discovery mission which will continuously monitor the brightness of at least 100,000 main sequence stars, to detect the transits of terrestrial and larger planets. It is scheduled to be launched in 2007 into an Earth-trailing heliocentric orbit. It is a wide-field photometer with a Schmidt-type telescope and array of 42 CCDs covering the 100 square degree field-of-view. It has a 1-m aperture which enables a differential photometric precision of 2 parts in 100,000 for 12th magnitude solar-like stars over a 6.5-hour transit duration. It will continuously observe dwarf stars from 8th to 15th magnitude in the Cygnus constellation, for a period of four years, with a cadence of 4 measurements per hour. Hundreds of terrestrial planets should be detected if they are common around solar-type stars. Ground-based spectrometry of stars with planetary candidates will help eliminate false-positives, and determine stellar characteristics such as mass and metallicity. A null result would imply that terrestrial planets are rare.

To better understand the dynamics of early hepatitis C virus (HCV) infection, we determined how rapidly non-cirrhotic HCV-uninfected liver allografts clear HCV from the circulation of cirrhotic HCV-infected patients at the time of transplantation but before administration of immunosuppression. Specifically, we characterized serum HCV kinetics during the first 90 min of reperfusion for 19 chronically HCV-infected patients transplanted with an HCV-uninfected liver by measuring serum viral load immediately prior to reperfusion (t = 0) and then every 15 min for a total of 90 min (t = 90). Immunosuppression was withheld until all samples were taken to better model primary infection. During this period, rates of viral clearance varied more than 20-fold with a median rate constant of 0.0357 1/min, range 0.0089–0.2169; half-life (minutes) median 19.4, range 3.2–77.8. The majority of viral clearance occurred within the first 60 min. The amount of blood transfused during this 90-min period (a potential confounding variable of this human liver transplant model of primary infection) accounted for 53% and 59% of k (r = 0.53, p = 0.05) and half-life (r = 0.59, p = 0.03) variability, respectively. No other clinical variables tested (age, allograft weight, and degree of reperfusion injury as assessed by peak postoperative ALT or AST) accounted for the remaining variability (p>0.05). Conclusion: In a human liver transplant model of primary infection, HCV rapidly clears the bloodstream. With approximately 90% of clearance occurring in the first 90 minutes of reperfusion, studies of HCV entry inhibition could utilize rate of clearance during this early period as an outcome measure.

Left ventricular dysfunction resulting in cardiogenic shock occurs infrequently following organ reperfusion in liver transplantation. The etiology of the cardiogenic shock is often multifactorial and difficult to manage due to the complex nature of the procedure and the patient's baseline physiology. Traditionally, this hemodynamic instability is managed medically using inotropic agents and vasopressor support. If medical treatment is insufficient, the use of an intra-aortic balloon pump for counterpulsation may be employed to improve the hemodynamics and stabilize the patient. Here, we analyze three cases and review the literature.