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 overrepresentation 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. (HEPATOLOGY 2010)
Over the past three decades a new spectroscopic technique with unique possibilities has emerged. Based on coherent and time‐resolved detection of the electric field of ultrashort radiation bursts in ...the far‐infrared, this technique has become known as terahertz time‐domain spectroscopy (THz‐TDS). In this review article the authors describe the technique in its various implementations for static and time‐resolved spectroscopy, and illustrate the performance of the technique with recent examples from solid‐state physics and physical chemistry as well as aqueous chemistry. Examples from other fields of research, where THz spectroscopic techniques have proven to be useful research tools, and the potential for industrial applications of THz spectroscopic and imaging techniques are discussed.
During previous decades a new spectroscopic technique with unique possibilities has emerged. Based on coherent and time‐resolved detection of the electric field of ultrashort radiation bursts in the far‐infrared, this technique has become known as terahertz time‐domain spectroscopy (THz‐TDS). In this review, the technique is described in its various implementations for static and time‐resolved spectroscopy. It performance is illustrated the with recent examples from solid‐state physics and physical chemistry as well as aqueous chemistry.
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that ...activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.
Patients with acute liver failure (ALF) have a high risk of death that can be substantially reduced with liver transplantation. It is a challenge to predict which patients with ALF will survive ...without liver transplant because available prognostic scoring systems are inadequate. We devised a mathematical model, using a large dataset collected by the Acute Liver Failure Study Group, which can predict transplant-free survival in patients with ALF.
We performed a retrospective analysis of data from 1974 subjects who met criteria for ALF (coagulopathy and hepatic encephalopathy within 26 weeks of the first symptoms, without pre-existing liver disease) enrolled in the Acute Liver Failure Study Group database from January 1, 1998 through June 11, 2013. We randomly assigned the subjects to development and validation cohorts. Data from the development cohort were analyzed to identify factors associated with transplant-free survival (alive without transplantation by 21 days after admission to the study). Statistically significant variables were used to create a multivariable logistic regression model.
Most subjects were women (70%) and white (78%); acetaminophen overdose was the most common cause (48% of subjects). The rate of transplant-free survival was 50%. Admission values of hepatic encephalopathy grade, ALF etiology, vasopressor use, and log transformations of bilirubin and international normalized ratio were significantly associated with transplant-free survival, based on logistic regression analysis. In the validation cohort, the resulting model predicted transplant-free survival with a C statistic value of 0.84, 66.3% accuracy (95% confidence interval, 63.1%-69.4%), 37.1% sensitivity (95% confidence interval, 32.5%-41.8%), and 95.3% specificity (95% confidence interval, 92.9%-97.1%).
Using data from the Acute Liver Failure Study Group, we developed a model that predicts transplant-free survival of patients with ALF based on easily identifiable hospital admission data. External validation studies are required.
We present a statistical analysis that demonstrates that the overwhelming majority of Kepler candidate multiple transiting systems (multis) indeed represent true, physically associated transiting ...planets. Binary stars provide the primary source of false positives among Kepler planet candidates, implying that false positives should be nearly randomly distributed among Kepler targets. In contrast, true transiting planets would appear clustered around a smaller number of Kepler targets if detectable planets tend to come in systems and/or if the orbital planes of planets encircling the same star are correlated. There are more than one hundred times as many Kepler planet candidates in multi-candidate systems as would be predicted from a random distribution of candidates, implying that the vast majority are true planets. Most of these multis are multiple-planet systems orbiting the Kepler target star, but there are likely cases where (1) the planetary system orbits a fainter star, and the planets are thus significantly larger than has been estimated, or (2) the planets orbit different stars within a binary/multiple star system. We use the low overall false-positive rate among Kepler multis, together with analysis of Kepler spacecraft and ground-based data, to validate the closely packed Kepler-33 planetary system, which orbits a star that has evolved somewhat off of the main sequence. Kepler-33 hosts five transiting planets, with periods ranging from 5.67 to 41 days.
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.
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.
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.
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.
We report the distribution of planets as a function of planet radius, orbital period, and stellar effective temperature for orbital periods less than 50 days around solar-type (GK) stars. These ...results are based on the 1235 planets (formally "planet candidates") from the Kepler mission that include a nearly complete set of detected planets as small as 2 R. For all planets with orbital periods less than 50 days, we measure occurrence of 0.130 + or - 0.008, 0.023 + or - 0.003, and 0.013 + or - 0.002 planets per star for planets with radii 2-4, 4-8, and 8-32 R, in agreement with Doppler surveys. We fit occurrence as a function of P to a power-law model with an exponential cutoff below a critical period Psub 0. For smaller planets, Psub 0 has larger values, suggesting that the "parking distance" for migrating planets moves outward with decreasing planet size.
Light curves from the Kepler Mission contain valuable information on the nature of the phenomena producing the transit-like signals. To assist in exploring the possibility that they are due to an ...astrophysical false positive, we describe a procedure (BLENDER) to model the photometry in terms of a 'blend' rather than a planet orbiting a star. A blend may consist of a background or foreground eclipsing binary (or star-planet pair) whose eclipses are attenuated by the light of the candidate and possibly other stars within the photometric aperture. We apply BLENDER to the case of Kepler-9 (KIC 3323887), a target harboring two previously confirmed Saturn-size planets (Kepler-9 b and Kepler-9 c) showing transit timing variations, and an additional shallower signal with a 1.59 day period suggesting the presence of a super-Earth-size planet. Using BLENDER together with constraints from other follow-up observations we are able to rule out all blends for the two deeper signals and provide independent validation of their planetary nature. For the shallower signal, we rule out a large fraction of the false positives that might mimic the transits. The false alarm rate for remaining blends depends in part (and inversely) on the unknown frequency of small-size planets. Based on several realistic estimates of this frequency, we conclude with very high confidence that this small signal is due to a super-Earth-size planet (Kepler-9 d) in a multiple system, rather than a false positive. The radius is determined to be 1.64+0.19 --0.14 R {circled plus}, and current spectroscopic observations are as yet insufficient to establish its mass.
About one-third of the ~1200 transiting planet candidates detected in the first four months of Kepler data are members of multiple candidate systems. There are 115 target stars with two candidate ...transiting planets, 45 with three, 8 with four, and 1 each with five and six. We characterize the dynamical properties of these candidate multi-planet systems. The distribution of observed period ratios shows that the vast majority of candidate pairs are neither in nor near low-order mean-motion resonances. Nonetheless, there are small but statistically significant excesses of candidate pairs both in resonance and spaced slightly too far apart to be in resonance, particularly near the 2:1 resonance. We find that virtually all candidate systems are stable, as tested by numerical integrations that assume a nominal mass-radius relationship. Several considerations strongly suggest that the vast majority of these multi-candidate systems are true planetary systems. Using the observed multiplicity frequencies, we find that a single population of planetary systems that matches the higher multiplicities underpredicts the number of singly transiting systems. We provide constraints on the true multiplicity and mutual inclination distribution of the multi-candidate systems, revealing a population of systems with multiple super-Earth-size and Neptune-size planets with low to moderate mutual inclinations.
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