Background and Aims
Direct oral anticoagulants (DOAC) are important new anticoagulant therapies that are not well studied in patients with chronic liver disease. The aim of this study was to compare ...rates of bleeding in cirrhosis patients treated with DOAC (factor Xa inhibitors: rivaroxaban and apixaban) to those in cirrhosis patients treated with traditional anticoagulation (warfarin and low molecular weight heparin).
Methods
We identified a total of 39 patients with cirrhosis who received anticoagulation therapy over a 3-year period (20 DOAC and 19 traditional anticoagulation) from a research database. Medical records were reviewed to obtain clinical data to compare between the groups.
Results
Clinical characteristics between the two groups were similar. There were three documented bleeding events in the traditional anticoagulation group and four bleeding events in the DOAC group (
p
= 0.9). There were two major bleeding events in the traditional anticoagulation group and one major bleeding event in the DOAC group. There were no documented reports of drug-induced liver injury during this study period. Among all patients, no significant predictors of bleeding were identified using univariate regression and Cox proportional hazard modeling.
Conclusions
This is the first clinical study evaluating the use of DOAC in patients with cirrhosis. DOAC display similar safety characteristics when compared to traditional anticoagulation in patients with cirrhosis and are potentially attractive agents for anticoagulation therapy. Larger studies are now needed to better understand the safety and efficacy of these agents in cirrhosis.
The most recent ice age was characterized by rapid and hemispherically asynchronous climate oscillations, whose origin remains unresolved. Variations in oceanic meridional heat transport may ...contribute to these repeated climate changes, which were most pronounced during marine isotope stage 3, the glacial interval 25 thousand to 60 thousand years ago. We examined climate and ocean circulation proxies throughout this interval at high resolution in a deep North Atlantic sediment core, combining the kinematic tracer protactinium/thorium (Pa/Th) with the deep water-mass tracer, epibenthic δ¹³C. These indicators suggest reduced Atlantic overturning circulation during every cool northern stadial, with the greatest reductions during episodic Hudson Strait iceberg discharges, while sharp northern warming followed reinvigorated overturning. These results provide direct evidence for the ocean's persistent, central role in abrupt glacial climate change.
We present 16 new ultrabright HAB 25 galaxy candidates at z ∼ 8 identified over the COSMOS/UltraVISTA field. The new search takes advantage of the deepest-available ground-based optical and ...near-infrared observations, including the DR3 release of UltraVISTA and full-depth Spitzer/IRAC observations from the SMUVS and SPLASH programs. Candidates are selected using Lyman-break color criteria, combined with strict optical non-detection and SED-fitting criteria, designed to minimize contamination by low-redshift galaxies and low-mass stars. HST/WFC3 coverage from the DASH program reveals that one source evident in our ground-based near-IR data has significant substructure and may actually correspond to 3 separate z ∼ 8 objects, resulting in a total sample of 18 galaxies, 10 of which seem to be fairly robust (with a >97% probability of being at z > 7). The UV-continuum slope β for the bright z ∼ 8 sample is β = −2.2 0.6, bluer but still consistent with that of similarly bright galaxies at z ∼ 6 (β = −1.55 0.17) and z ∼ 7 (β = −1.75 0.18). Their typical stellar masses are M , with the SFRs of yr−1, specific SFR of Gyr−1, stellar ages of Myr, and low dust content mag. Using this sample we constrain the bright end of the z ∼ 8 UV luminosity function. When combined with recent empty field luminosity function estimates at similar redshifts, the resulting z ∼ 8 luminosity function can be equally well represented by either a Schechter or a double-power-law form. Assuming a Schechter parameterization, the best-fit characteristic magnitude is mag with a very steep faint-end slope . These new candidates include some of the brightest objects found at these redshifts, 0.5-1.0 magnitude brighter than those found over CANDELS, and providing excellent targets for spectroscopic and longer-wavelength follow-up studies.
ABSTRACT We present a robust measurement and analysis of the rest-frame ultraviolet (UV) luminosity functions at z = 4-8. We use deep Hubble Space Telescope imaging over the Cosmic Assembly ...Near-infrared Deep Extragalactic Legacy Survey/GOODS fields, the Hubble Ultra Deep Field, and the Hubble Frontier Field deep parallel observations near the Abell 2744 and MACS J0416.1-2403 clusters. The combination of these surveys provides an effective volume of 0.6-1.2 × 106 Mpc3 over this epoch, allowing us to perform a robust search for faint 18) and bright (M 21) high-redshift galaxies. We select candidate galaxies using a well-tested photometric redshift technique with careful screening of contaminants, finding a sample of 7446 candidate galaxies at 3.5 8.5, with >1000 galaxies at 6-8. We measure both a stepwise luminosity function for candidate galaxies in our redshift samples, and a Schechter function, using a Markov Chain Monte Carlo analysis to measure robust uncertainties. At the faint end, our UV luminosity functions agree with previous studies, yet we find a higher abundance of UV-bright candidate galaxies at 6. Our best-fit value of the characteristic magnitude is consistent with −21 at 5, which is different than that inferred based on previous trends at lower redshift, and brighter at ∼2 significance than previous measures at z = 6 and 7. At z = 8, a single power law provides an equally good fit to the UV luminosity function, while at z = 6 and 7 an exponential cutoff at the bright end is moderately preferred. We compare our luminosity functions to semi-analytical models, and find that the lack of evolution in is consistent with models where the impact of dust attenuation on the bright end of the luminosity function decreases at higher redshift, although a decreasing impact of feedback may also be possible. We measure the evolution of the cosmic star-formation rate (SFR) density by integrating our observed luminosity functions to , correcting for dust attenuation, and find that the SFR density declines proportionally to (1 ) at 4, which is consistent with observations at 9. Our observed luminosity functions are consistent with a reionization history that starts at 10, completes at 6, and reaches a midpoint (x 0.5) at 6.7 9.4. Finally, using a constant cumulative number density selection and an empirically derived rising star-formation history, our observations predict that the abundance of bright z = 9 galaxies is likely higher than previous constraints, although consistent with recent estimates of bright 10 galaxies.
Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used ...method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice.
In multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These “scanner effects” can hinder detection of biological features of interest, produce ...inconsistent results, and lead to spurious associations. We propose mica (multisite image harmonization by cumulative distribution function alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite studies so these can be reduced as a preprocessing step. We illustrate scanner effects in a brain MRI study in which the same subject was measured twice on seven scanners, and assess our method’s performance in a second study in which ten subjects were scanned on two machines. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by aligning intensity distributions. We further studied the ability to predict image harmonization results for a scan taken on an existing subject at a new site using cross-validation.
ABSTRACT We present galaxy stellar mass functions (GSMFs) at z = 4-8 from a rest-frame ultraviolet (UV) selected sample of ∼4500 galaxies, found via photometric redshifts over an area of ∼280 arcmin2 ...in the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS)/Great Observatories Origins Deep Survey (GOODS) fields and the Hubble Ultra Deep Field. The deepest Spitzer/IRAC data to date and the relatively large volume allow us to place a better constraint at both the low- and high-mass ends of the GSMFs compared to previous space-based studies from pre-CANDELS observations. Supplemented by a stacking analysis, we find a linear correlation between the rest-frame UV absolute magnitude at 1500 Å ( ) and logarithmic stellar mass ( ) that holds for galaxies with . We use simulations to validate our method of measuring the slope of the -MUV relation, finding that the bias is minimized with a hybrid technique combining photometry of individual bright galaxies with stacked photometry for faint galaxies. The resultant measured slopes do not significantly evolve over z = 4-8, while the normalization of the trend exhibits a weak evolution toward lower masses at higher redshift. We combine the -MUV distribution with observed rest-frame UV luminosity functions at each redshift to derive the GSMFs, finding that the low-mass-end slope becomes steeper with increasing redshift from at z = 4 to at z = 8. The inferred stellar mass density, when integrated over -1013 M , increases by a factor of between z = 7 and z = 4 and is in good agreement with the time integral of the cosmic star formation rate density.
Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in ...RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations.
Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.
LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein −/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.
These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.
The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, ...open‐label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10‐fold) and were associated significantly with CYP2A6 genotypes (P < 0.0001), body mass index (BMI) (P < 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.
Clinical Pharmacology & Therapeutics (2011); 90 5, 693–700. doi:10.1038/clpt.2011.174
Background: The family represents the most essential and supportive environment for children with cerebral palsy (CP). To improve children’s outcomes, it is crucial to consider the needs of families ...in order to offer family-centered care, which tailors services to these needs. Objective: We conducted a needs assessment to identify the family needs of patients with CP attending two hospitals in Accra. Methods: The study was a cross-sectional study involving primary caregivers of children with CP attending neurodevelopmental clinics. Structured questionnaires were used to collect data spanning an 8-month period. The data were summarized, and statistical inference was made. Results: Service needs identified were childcare, counseling, support groups, financial assistance, and recreational facilities. Information needs included adult education, job training/employment opportunities, education, health and social programs, knowledge about child development, and management of behavioral and feeding/nutrition problems. Reducing extensive travel time was desirable to improve access to healthcare. With the increasing severity of symptoms came the need for improved accessibility in the home to reduce the child’s hardship, as well as assistive devices, recreational facilities, and respite for the caregiver(s). Conclusion: Families of children with CP have information, service, and access needs related to their disease severity and family context.
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