Predictors of Non-Variceal Hemorrhage in a National Cohort of Patients With Chronic Liver Disease.

Background: Non-variceal hemorrhage in patients with chronic liver disease (CLD) increases morbidity, mortality, and healthcare costs. There are limited data on risk factors for non-variceal hemorrhage in the CLD population. The aim of this study was to assess the predictive value of various clinical and laboratory parameters for non-variceal hemorrhage in CLD patients. Methods: We conducted a retrospective cohort study of US veterans diagnosed with CLD between 2002 and 2018 within the Veterans Health Administration database. We derived candidate variables from existing risk prediction models for hemorrhage, risk calculators for severity of liver disease, Charlson index of prognostic comorbidities, and prior literature. We used a competing risk analysis to study the relationship between putative risk factors and incidence of non-variceal hemorrhage in patients with CLD. Results: Of 15,183 CLD patients with no history of cancer or anticoagulation use, 674 experienced non-variceal hemorrhage within 1 year of CLD diagnosis. In multivariable analysis, 11 of the 26 candidate variables independently predicted non-variceal hemorrhage: race, international normalized ratio (INR) > 1.5, bilirubin ≥ 2 mg/dL, albumin ≤ 3.5 g/dL, anemia, alcohol abuse, antiplatelet therapy, chronic kidney disease, dementia, proton pump inhibitor prescription, and recent infection. Conclusions: In this study of almost 15,000 veterans, risk factors for non-variceal bleeding within the first year after diagnosis of CLD included non-Caucasian race, laboratory parameters indicating severe liver disease and recent infection in addition to the risk factors for bleeding observed in a general non-CLD population.

Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration.

Axolotl limb regeneration is accompanied by the transient induction of cellular senescence within the blastema, the structure that nucleates regeneration. The precise role of this blastemal senescent cell (bSC) population, however, remains unknown. Here, through a combination of gain- and loss-of-function assays, we elucidate the functions and molecular features of cellular senescence in vivo. We demonstrate that cellular senescence plays a positive role during axolotl regeneration by creating a pro-proliferative niche that supports progenitor cell expansion and blastema outgrowth. Senescent cells impact their microenvironment via Wnt pathway modulation. Further, we identify a link between Wnt signaling and senescence induction and propose that bSC-derived Wnt signals facilitate the proliferation of neighboring cells in part by preventing their induction into senescence. This work defines the roles of cellular senescence in the regeneration of complex structures.

Impact of Health Care Reform on Technology and Innovation.

The medical device industry has long been subject to criticism for lack of price transparency and minimal regulations surrounding device approval, which have functioned as barriers to providing quality and cost-effective care. Recent health care reforms aimed at overcoming these barriers, including improving market approval regulations, increasing postmarket surveillance, and using comparative effectiveness research, have drastically changed industry practices. These reforms have also prompted increasingly cost-aware health care practices, which have encouraged new trends in medical device innovation such as frugal innovation and deinstitutionalization. This article explores the challenges faced by industry, physicians, and patients in light of these reforms.

Distinguishing Specific and Nonspecific Complexes of Alkyladenine DNA Glycosylase.

Human alkyladenine DNA glycosylase (AAG) recognizes many alkylated and deaminated purine lesions and excises them to initiate the base excision DNA repair pathway. AAG employs facilitated diffusion to rapidly scan nonspecific sites and locate rare sites of damage. Nonspecific DNA binding interactions are critical to the efficiency of this search for damage, but little is known about the binding footprint or the affinity of AAG for nonspecific sites. We used biochemical and biophysical approaches to characterize the binding of AAG to both undamaged and damaged DNA. Although fluorescence anisotropy is routinely used to study DNA binding, we found unexpected complexities in the data for binding of AAG to DNA. Systematic comparison of different fluorescent labels and different lengths of DNA allowed binding models to be distinguished and demonstrated that AAG can bind with high affinity and high density to nonspecific DNA. Fluorescein-labeled DNA gave the most complex behavior but also showed the greatest potential to distinguish specific and nonspecific binding modes. We suggest a unified model that is expected to apply to many DNA binding proteins that exhibit affinity for nonspecific DNA. Although AAG strongly prefers to excise lesions from duplex DNA, nonspecific binding is comparable for single- and double-stranded nonspecific sites. The electrostatically driven binding of AAG to small DNA sites (∼5 nucleotides of single-stranded and ∼6 base pairs of duplex) facilitates the search for DNA damage in chromosomal DNA, which is bound by nucleosomes and other proteins.