Reforming the Veterans Health Administration-Beyond Palliation of Symptoms

The Veterans Health Administration (VHA) is one of the largest health care delivery systems in the United States, with 9.1 million enrollees, 20,000 physicians, 1600 facilities, 288,000 employees, and a $59 billion budget. In response to highly publicized concerns regarding delayed access to care, preventable deaths in patients awaiting care, and falsification of lists to make waiting times appear shorter, Congress passed and President Barack Obama signed the Veterans Access, Choice, and Accountability Act of 2014. In addition to expanding non-VHA treatment options for veterans, this law requires a comprehensive, independent assessment of 12 areas of VHA care delivery and management (see box). Eleven assessments were conducted under the Centers for Medicare and Medicaid Services Alliance to Modernize Healthcare, operated by the MITRE Corporation; the assessment of one area, “Access Standards,” was conducted by the Institute of Medicine. An independent blue-ribbon panel of experts was formed to examine and advise on all aspects of data collection and review, best practices, assessments, and recommendations. That panel, which we chaired, unanimously endorsed an integrated report, which was delivered to Secretary of Veterans Affairs Robert McDonald and Congress on September 1, 2015, and publicly released on September 18.

Hit and run versus long-term activation of PARP-1 by its different domains fine-tunes nuclear processes.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a multidomain multifunctional nuclear enzyme involved in the regulation of the chromatin structure and transcription. PARP-1 consists of three functional domains: the N-terminal DNA-binding domain (DBD) containing three zinc fingers, the automodification domain (A), and the C-terminal domain, which includes the protein interacting WGR domain (W) and the catalytic (Cat) subdomain responsible for the poly(ADP ribosyl)ating reaction. The mechanisms coordinating the functions of these domains and determining the positioning of PARP-1 in chromatin remain unknown. Using multiple deletional isoforms of PARP-1, lacking one or another of its three domains, as well as consisting of only one of those domains, we demonstrate that different functions of PARP-1 are coordinated by interactions among these domains and their targets. Interaction between the DBD and damaged DNA leads to a short-term binding and activation of PARP-1. This hit and run activation of PARP-1 initiates the DNA repair pathway at a specific point. The long-term chromatin loosening required to sustain transcription takes place when the C-terminal domain of PARP-1 binds to chromatin by interacting with histone H4 in the nucleosome. This long-term activation of PARP-1 results in a continuous accumulation of pADPr, which maintains chromatin in the loosened state around a certain locus so that the transcription machinery has continuous access to DNA. Cooperation between the DBD and C-terminal domain occurs in response to heat shock (HS), allowing PARP-1 to scan chromatin for specific binding sites

Therapeutic efficacy of favipiravir against Bourbon virus in mice

Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV

Tracking internal temperature and structural dynamics during nail penetration of lithium-ion cells

Mechanical abuse of lithium-ion batteries is widely used during testing to induce thermal runaway, characterize associated risks, and expose cell and module vulnerabilities. However, the repeatability of puncture or ‘nail penetration’ tests is a key issue as there is often a high degree of variability in the resulting thermal runaway process. In this work, the failure mechanisms of 18650 cells punctured at different locations and orientations are characterized with respect to their internal structural degradation, and both their internal and surface temperature, all of which are monitored in real time. The initiation and propagation of thermal runaway is visualized via high-speed synchrotron X-ray radiography at 2000 frames per second, and the surface and internal temperatures are recorded via infrared imaging and a thermocouple embedded in the tip of the penetrating nail, respectively. The influence of the nail, as well as how and where it penetrates the cell, on the initiation and propagation of thermal runaway is described and the suitability of this test method for representing in-field failures is discussed

A social network of crime : A review of the use of social networks for crime and the detection of crime

Social media is used to commit and detect crimes. With automated methods, it is possible to scale both crime and detection of crime to a large number of people. The ability of criminals to reach large numbers of people has made this area subject to frequent study, and consequently, there have been several surveys that have reviewed specific crimes committed on social platforms. Until now, there has not been a review article that considers all types of crimes on social media, their similarity as well as their detection. The demonstration of similarity between crimes and their detection methods allows for the transfer of techniques and data between domains. This survey, therefore, seeks to document the crimes that have been committed on social media, and demonstrate their similarity through a taxonomy of crimes. Also, this survey documents publicly available datasets. Finally, this survey provides suggestions for further research in this field

High CO2 permeability in supported molten-salt membranes with highly dense and aligned pores produced by directional solidification

Composite molten salt-ceramic membranes are promising devices for high-temperature CO2 separation. Intensive material properties impact on separation performance as do membrane geometry (thickness) and microstructure (pore volume fraction, size, connectivity, and tortuosity factor). Although controlling pore size is considered somewhat routine, achieving pore alignment and connectivity is still challenging. Here we report the production of the first gas separation membrane using a porous ceramic matrix obtained from a directionally-solidified magnesium-stabilised zirconia (MgSZ) - MgO fibrilar eutectic as the membrane support. MgO was removed from the parent material by acid-etching to create a porous matrix with highly aligned pores with diameters of similar to 1 mu m. X-ray nano-computed tomography of a central portion (similar to 32, 000 mu m(3)) of the support identified similar to 21% porosity, with all pores aligned within 10 degrees and similar to 76% percolating along the longest sampled length. Employing the matrix as a support for a carbonate molten salt, a high CO2 permeability of 1.41x10(-10) mol m(-1).s(-1).Pa-1 at 815 degrees C was achieved, among the highest reported for supported molten-carbonate membranes (typically 10(-12) to 10(-10) mol m(-1).s(-1).Pa-1 at similar temperatures). We suggest that the high permeability is attributable to the excellent pore characteristics resulting from directional solidification, namely a dense array of parallel, micron-scale pores connecting the feed and permeate sides of the membrane

Solvent inhibition in the liquid-phase catalytic oxidation of 1,4-butanediol: Understanding the catalyst behaviour from NMR relaxation time measurements

Solvent inhibition over surfaces affects behaviour and performances of heterogeneous catalysts.Johnson Matthey, EvonikDegussa, Technology Strategy Board (Grant ID: TP/7/ZEE/6/I/N0262B), Engineering and Physical Sciences Research Council and CASTech consortium (Grant ID: EP/G011397/1), Wolfson College Cambridg

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care