Ethical difficulties in clinical practice : experiences of European doctors

Background: Ethics support services are growing in Europe to help doctors in dealing with ethical difficulties. Currently, insufficient attention has been focused on the experiences of doctors who have faced ethical difficulties in these countries to provide an evidence base for the development of these services. Methods: A survey instrument was adapted to explore the types of ethical dilemma faced by European doctors, how they ranked the difficulty of these dilemmas, their satisfaction with the resolution of a recent ethically difficult case and the types of help they would consider useful. The questionnaire was translated and given to general internists in Norway, Switzerland, Italy and the UK. Results: Survey respondents (n = 656, response rate 43%) ranged in age from 28 to 82 years, and averaged 25 years in practice. Only a minority (17.6%) reported having access to ethics consultation in individual cases. The ethical difficulties most often reported as being encountered were uncertain or impaired decisionmaking capacity (94.8%), disagreement among caregivers (81.2%) and limitation of treatment at the end of life (79.3%). The frequency of most ethical difficulties varied among countries, as did the type of issue considered most difficult. The types of help most often identified as potentially useful were professional reassurance about the decision being correct (47.5%), someone capable of providing specific advice (41.1%), help in weighing outcomes (36%) and clarification of the issues (35.9%). Few of the types of help expected to be useful varied among countries. Conclusion: Cultural differences may indeed influence how doctors perceive ethical difficulties. The type of help needed, however, did not vary markedly. The general structure of ethics support services would not have to be radically altered to suit cultural variations among the surveyed countries

Stellar and Gaseous Nuclear Disks Observed in Nearby (U)LIRGs

We present near-infrared integral field spectroscopy of the central kiloparsec of 17 nearby luminous and ultra-luminous infrared galaxies undergoing major mergers. These observations were taken with OSIRIS assisted by the Keck I and II Adaptive Optics systems, providing spatial resolutions of a few tens of parsecs. The resulting kinematic maps reveal gas disks in at least 16 out of 19 nuclei and stellar disks in 11 out of 11 nuclei observed in these galaxy merger systems. In our late-stages mergers, these disks are young (stellar ages $<30$ Myr) and likely formed as gas disks which became unstable to star formation during the merger. On average, these disks have effective radii of a few hundred parsecs, masses between $10^{8}$ and $10^{10} M_{Sun}$, and $v/\sigma$ between 1 and 5. These disks are similar to those created in high-resolution hydrodynamical simulations of gas-rich galaxy mergers, and favor short coalescence times for binary black holes. The few galaxies in our sample in earlier stages of mergers have disks which are larger ($r_{eff}\sim200-1800$ pc) and likely are remnants of the galactic disks that have not yet been completely disrupted by the merger.Comment: accepted for publication in Ap

Research and Education in Computational Science and Engineering

Over the past two decades the field of computational science and engineering (CSE) has penetrated both basic and applied research in academia, industry, and laboratories to advance discovery, optimize systems, support decision-makers, and educate the scientific and engineering workforce. Informed by centuries of theory and experiment, CSE performs computational experiments to answer questions that neither theory nor experiment alone is equipped to answer. CSE provides scientists and engineers of all persuasions with algorithmic inventions and software systems that transcend disciplines and scales. Carried on a wave of digital technology, CSE brings the power of parallelism to bear on troves of data. Mathematics-based advanced computing has become a prevalent means of discovery and innovation in essentially all areas of science, engineering, technology, and society; and the CSE community is at the core of this transformation. However, a combination of disruptive developments---including the architectural complexity of extreme-scale computing, the data revolution that engulfs the planet, and the specialization required to follow the applications to new frontiers---is redefining the scope and reach of the CSE endeavor. This report describes the rapid expansion of CSE and the challenges to sustaining its bold advances. The report also presents strategies and directions for CSE research and education for the next decade.Comment: Major revision, to appear in SIAM Revie

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an I

Multicenter study of the impact of community-onset Clostridium difficile infection on surveillance for C. difficile infection

OBJECTIVE: To evaluate the influence of community-onset/healthcare facility-associated cases on Clostridium difficile infection (CDI) incidence and outbreak detection. DESIGN: Retrospective cohort. SETTING: Five acute-care healthcare facilities in the United States. METHODS: Positive stool C. difficile toxin assays from July 2000 through June 2006 and healthcare facility exposure information were collected. CDI cases were classified as hospital-onset (HO) if they were diagnosed > 48 hours after admission or community-onset/healthcare facility-associated if they were diagnosed ≤ 48 hours from admission and had recently been discharged from the healthcare facility. Four surveillance definitions were compared: HO cases only and HO plus community-onset/healthcare facility-associated cases diagnosed within 30 (HCFA-30), 60 (HCFA-60) and 90 (HCFA-90) days after discharge from the study hospital. Monthly CDI rates were compared. Control charts were used to identify potential CDI outbreaks. RESULTS: The HCFA-30 rate was significantly higher than the HO rate at two healthcare facilities (p<0.01). The HCFA-30 rate was not significantly different from the HCFA-60 or HCFA-90 rates at any healthcare facility. The correlations between each healthcare facility’s monthly rates of HO and HCFA-30 CDI were almost perfect (range, 0.94–0.99, p<0.001). Overall, 12 time points had a CDI rate >3 SD above the mean, including 11 by the HO definition and 9 by the HCFA-30 definition, with discordant results at 4 time points (κ = 0.794, p<0.001). CONCLUSIONS: Tracking community-onset/healthcare facility-associated cases in addition to HO cases captures significantly more CDI cases but surveillance of HO CDI alone is sufficient to detect an outbreak

Noroviruses Co-opt the Function of Host Proteins VAPA and VAPB for Replication via a Phenylalanine-Phenylalanine-Acidic-Tract-Motif Mimic in Nonstructural Viral Protein NS1/2.

The Norovirus genus contains important human pathogens, but the role of host pathways in norovirus replication is largely unknown. Murine noroviruses provide the opportunity to study norovirus replication in cell culture and in small animals. The human norovirus nonstructural protein NS1/2 interacts with the host protein VAMP-associated protein A (VAPA), but the significance of the NS1/2-VAPA interaction is unexplored. Here we report decreased murine norovirus replication in VAPA- and VAPB-deficient cells. We characterized the role of VAPA in detail. VAPA was required for the efficiency of a step(s) in the viral replication cycle after entry of viral RNA into the cytoplasm but before the synthesis of viral minus-sense RNA. The interaction of VAPA with viral NS1/2 proteins is conserved between murine and human noroviruses. Murine norovirus NS1/2 directly bound the major sperm protein (MSP) domain of VAPA through its NS1 domain. Mutations within NS1 that disrupted interaction with VAPA inhibited viral replication. Structural analysis revealed that the viral NS1 domain contains a mimic of the phenylalanine-phenylalanine-acidic-tract (FFAT) motif that enables host proteins to bind to the VAPA MSP domain. The NS1/2-FFAT mimic region interacted with the VAPA-MSP domain in a manner similar to that seen with bona fide host FFAT motifs. Amino acids in the FFAT mimic region of the NS1 domain that are important for viral replication are highly conserved across murine norovirus strains. Thus, VAPA interaction with a norovirus protein that functionally mimics host FFAT motifs is important for murine norovirus replication.IMPORTANCE Human noroviruses are a leading cause of gastroenteritis worldwide, but host factors involved in norovirus replication are incompletely understood. Murine noroviruses have been studied to define mechanisms of norovirus replication. Here we defined the importance of the interaction between the hitherto poorly studied NS1/2 norovirus protein and the VAPA host protein. The NS1/2-VAPA interaction is conserved between murine and human noroviruses and was important for early steps in murine norovirus replication. Using structure-function analysis, we found that NS1/2 contains a short sequence that molecularly mimics the FFAT motif that is found in multiple host proteins that bind VAPA. This represents to our knowledge the first example of functionally important mimicry of a host FFAT motif by a microbial protein

Heavy Alcohol Use Is Associated With Worse Retention in HIV Care

Poor retention in HIV care is associated with worse clinical outcomes and increased HIV transmission. We examined the relationship between self-reported alcohol use, a potentially modifiable behavior, and retention