Novel cruzain inhibitors for the treatment of Chagas' disease.

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T. cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas' disease

On the Role of Dewetting Transitions in Host-Guest Binding Free Energy Calculations.

We use thermodynamic integration (TI) and explicit solvent molecular dynamics (MD) simulation to estimate the absolute free energy of host-guest binding. In the unbound state, water molecules visit all of the internally accessible volume of the host, which is fully hydrated on all sides. Upon binding of an apolar guest, the toroidal host cavity is fully dehydrated; thus, during the intermediate λ stages along the integration, the hydration of the host fluctuates between hydrated and dehydrated states. Estimating free energies by TI can be especially challenging when there is a considerable difference in hydration between the two states of interest. We investigate these aspects using the popular TIP3P and TIP4P water models. TI free energy estimates through MD largely depend on water-related interactions, and water dynamics significantly affect the convergence of binding free energy calculations. Our results indicate that wetting/dewetting transitions play a major role in slowing the convergence of free energy estimation. We employ two alternative approaches-one analytical and the other empirically based on actual MD sampling-to correct for the standard state free energy. This correction is sizable (up to 4 kcal/mol), and the two approaches provide corrections that differ by about 1 kcal/mol. For the system considered here, the TIP4P water model combined with an analytical correction for the standard state free energy provides higher overall accuracy. This observation might be transferable to other systems in which water-related contributions dominate the binding process

Validation of a new measure of concept of a good death

BACKGROUND: The concept of a good death is central to end-of-life care research. Despite its importance and the high interest in the topic, there are few measures currently available for use in clinical research. PURPOSE: The present work describes the development and testing of a set of items intended to measure the importance of several components posited to be critical to the concept of a good death. It is intended for use with health care providers and lay people in the context of end-of-life care research and education. POPULATION: Four cohorts (n = 596) were recruited to participate, representing two helping profession disciplines, nonhelping professionals, and a range of ages, specifically: (1) undergraduate medical students; (2) master\u27s degree students in nursing; (3) graduate students from the life sciences; and (4) practicing hospice nurses. METHODS: Participants completed self-report questionnaires at baseline and retest. Psychometric analyses included item frequency distributions, factor analysis, alpha reliability, intraclass correlation, and measures of association. RESULTS: The new Concept of a Good Death measure demonstrated good item frequency distributions, acceptable internal consistency reliability, and test-retest stability. Its factor structure revealed that three distinct domains are measured, reflecting the psychosocial/spiritual, physical, and clinical aspects of a good death. An examination of patterns of correlations showed differential associations with death anxiety, spiritual beliefs and practices, anxious mood, and sociodemographic characteristics. CONCLUSIONS: The new Concept of a Good Death instrument appears to measure three distinct factors which people consider important to a Good Death. Ratings of the importance of these factors are reliable and valid. The instrument has the advantage of being a brief, self-report index for use in end-of-life care research

Fidelity monitoring across the seven studies in the Consortium of Hospitals Advancing Research on Tobacco (CHART)

Background This paper describes fidelity monitoring (treatment differentiation, training, delivery, receipt and enactment) across the seven National Institutes of Health-supported Consortium of Hospitals Advancing Research on Tobacco (CHART) studies. The objectives of the study were to describe approaches to monitoring fidelity including treatment differentiation (lack of crossover), provider training, provider delivery of treatment, patient receipt of treatment, and patient enactment (behavior) and provide examples of application of these principles. Methods Conducted between 2010 and 2014 and collectively enrolling over 9500 inpatient cigarette smokers, the CHART studies tested different smoking cessation interventions (counseling, medications, and follow-up calls) shown to be efficacious in Cochrane Collaborative Reviews. The CHART studies compared their unique treatment arm(s) to usual care, used common core measures at baseline and 6-month follow-up, but varied in their approaches to monitoring the fidelity with which the interventions were implemented. Results Treatment differentiation strategies included the use of a quasi-experimental design and monitoring of both the intervention and control group. Almost all of the studies had extensive training for personnel and used a checklist to monitor the intervention components, but the items on these checklists varied widely and were based on unique aspects of the interventions, US Public Health Service and Joint Commission smoking cessation standards, or counselor rapport. Delivery of medications ranged from 31 to 100 % across the studies, with higher levels from studies that gave away free medications and lower levels from studies that sought to obtain prescriptions for the patient in real world systems. Treatment delivery was highest among those studies that used automated (interactive voice response and website) systems, but this did not automatically translate into treatment receipt and enactment. Some studies measured treatment enactment in two ways (e.g., counselor or automated system report versus patient report) showing concurrence or discordance between the two measures. Conclusions While fidelity monitoring can be challenging especially in dissemination trials, the seven CHART studies used a variety of methods to enhance fidelity with consideration for feasibility and sustainability. Trial registration - Dissemination of Tobacco Tactics for hospitalized smokers. Clinical Trials Registration No. NCT01309217. - Smoking cessation in hospitalized smokers. Clinical Trials Registration No. NCT01289275. - Using “warm handoffs” to link hospitalized smokers with tobacco treatment after discharge: study protocol of a randomized controlled trial. Clinical Trials Registration No. NCT01305928. - Web-based smoking cessation intervention that transitions from inpatient to outpatient. Clinical Trials Registration No. NCT01277250. - Effectiveness of smoking-cessation interventions for urban hospital patients. Clinical Trials Registration No. NCT01363245. - Comparative effectiveness of post-discharge interventions for hospitalized smokers. Clinical Trials Registration No. NCT01177176. - Health and economic effects from linking bedside and outpatient tobacco cessation services for hospitalized smokers in two large hospitals. Clinical Trials Registration No. NCT01236079

\u3ci\u3eProsopis glandulosa\u3c/i\u3e persistence is facilitated by differential protection of buds during low- and high-energy fires

Rangelands worldwide have experienced significant shifts from grass-dominated to woody-plant dominated states over the past century. In North America, these shifts are largely driven by overgrazing and landscape-scale fire suppression. Such shifts reduce productivity for livestock, can have broad-scale impacts to biodiversity, and are often difficult to reverse. Restoring grass dominance often involves restoring fire as an ecological process. However, many resprouting woody plants persist following disturbance, including fire, by resprouting from protected buds, rendering fire ineffective for reducing resprouting woody plant density. Recent research has shown that extreme fire (high-energy fires during periods of water stress) may reduce resprouting capacity. This previous research did not examine whether high-energy fires alone would be sufficient to cause mortality. We created an experimental framework for assessing the “buds-protection-resources” hypothesis of resprouting persistence under different fire energies. In July–August 2018 we exposed 48 individuals of a dominant resprouting woody plant in the region, honey mesquite (Prosopis glandulosa), to two levels of fire energy (high and low) and root crown exposure (exposed vs unexposed) and evaluated resprouting capacity. We censused basal and epicormic resprouts for two years following treatment. Water stress was moderate for several months leading up to fires but low in subsequent years. Epicormic and basal buds were somewhat protected from lowand high-energy fire. However, epicormic buds were protected in very few mesquites subjected to high-energy fires. High-energy fires decreased survival, caused loss of apical dominance, and left residual dead stems, which may increase chances of mortality from future fires. Basal resprout numbers were reduced by high-energy fires, which may have additional implications for long-term mesquite survival. While the buds, protection, and resources components of resprouter persistence all played a role in resprouting, high-energy fire decreased mesquite survival and reduced resprouting. This suggests that high-energy fires affect persistence mechanisms to different extents than low-energy fires. In addition, high-energy fires during normal rainfall can have negative impacts on resprouting capacity; water stress is not a necessary precursor to honey mesquite mortality from highenergy fire

Strategies for Improved CALIPSO Aerosol Optical Depth Estimates

In the spring of 2010, the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) project will be releasing version 3 of its level 2 data products. In this paper we describe several changes to the algorithms and code that yield substantial improvements in CALIPSO's retrieval of aerosol optical depths (AOD). Among these are a retooled cloud-clearing procedure and a new approach to determining the base altitudes of aerosol layers in the planetary boundary layer (PBL). The results derived from these modifications are illustrated using case studies prepared using a late beta version of the level 2 version 3 processing code

A Nightingale-Based Model for Dementia Care and its Relevance for Korean Nursing

This article addresses the synchrony between a Western middle-range theory of care for persons with dementia and traditional Korean nursing care. The Western theory is called a need-driven, dementia-compromised behavior model and is heavily influenced by the assessment categories outlined in Nightingale’s work. This model is presented as congruent with Nightingale’s work and then viewed from the perspective of traditional Korean nursing. Several congruencies and a few incongruencies are found between these Western and Eastern views, and suggestions are made for greater consistency between these views.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68880/2/10.1177_08943189922107043.pd

Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome

Background: Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS. Methods: This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio). Results: This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU. Conclusions: Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses. Trial registration Clinical Trials Registration: NCT01775774 and NCT02097641

Long astral microtubules uncouple mitotic spindles from the cytokinetic furrow

Depletion of MCAK, which lengthens astral microtubules, induces oscillations of the mitotic spindle, and displaces the plane of cell division