Circadian Activity of Topical 0.05% Betamethasone Dipropionate in Human Skin In Vivo

The influence of treatment duration, vehicle, and time of day of application on topical 0.05% betamethasone dipropionate uptake into human stratum corneum and the resulting skin- blanching response was investigated in human subjects. Drug uptake into stratum corneum and the resulting skin color changes measured with a chromameter demonstrate an equilibrium delay. Maximal drug uptake occurred at 2 h, whereas maximal skin color changes occurred 6h after a single application. Extent of decreased skin color was dependent on vehicle, treatment duration, and time of day of application. Time of maximal decreased skin color occurred at midnight independent of vehicle, treatment duration, or time of day of application. This time of maximal drug activity coincides with the well-known time period of lowest circulating cortisol concentrations (2000-0400 h). Application of a single 2- or 6-h dose of the 0.05% cream at 1600h produced more extensive and prolonged changes in skin color over 24h than a 0900-h application in the same subject. These data demonstrate that the extent and duration of topical corticosteroid activity in human skin is influenced by vehicle, treatment duration, and time of day of application. The prolonged changes in skin color measured with a single dose applied at 1600h suggest that a once-a-day dosing regimen in the late afternoon may be sufficient for dermatologic therapy. Elucidation of these circadian responses with topical corticosteroids may provide a rational basis for the future re-evaluation of the appropriate therapeutic regimen with this class of drugs in dermatologic medicine

Critical Thinking in Occupational Therapy Education: A Systematic Mapping Review

Critical thinking is a component of occupational therapy education that is often intertwined with professional reasoning, even though it is a distinct construct. While other professions have focused on describing and studying the disciplinary-specific importance of critical thinking, the small body of literature in occupational therapy education on critical thinking has not been systematically analyzed. Therefore, a systematic mapping review was conducted to examine, describe, and map existing scholarly work about critical thinking in occupational therapy education. Inclusion/exclusion criteria were set, database searches conducted, and 63 articles identified that met criteria for full review based on their abstracts. Thirty-five articles were excluded during full review, leaving 28 articles for analysis and coding using a data extraction tool. Eleven articles (39%) had a primary focus of critical thinking, and of those 11 articles, the majority were about instructional methods. Qualitative inquiry (n = 9) was the most frequently used method to examine critical thinking among the study full sample (N = 28). Four themes emerged: 1) critical thinking is a process with varied outcomes; 2) learner aptitude is essential for developing critical thinking; 3) critical thinking can be facilitated through various methods; and 4) critical thinking underpins other important constructs in occupational therapy. Needs that were identified were that critical thinking is best intentionally threaded across a curriculum with outcomes in mind; and more studies examining critical thinking in occupational therapy education, employing diverse designs, are needed

A primate model of severe malarial anaemia: a comparative pathogenesis study.

Severe malarial anaemia (SMA) is the most common life-threatening complication of Plasmodium falciparum infection in African children. SMA is characterised by haemolysis and inadequate erythropoiesis, and is associated with dysregulated inflammatory responses and reduced complement regulatory protein levels (including CD35). However, a deeper mechanistic understanding of the pathogenesis requires improved animal models. In this comparative study of two closely related macaque species, we interrogated potential causal factors for their differential and temporal relationships to onset of SMA. We found that rhesus macaques inoculated with blood-stage Plasmodium coatneyi developed SMA within 2 weeks, with no other severe outcomes, whereas infected cynomolgus macaques experienced only mild/ moderate anaemia. The abrupt drop in haematocrit in rhesus was accompanied by consumption of haptoglobin (haemolysis) and poor reticulocyte production. Rhesus developed a greater inflammatory response than cynomolgus macaques, and had lower baseline levels of CD35 on red blood cells (RBCs) leading to a significant reduction in the proportion of CD35+ RBCs during infection. Overall, severe anaemia in rhesus macaques infected with P. coatneyi has similar features to SMA in children. Our comparisons are consistent with an association of low baseline CD35 levels on RBCs and of early inflammatory responses with the pathogenesis of SMA

Frequency domain analysis for detecting pipeline leaks

The original publication can be found at http://scitation.aip.org/hyoThis paper introduces leak detection methods that involve the injection of a fluid transient into the pipeline, with the resultant transient trace analyzed in the frequency domain. Two methods of leak detection using the frequency response of the pipeline are proposed. The inverse resonance method involves matching the modeled frequency responses to those observed to determine the leak parameters. The peak-sequencing method determines the region in which the leak is located by comparing the relative sizes between peaks in the frequency response diagram. It was found that a unique pattern was induced on the peaks of the frequency response for each specific location of the leak within the pipeline. The leak location can be determined by matching the observed pattern to patterns generated numerically within a lookup table. The procedure for extracting the linear frequency response diagram, including the optimum measurement position, the effect of unsteady friction, and the way in which the technique can be extended into pipeline networks, are also discussed within the paper.Pedro J. Lee, John P. Vítkovský, Martin F. Lambert, Angus R. Simpson and James A. Ligget

A longitudinal investigation of repressive coping and ageing

This is an Accepted Manuscript of an article published by Taylor & Francis in Aging & Mental Health on October 2016, available online: http://www.tandfonline.com/doi/full/10.1080/13607863.2015.1060941.Two studies investigated the possibility that repressive coping is more prevalent in older adults and that this represents a developmental progression rather than a cohort effect. Study 1 examined repressive coping and mental health cross-sectionally in young and old adults. Study 2 examined whether there was a developmental progression of repressive coping prevalence rates in a longitudinal sample of older adults.Peer reviewedFinal Accepted Versio

HEPPA-II model-measurement intercomparison project : EPP indirect effects during the dynamically perturbed NH winter 2008-2009

We compare simulations from three high-top (with upper lid above 120 km) and five medium-top (with upper lid around 80 km) atmospheric models with observations of odd nitrogen (NOx D NO+NO2), temperature, and carbon monoxide from seven satellite instruments (ACE-FTS on SciSat, GOMOS, MIPAS, and SCIAMACHY on Envisat, MLS on Aura, SABER on TIMED, and SMR on Odin) during the Northern Hemisphere (NH) polar winter 2008/2009. The models included in the comparison are the 3-D chemistry transport model 3dCTM, the ECHAM5/MESSy Atmospheric Chemistry (EMAC) model, FinROSE, the Hamburg Model of the Neutral and Ionized Atmosphere (HAMMO-NIA), the Karlsruhe Simulation Model of the Middle Atmosphere (KASIMA), the modelling tools for SOlar Climate Ozone Links studies (SOCOL and CAO-SOCOL), and the Whole Atmosphere Community Climate Model (WACCM4). The comparison focuses on the energetic particle precipitation (EPP) indirect effect, that is, the polar winter descent of NOx largely produced by EPP in the mesosphere and lower thermosphere. A particular emphasis is given to the impact of the sudden stratospheric warming (SSW) in January 2009 and the subsequent elevated stratopause (ES) event associated with enhanced descent of mesospheric air. The chemistry climate model simulations have been nudged toward reanalysis data in the troposphere and stratosphere while being unconstrained above. An odd nitrogen upper boundary condition obtained from MIPAS observations has further been applied to medium-top models. Most models provide a good representation of the mesospheric tracer descent in general, and the EPP indirect effect in particular, during the unperturbed (pre-SSW) period of the NH winter 2008/2009. The observed NOx descent into the lower mesosphere and stratosphere is generally reproduced within 20 %. Larger discrepancies of a few model simulations could be traced back either to the impact of the models' gravity wave drag scheme on the polar wintertime meridional circulation or to a combination of prescribed NOx mixing ratio at the uppermost model layer and low vertical resolution. In March-April, after the ES event, however, modelled mesospheric and stratospheric NOx distributions deviate significantly from the observations. The too-fast and early downward propagation of the NO x tongue, encountered in most simulations, coincides with a temperature high bias in the lower mesosphere (0.2-0.05 hPa), likely caused by an overestimation of descent velocities. In contrast, upper-mesospheric temperatures (at 0.05-0.001 hPa) are generally underestimated by the high-top models after the onset of the ES event, being indicative for too-slow descent and hence too-low NOx fluxes. As a consequence, the magnitude of the simulated NOx tongue is generally underestimated by these models. Descending NOx amounts simulated with mediumtop models are on average closer to the observations but show a large spread of up to several hundred percent. This is primarily attributed to the different vertical model domains in which the NOx upper boundary condition is applied. In general, the intercomparison demonstrates the ability of state-of- the-art atmospheric models to reproduce the EPP indirect effect in dynamically and geomagnetically quiescent NH winter conditions. The encountered differences between observed and simulated NOx, CO, and temperature distributions during the perturbed phase of the 2009 NH winter, however, emphasize the need for model improvements in the dynamical representation of elevated stratopause events in order to allow for a better description of the EPP indirect effect under these particular conditions.Peer reviewe

HEPPA-II model–measurement intercomparison project: EPP indirect effects during the dynamically perturbed NH winter 2008-2009

We compare simulations from three high-top (with upper lid above 120 km) and five medium-top (with upper lid around 80 km) atmospheric models with observations of odd nitrogen (NOx  =  NO + NO2), temperature, and carbon monoxide from seven satellite instruments (ACE-FTS on SciSat, GOMOS, MIPAS, and SCIAMACHY on Envisat, MLS on Aura, SABER on TIMED, and SMR on Odin) during the Northern Hemisphere (NH) polar winter 2008/2009. The models included in the comparison are the 3-D chemistry transport model 3dCTM, the ECHAM5/MESSy Atmospheric Chemistry (EMAC) model, FinROSE, the Hamburg Model of the Neutral and Ionized Atmosphere (HAMMONIA), the Karlsruhe Simulation Model of the Middle Atmosphere (KASIMA), the modelling tools for SOlar Climate Ozone Links studies (SOCOL and CAO-SOCOL), and the Whole Atmosphere Community Climate Model (WACCM4). The comparison focuses on the energetic particle precipitation (EPP) indirect effect, that is, the polar winter descent of NOx largely produced by EPP in the mesosphere and lower thermosphere. A particular emphasis is given to the impact of the sudden stratospheric warming (SSW) in January 2009 and the subsequent elevated stratopause (ES) event associated with enhanced descent of mesospheric air. The chemistry climate model simulations have been nudged toward reanalysis data in the troposphere and stratosphere while being unconstrained above. An odd nitrogen upper boundary condition obtained from MIPAS observations has further been applied to medium-top models. Most models provide a good representation of the mesospheric tracer descent in general, and the EPP indirect effect in particular, during the unperturbed (pre-SSW) period of the NH winter 2008/2009. The observed NOx descent into the lower mesosphere and stratosphere is generally reproduced within 20 %. Larger discrepancies of a few model simulations could be traced back either to the impact of the models\u27 gravity wave drag scheme on the polar wintertime meridional circulation or to a combination of prescribed NOx mixing ratio at the uppermost model layer and low vertical resolution. In March–April, after the ES event, however, modelled mesospheric and stratospheric NOx distributions deviate significantly from the observations. The too-fast and early downward propagation of the NOx tongue, encountered in most simulations, coincides with a temperature high bias in the lower mesosphere (0.2–0.05 hPa), likely caused by an overestimation of descent velocities. In contrast, upper-mesospheric temperatures (at 0.05–0.001 hPa) are generally underestimated by the high-top models after the onset of the ES event, being indicative for too-slow descent and hence too-low NOx fluxes. As a consequence, the magnitude of the simulated NOx tongue is generally underestimated by these models. Descending NOx amounts simulated with medium-top models are on average closer to the observations but show a large spread of up to several hundred percent. This is primarily attributed to the different vertical model domains in which the NOx upper boundary condition is applied. In general, the intercomparison demonstrates the ability of state-of-the-art atmospheric models to reproduce the EPP indirect effect in dynamically and geomagnetically quiescent NH winter conditions. The encountered differences between observed and simulated NOx, CO, and temperature distributions during the perturbed phase of the 2009 NH winter, however, emphasize the need for model improvements in the dynamical representation of elevated stratopause events in order to allow for a better description of the EPP indirect effect under these particular conditions

Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency

A PfRH5-Based Vaccine Is Efficacious against Heterologous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys

SummaryAntigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans

Survival Data and Predictors of Functional Outcome an Average of 15 Years after the Fontan Procedure: The Pediatric Heart Network Fontan Cohort

ObjectiveMulticenter longitudinal outcome data for Fontan patients surviving into adulthood are lacking. The aim of this study was to better understand contemporary outcomes in Fontan survivors by collecting follow‐up data in a previously well‐characterized cohort.DesignBaseline data from the Fontan Cross‐Sectional Study (Fontan 1) were previously obtained in 546 Fontan survivors aged 11.9 ± 3.4 years. We assessed current transplant‐free survival status in all subjects 6.8 ± 0.4 years after the Fontan 1 study. Anatomic, clinical, and surgical data were collected along with socioeconomic status and access to health care.ResultsThirty subjects (5%) died or underwent transplantation since Fontan 1. Subjects with both an elevated (>21 pg/mL) brain natriuretic peptide and a low Child Health Questionnaire physical summary score (<44) measured at Fontan 1 were significantly more likely to die or undergo transplant than the remainder, with a hazard ratio of 6.2 (2.9–13.5). Among 516 Fontan survivors, 427 (83%) enrolled in this follow‐up study (Fontan 2) at 18.4 ± 3.4 years of age. Although mean scores on functional health status questionnaires were lower than the general population, individual scores were within the normal range in 78% and 88% of subjects for the Child Health Questionnaire physical and psychosocial summary score, and 97% and 91% for the SF‐36 physical and mental aggregate score, respectively. Since Fontan surgery, 119 (28%) had additional cardiac surgery; 55% of these (n = 66) in the interim between Fontan 1 and Fontan 2. A catheter intervention occurred in 242 (57%); 32% of these (n = 78) after Fontan 1. Arrhythmia requiring treatment developed in 118 (28%) after Fontan surgery; 58% of these (n = 68) since Fontan 1.ConclusionsWe found 95% interim transplant‐free survival for Fontan survivors over an average of 7 years of follow‐up. Continued longitudinal investigation into adulthood is necessary to better understand the determinants of long‐term outcomes and to improve functional health status.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110738/1/chd12193.pd