The relative importance of training volume and coach autonomy support for preventing youth swimming attrition

There are hypothesized associations between high training volume in youth sport and negative psychological and behavioral outcomes such as decreased enjoyment, and increased burnout and dropout. Autonomy support, however, is associated with positive motivational and behavioral outcomes. The purpose of this study was to concurrently explore the relationships of training volume and perceived coach autonomy support with enjoyment, commitment, burnout symptoms, and dropout from swimming. Survey data were collected from 265 swimmers (Mage = 13.78 ± 1.60) representing more than 50 clubs across Canada. Their parents provided training volume data. Several months later, at the start of the next swimming season, a follow-up survey identified which swimmers dropped out. Structural equation modeling did not show a significant relationship between training volume and enjoyment, but there was a significant pathway from autonomy support to enjoyment, which predominantly predicted functional commitment. Obligatory and functional commitment differentially predicted burnout and intentions to continue swimming. Swimmers who dropped out had significantly lower training volume, enjoyment, functional commitment, and intentions to continue swimming, and higher sport devaluation, compared to those who continued swimming in the following season. Perceptions of an enjoyable, autonomy-supportive training context in adolescent swimming seem to have greater associations than training volume with several psychological and behavioral outcomes, including burnout symptoms and dropout

Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice

Peer reviewedPublisher PD

Kynurenine pathway inhibition reduces central nervous system inflammation in a model of human African trypanosomiasis

Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasites <i>Trypanosoma brucei rhodesiense</i> or <i>Trypanosoma brucei gambiense</i>, and is a major cause of systemic and neurological disability throughout sub-Saharan Africa. Following early-stage disease, the trypanosomes cross the blood-brain barrier to invade the central nervous system leading to the encephalitic, or late stage, infection. Treatment of human African trypanosomiasis currently relies on a limited number of highly toxic drugs, but untreated, is invariably fatal. Melarsoprol, a trivalent arsenical, is the only drug that can be used to cure both forms of the infection once the central nervous system has become involved, but unfortunately, this drug induces an extremely severe post-treatment reactive encephalopathy (PTRE) in up to 10% of treated patients, half of whom die from this complication. Since it is unlikely that any new and less toxic drug will be developed for treatment of human African trypanosomiasis in the near future, increasing attention is now being focussed on the potential use of existing compounds, either alone or in combination chemotherapy, for improved efficacy and safety. The kynurenine pathway is the major pathway in the metabolism of tryptophan. A number of the catabolites produced along this pathway show neurotoxic or neuroprotective activities, and their role in the generation of central nervous system inflammation is well documented. In the current study, Ro-61-8048, a high affinity kynurenine-3-monooxygenase inhibitor, was used to determine the effect of manipulating the kynurenine pathway in a highly reproducible mouse model of human African trypanosomiasis. It was found that Ro-61-8048 treatment had no significant effect (P = 0.4445) on the severity of the neuroinflammatory pathology in mice during the early central nervous system stage of the disease when only a low level of inflammation was present. However, a significant (P = 0.0284) reduction in the severity of the neuroinflammatory response was detected when the inhibitor was administered in animals exhibiting the more severe, late central nervous system stage, of the infection. <i>In vitro</i> assays showed that Ro-61-8048 had no direct effect on trypanosome proliferation suggesting that the anti-inflammatory action is due to a direct effect of the inhibitor on the host cells and not a secondary response to parasite destruction. These findings demonstrate that kynurenine pathway catabolites are involved in the generation of the more severe inflammatory reaction associated with the late central nervous system stages of the disease and suggest that Ro-61-8048 or a similar drug may prove to be beneficial in preventing or ameliorating the PTRE when administered as an adjunct to conventional trypanocidal chemotherap

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

Active Site Mutations Change the Cleavage Specificity of Neprilysin

Neprilysin (NEP), a member of the M13 subgroup of the zinc-dependent endopeptidase family is a membrane bound peptidase capable of cleaving a variety of physiological peptides. We have generated a series of neprilysin variants containing mutations at either one of two active site residues, Phe563 and Ser546. Among the mutants studied in detail we observed changes in their activity towards leucine5-enkephalin, insulin B chain, and amyloid β1–40. For example, NEPF563I displayed an increase in preference towards cleaving leucine5-enkephalin relative to insulin B chain, while mutant NEPS546E was less discriminating than neprilysin. Mutants NEPF563L and NEPS546E exhibit different cleavage site preferences than neprilysin with insulin B chain and amyloid ß1–40 as substrates. These data indicate that it is possible to alter the cleavage site specificity of neprilysin opening the way for the development of substrate specific or substrate exclusive forms of the enzyme with enhanced therapeutic potential

X-ray and IR Point Source Identification and Characteristics in the Embedded, Massive Star-Forming Region RCW 108

We report on the results of an approximately 90 ks Chandra observation of a complex region that hosts multiple sites of recent and active star formation in ARA OB1a. The field is centered on the embedded cluster RCW 108-IR and includes and a large portion of the open cluster NGC 6193. We detect over 420 X-ray sources in the field and combined these data with deep near-IR, Spitzer/IRAC and MSX mid-IR data. We find about 360 of the X-ray sources have near--IR counterparts. We divide the region into 5 parts based on the X-ray point source characteristics and extended 8 micron emission. The most clearly defined regions are the central region - identified by embedded sources with high luminosities in the both the near-IR and X-ray as well as high X-ray temperatures (about 3 keV) and the eastern region - identified by low extinction and 1 keV X-ray temperatures. Other regions, identified by their directional relationship to RCW 108-IR are less uniform - representing combinations of the first two regions, independent star formation epochs, or both. Over 18% percent of the cluster members with over 100 counts exhibit flares. Overall about 50% of the stars appear to have optically thick disks when IRAC data are employed. The largest fraction of X-ray sources are best described as possessing some disk material via a more detailed extinction fitting. We estimate that the total number of pre--main sequence stars in the field is about 1600. Approximately 800 are confined to (1.1 pc) central region.Comment: 63 pages including 18 figures, and 15 tables. Tables 1,2,5,7,10,and 11 have been stubbed in the text and included as ancillary files. Accepted by the Astronomical Journa

An embedded longitudinal multi-faceted qualitative evaluation of a complex cluster randomized controlled trial aiming to reduce clinically important errors in medicines management in general practice

<p>Abstract</p> <p>Background</p> <p>There is a need to shed light on the pathways through which complex interventions mediate their effects in order to enable critical reflection on their transferability. We sought to explore and understand key stakeholder accounts of the acceptability, likely impact and strategies for optimizing and rolling-out a successful pharmacist-led information technology-enabled (PINCER) intervention, which substantially reduced the risk of clinically important errors in medicines management in primary care.</p> <p>Methods</p> <p>Data were collected at two geographical locations in central England through a combination of one-to-one longitudinal semi-structured telephone interviews (one at the beginning of the trial and another when the trial was well underway), relevant documents, and focus group discussions following delivery of the PINCER intervention. Participants included PINCER pharmacists, general practice staff, researchers involved in the running of the trial, and primary care trust staff. PINCER pharmacists were interviewed at three different time-points during the delivery of the PINCER intervention. Analysis was thematic with diffusion of innovation theory providing a theoretical framework.</p> <p>Results</p> <p>We conducted 52 semi-structured telephone interviews and six focus group discussions with 30 additional participants. In addition, documentary data were collected from six pharmacist diaries, along with notes from four meetings of the PINCER pharmacists and feedback meetings from 34 practices. Key findings that helped to explain the success of the PINCER intervention included the perceived importance of focusing on prescribing errors to all stakeholders, and the credibility and appropriateness of a pharmacist-led intervention to address these shortcomings. Central to this was the face-to-face contact and relationship building between pharmacists and a range of practice staff, and pharmacists’ explicitly designated role as a change agent. However, important concerns were identified about the likely sustainability of this new model of delivering care, in the absence of an appropriate support network for pharmacists and career development pathways.</p> <p>Conclusions</p> <p>This embedded qualitative inquiry has helped to understand the complex organizational and social environment in which the trial was undertaken and the PINCER intervention was delivered. The longitudinal element has given insight into the dynamic changes and developments over time. Medication errors and ways to address these are high on stakeholders’ agendas. Our results further indicate that pharmacists were, because of their professional standing and skill-set, able to engage with the complex general practice environment and able to identify and manage many clinically important errors in medicines management. The transferability of the PINCER intervention approach, both in relation to other prescribing errors and to other practices, is likely to be high.</p

Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated

Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies

Galaxy evolution probe

The Galaxy Evolution Probe (GEP) is a concept for a mid- and far-infrared space observatory to measure key properties of large samples of galaxies with large and unbiased surveys. GEP will attempt to achieve zodiacal light and Galactic dust emission photon background-limited observations by utilizing a 6-K, 2.0-m primary mirror and sensitive arrays of kinetic inductance detectors (KIDs). It will have two instrument modules: a 10 to 400  μm hyperspectral imager with spectral resolution R  =  λ  /  Δλ  ≥  8 (GEP-I) and a 24 to 193  μm, R  =  200 grating spectrometer (GEP-S). GEP-I surveys will identify star-forming galaxies via their thermal dust emission and simultaneously measure redshifts using polycyclic aromatic hydrocarbon emission lines. Galaxy luminosities derived from star formation and nuclear supermassive black hole accretion will be measured for each source, enabling the cosmic star formation history to be measured to much greater precision than previously possible. Using optically thin far-infrared fine-structure lines, surveys with GEP-S will measure the growth of metallicity in the hearts of galaxies over cosmic time and extraplanar gas will be mapped in spiral galaxies in the local universe to investigate feedback processes. The science case and mission architecture designed to meet the science requirements is described, and the KID and readout electronics state of the art and needed developments are described. This paper supersedes the GEP concept study report cited in it by providing new content, including: a summary of recent mid-infrared KID development, a discussion of microlens array fabrication for mid-infrared KIDs, and additional context for galaxy surveys. The reader interested in more technical details may want to consult the concept study report