Doug Murphy

Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7 , a potent and selective brain-penetrant ATP-competitive mTOR inhibitor...

INTRODUCTION: Canadians report persistent problems accessing primary care despite an increasing per-capita supply of primary care physicians (PCPs). There is speculation that PCPs, especially those early in their careers, may now be working less and/or choosing to practice in focused clinical areas rather than comprehensive family medicine, but little evidence to support or refute this. The goal of this study is to inform primary care planning by: (1) identifying values and preferences shaping the practice intentions and choices of family medicine residents and early career PCPs, (2) comparing practice patterns of early-career and established PCPs to determine if changes over time reflect cohort effects (attributes unique to the most recent cohort of PCPs) or period effects (changes over time across all PCPs) and (3) integrating findings to understand the dynamics among practice intentions, practice choices and practice patterns and to identify policy implications...

The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein.

BACKGROUND: The use of bilateral internal thoracic arteries (BITA) for coronary artery bypass grafting (CABG) may improve survival compared with CABG using single internal thoracic arteries (SITA). We assessed the long-term costs of BITA compared with SITA. METHODS: Between June 2004 and December 2007, 3102 patients from 28 hospitals in seven countries were randomised to CABG surgery using BITA (n=1548) or SITA (n=1554). Detailed resource use data were collected from the initial hospital episode and annually up to 5 years...

OBJECTIVE: This study aimed to: (a) identify the association between external-workloads and injury-risk in the subsequent week; and (b) understand the effectiveness of workload variables in establishing injury-risk. DESIGN: Retrospective cohort study. METHODS: Workload and injury data (soft-tissue) were collected from forty-eight professional male rugby league players. Load variables included duration (min), total distance (m), relative distance (mmin-1 ), high speed distance ([m]>20kmh-1 ), very-high speed distance ([m]>25kmh-1 ), acceleration and deceleration efforts (count) and PlayerLoad (Arbitrary Unit: AU)...

Muon attenuation in matter can be used to infer the average material density along the path length of muons underground. By mapping the intensity of cosmic ray muons with an underground sensor, a radiographic image of the overburden above the sensor can be derived. Multiple such images can be combined to reconstruct a three-dimensional density model of the subsurface. This article summarizes selected case studies in applying muon tomography to mineral exploration, which we call muon geotomography.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'...

The aims of this study were to investigate the frequency, magnitude, and distribution of head impacts sustained by youth AF players over a season of games and report subjective descriptions on the mechanism-of-injury and sign and symptoms experienced. A prospective observational cohort study with participants (n = 19) (age range 13-14 yr., mean ± SD 13.9 ± 0.3 yr.) wearing a wireless impact measuring device behind their right ear over the mastoid process prior to game participation. Participants completed an individual post-game logbook providing feedback responses on recalling having a direct hit to their head with another player or the surface...

OBJECTIVES: Sport-related concussion (SRC) can result in impaired oculomotor function. Oculomotor performance, measured utilizing the King-Devick/Eye Tracking test (K-D/ET), is reported to be able to identify sub-optimal brain function. The objectives of the study were to determine the diagnostic accuracy of the K-D/ET in identifying SRC occurring from game participation and to perform a comparative analysis on saccade and blink counts for each K-D card individually and total counts between baseline and post-concussion...

This study measured and compared the frequency, magnitude, and distribution of head impacts sustained by junior and adult Australian football players, respectively, and between player positions over a season of games. Twelve junior and twelve adult players were tracked using a skin-mounted impact sensor. Head impact exposure, including frequency, magnitude, and location of impacts, was quantified using previously established methods. Over the collection period, there were no significant differences in the impact frequency between junior and adult players...

April 12, 2017 marked a significant day in the evolution of digital pathology in the United States, when the US Food and Drug Administration announced its approval of the Philips IntelliSite Pathology Solution for primary diagnosis in surgical pathology. Although this event is expected to facilitate more widespread adoption of whole slide imaging for clinical applications in the United States, it also raises a number of questions as to the means by which pathologists might choose to incorporate this technology into their clinical practice...

OBJECTIVES: Sport-related concussion (SRC) research has focused on impaired oculomotor function. The King-Devick (K-D) test measures oculomotor performance and is reported to identify suboptimal brain function. The use of the K-D test in Australian football (AF), a sport involving body contact and tackling, has not been documented. Therefore, the objective of this study was to determine the test-retest reliability and diagnostic accuracy of the K-D test on a sub-elite AF team. DESIGN: Prospective cohort study METHODS: In total, 22 male players (19...

The development of any novel reproductive technology involving manipulation of human embryos is almost inevitably going to be controversial and evoke sincerely held, but diametrically opposing views. The plethora of scientific, ethical and legal issues that surround the clinical use of such techniques fuels this divergence of opinion. During the policy change that was required to allow the use of mitochondrial donation in the UK, many of these issues were intensely scrutinised by a variety of people and in multiple contexts...

The goal of patient-centered outcomes research (PCOR) is to help patients and those who care for them make informed decisions about healthcare. However, the clinical research enterprise has not involved patients, caregivers, and other nonproviders routinely in the process of prioritizing, designing, and conducting research in hematopoietic cell transplantation (HCT). To address this need the National Marrow Donor Program/Be The Match engaged patients, caregivers, researchers, and other key stakeholders in a 2-year project with the goal of setting a PCOR agenda for the HCT community...

Crosstalk between metabolic and immune pathways has recently become appreciated to be key to the regulation of host defence. The hypoxia-inducible factor (HIF) is a transcription factor which was initially described as a ubiquitous master regulator of the transcriptional response to hypoxia. In this role, HIF regulates genes promoting adaptation to hypoxia including a number which influence the cellular metabolic strategy of a cell. It has more recently been appreciated that the regulation of HIF is not restricted to oxygen-dependent pathways, and is now known to be mediated by a number of additional metabolic and immune cues including metabolites and cytokines respectively...

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BACKGROUND: Although triptans are widely used in the acute management of migraine, there is uncertainty around the comparative efficacy of triptans among each other and vs non-triptan migraine treatments. We conducted systematic reviews and network meta-analyses to compare the relative efficacy of triptans (alone or in combination with other drugs) for acute treatment of migraines compared with other triptan agents, non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA), acetaminophen, ergots, opioids, or anti-emetics...

BACKGROUND AND OBJECTIVE: There are few data on the rate and characterization of medication-related visits (MRVs) to the emergency department (ED) in pediatric patients. We sought to evaluate the frequency, severity, preventability, and classification of MRVs to the ED in pediatric patients. METHODS: We performed a prospective observational study of pediatric patients presenting to the ED over a 12-month period. A medication-related ED visit was identified by using pharmacist assessment, emergency physician assessment, and an independent adjudication committee...

Accurate and reliable quantification of the abundance of mitochondrial DNA (mtDNA) molecules, both wild-type and those harbouring pathogenic mutations, is important not only for understanding the progression of mtDNA disease but also for evaluating novel therapeutic approaches. A clear understanding of the sensitivity of mtDNA measurement assays under different experimental conditions is therefore critical, however it is routinely lacking for most published mtDNA quantification assays. Here, we comprehensively assess the variability of two quantitative Taqman real-time PCR assays, a widely-applied MT-ND1/MT-ND4 multiplex mtDNA deletion assay and a recently developed MT-ND1/B2M singleplex mtDNA copy number assay, across a range of DNA concentrations and mtDNA deletion/copy number levels...

OBJECTIVES: Cervical mobilization and manipulation have been shown to improve cervical range of motion and pain. Rotatory thrust manipulation applied to the lower cervical segments is associated with controversy and the potential for eliciting adverse reactions (AR). The purpose of this clinical trial was to describe two translatory non-thrust mobilization techniques and evaluate their effect on cervical pain, motion restriction, and whether any adverse effects were reported when applied to the C7 segment...

Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes...