Clinician-Scientists in Canada: Barriers to Career Entry and Progress

BACKGROUND: Clinician-scientists play an important role in translating between research and clinical practice. Significant concerns about a decline in their numbers have been raised. Potential barriers for career entry and progress are explored in this study. METHODS: Case-study research methods were used to identify barriers perceived by clinician-scientists and their research teams in two Canadian laboratories. These perceptions were then compared against statistical analysis of data from Canadian Institutes of Health Research (CIHR) databases on grant and award performance of clinician-scientists and non-clinical PhDs for fiscal years 2000 to 2008. RESULTS: Three main barriers were identified through qualitative analysis: research training, research salaries, and research grants. We then looked for evidence of these barriers in the Canada-wide statistical dataset for our study period. Clinician-scientists had a small but statistically significant higher mean number of degrees (3.3) than non-clinical scientists (3.2), potentially confirming the perception of longer training times. But evidence of the other two barriers was equivocal. For example, while overall growth in salary awards was minimal, awards to clinician-scientists increased by 45% compared to 6.3% for non-clinical PhDs. Similarly, in terms of research funding, awards to clinician-scientists increased by more than 25% compared with 5% for non-clinical PhDs. However, clinician-scientist-led grants funded under CIHR's Clinical thematic area decreased significantly from 61% to 51% (p-value<0.001) suggesting that clinician-scientists may be shifting their attention to other research domains. CONCLUSION: While clinician-scientists continue to perceive barriers to career entry and progress, quantitative results suggest improvements over the last decade. Clinician-scientists are awarded an increasing proportion of CIHR research grants and salary awards. Given the translational importance of this group, however, it may be prudent to adopt specific policy and funding incentives to ensure the ongoing viability of the career path

Loosening the GRIP (Gender Roles Inhibiting Prosociality) to Promote Gender Equality

Prosociality is an ideal context to begin shifting traditional gender role stereotypes and promoting equality. Men and women both help others frequently, but assistance often follows traditional gender role expectations, which further reinforces restrictive gender stereotypes in other domains. We propose an integrative process model of Gender Roles Inhibiting Prosociality (GRIP) to explain why and how this occurs. We argue that prosociality provides a unique entry point for change because it is (a) immediately rewarding (which cultivates positive attitude formation), (b) less likely to threaten the gender status hierarchy, and therefore less susceptible to social backlash (which translates into less restrictive social norms), and (c) a skill that that can be learned (which leads to stronger beliefs in one’s own ability to help). Using the GRIP model, we derive a series of hypothesized interventions to interrupt the self-reinforcing cycle of gender role stereotyping and facilitate progress toward broader gender equality

Overusage of Mouse DH Gene Segment, DFL16.1, Is Strain-Dependent and Determined by cis-Acting Elements

The DJH structure is of particular importance for diversity in the immunoglobulin heavy chain because it encodes most of CDR3. Here, we investigate mechanisms responsible for generating the DJH structure. We found DFL16.1 was used at a high frequency in normal and transformed pre-B cells (fetal liver > 50%, A-MuLV lines ≅ 25%). One DFL16.1JH1 structure was found repeatedly and was also present in DJH and VDJH databases, suggesting this structure may be conserved in the primary repertoire. Genetic analysis demonstrated that C57BL/6 mice use DFL16.1 in DJH structures more frequently than BALB/c. Examination of individual alleles in (C57BL/6 BALB/c)F1 A-MuLV cell lines revealed that the C57BL/6-derived allele used DFL16.1 twice as often as the BALB/c. This result indicates that part of the mechanism ensuring overusage of DFL16.1 gene segments is cis-acting

Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials

Background: This study assessed the immunogenicity of pegvaliase (recombinant Anabaena variabilis phenylalanine [Phe] ammonia lyase [PAL] conjugated with polyethylene glycol [PEG]) treatment in adults with phenylketonuria (PKU) and its impact on safety and efficacy. Methods: Immunogenicity was assessed during induction, upward titration, and maintenance dosing regimens in adults with PKU (n = 261). Total antidrug antibodies (ADA), neutralizing antibodies, immunoglobulin (Ig) M and IgG antibodies against PAL and PEG, IgG and IgM circulating immune complex (CIC) levels, complement components 3 and 4 (C3/C4), plasma Phe, and safety were assessed at baseline and throughout the study. Pegvaliase-specific IgE levels were measured in patients after hypersensitivity adverse events (HAE). Findings: All patients developed ADA against PAL, peaking by 6 months and then stabilizing. Most developed transient antibody responses against PEG, peaking by 3 months, then returning to baseline by 9 months. Binding of ADA to pegvaliase led to CIC formation and complement activation, which were highest during early treatment. Blood Phe decreased over time as CIC levels and complement activation declined and pegvaliase dosage increased. HAEs were most frequent during early treatment and declined over time. No patient with acute systemic hypersensitivity events tested positive for pegvaliase-specific IgE near the time of the event. Laboratory evidence was consistent with immune complex-mediated type III hypersensitivity. No evidence of pegvaliase-associated IC-mediated end organ damage was noted. Interpretation: Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. Fund: BioMarin Pharmaceutical Inc. Keywords: Enzyme replacement therapy, Antidrug antibody, Circulating immune complex, Hypersensitivity, Phenylalanin

Different trajectories of decline for global form and global motion processing in ageing, Mild Cognitive Impairment and Alzheimer’s disease

The visual processing of complex motion is impaired in Alzheimer's disease (AD). However, it is unclear whether these impairments are biased toward the motion stream or part of a general disruption of global visual processing, given some reports of impaired static form processing in AD. Here, for the first time, we directly compared the relative preservation of motion and form systems in AD, mild cognitive impairment, and healthy aging, by measuring coherence thresholds for well-established global rotational motion and static form stimuli known to be of equivalent complexity. Our data confirm a marked motion-processing deficit specific to some AD patients, and greater than any form-processing deficit for this group. In parallel, we identified a more gradual decline in static form recognition, with thresholds raised in mild cognitive impairment patients and slightly further in the AD group compared with controls. We conclude that complex motion processing is more vulnerable to decline in dementia than complex form processing, perhaps owing to greater reliance on long-range neural connections heavily targeted by AD pathology

High Viral Diversity and Mixed Infections in Cerebral Spinal Fluid From Cases of Varicella Zoster Virus Encephalitis.

BACKGROUND: Varicella zoster virus (VZV) may cause encephalitis, both with and without rash. Here we investigate whether viruses recovered from the central nervous system (CNS; encephalitis or meningitis) differ genetically from those recovered from non-CNS samples. METHODS: Enrichment-based deep sequencing of 45 VZV genomes from cerebral spinal fluid (CSF), plasma, bronchoalveolar lavage (BAL), and vesicles was carried out with samples collected from 34 patients with and without VZV infection of the CNS. RESULTS: Viral sequences from multiple sites in the same patient were identical at the consensus level. Virus from vesicle fluid and CSF in cases of meningitis showed low-level diversity. By contrast, plasma, BAL, and encephalitis had higher numbers of variant alleles. Two CSF-encephalitis samples had high genetic diversity, with variant frequency patterns typical of mixed infections with different clades. CONCLUSIONS: Low viral genetic diversity in vesicle fluid is compatible with previous observations that VZV skin lesions arise from single or low numbers of virions. A similar result was observed in VZV from cases of VZV meningitis, a generally self-limiting infection. CSF from cases of encephalitis had higher diversity with evidence for mixed clade infections in 2 cases. We hypothesize that reactivation from multiple neurons may contribute to the pathogenesis of VZV encephalitis.Action Medical research GN2424 This work was supported by a UK MRC New Investigator Award to D. P. D; UCL/UCLH BRC (J. B.); Action Medical Research (grant number GN2424 to C. J. H); Swedish Research Council (P. N. and T. B.). The work was also support by an NIHR Fellowship (grant number DRF-2013-06-168 to F. M.), the Meningitis Research Foundation (grant number 0904.0), an NIHR Programme Grant in Applied Research (grant number RP-PG-0108-10048 to T. S.), and the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool

Whole Genome Sequencing for Determining the Source of Mycobacterium bovis Infections in Livestock Herds and Wildlife in New Zealand.

The ability to DNA fingerprint Mycobacterium bovis isolates helped to define the role of wildlife in the persistence of bovine tuberculosis in New Zealand. DNA fingerprinting results currently help to guide wildlife control measures and also aid in tracing the source of infections that result from movement of livestock. During the last 5 years we have developed the ability to distinguish New Zealand (NZ) M. bovis isolates by comparing the sequences of whole genome sequenced (WGS) M. bovis samples. WGS provides much higher resolution than our other established typing methods and greatly improves the definition of the regional localization of NZ M. bovis types. Three outbreak investigations are described and results demonstrate how WGS analysis has led to the confirmation of epidemiological sourcing of infection, to better definition of new sources of infection by ruling out other possible sources, and has revealed probable wildlife infection in an area considered to be free of infected wildlife. The routine use of WGS analyses for sourcing new M. bovis infections will be an important component of the strategy employed to eradicate bovine TB from NZ livestock and wildlife

A framework for guiding the learning of ultrasound scanning

Ultrasound scanning is provided by a range of health professionals who need to be trained to a proficient level. In respect of education and training in ultrasound scanning, little attention has been given to how scanning skills are acquired and what assists and hinders the learning process. This study aims to develop a framework for guiding learning in ultrasound scanning. Overt participant observation and semi-structured interviews generated data on four learners undertaking a 12-month postgraduate ultrasound programme. Narrative analysis of the interview data was used to reveal dominant themes related to stages in learning to scan. Dominant themes associated with learning to scan were; communication with the patient, navigation skills, image interpretation skills, observation of practice, feedback on performance, random practise. Detailed interpretation of the themes through narrative analysis provided characteristics of learning for each stage of a four staged process. This study provides an insight into the key features of scan performance and how scanning skills are acquired over a four staged approach. These themes and characteristics are presented in a framework for guiding learning in ultrasound scanning

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy