Retention of provisionally licensed international medical graduates: a historical cohort study of general and family physicians in Newfoundland and Labrador

ABSTRACT Background: To alleviate the shortage of primary care physicians in rural communities, the Canadian province of Newfoundland and Labrador (NL) introduced provisional licensure for international medical graduates (IMGs), allowing them to practise in under-served communities while completing licensing requirements. Although provisional licensing has been seen as a needed recruitment strategy, little is known about its impact on physician retention. To assess the relationship between provincial retention time and type of initial practice licence, we compared the retention of: (1) IMGs who began practice with a provisional licence; (2) fully licensed Memorial University medical graduates (MMGs); and (3) fully licensed medical graduates from other Canadian medical schools (CMGs). Methods: Using administrative data from the NL College of Physicians and Surgeons, the 2004 Scott’s Medical Database, and the Memorial University postgraduate database, we identified family physicians/general practitioners (FPs/GPs) who began their practice in NL in the period 1997–2000 and determined where they were in 2004. We used Cox regression to examine differences in retention among these 3 groups of physicians. Results: There were 42 MMGs, 38 CMGs and 77 IMGs in our sample. The median time for IMGs to qualify for full licensure was 15 months. Twenty-one physicians (13.4%) stayed in NL after beginning their practice (35.7% MMGs, 5.3% CMGs, 5.2% IMGs; p < 0.000). The median retention time was 25 months (MMGs, 39 months; CMGs, 22 months; IMGs, 22 months; p < 0.000). After controlling for Certificant of the College of Family Physicians status, CMGs (hazard ratio [HR] = 2.15; 95% confidence interval [CI] 1.29–3.60) and IMGs (HR = 2.03; 95% CI 1.26–3.27) were more likely to leave NL than MMGs. Conclusions: Provisional licensing accounts for the largest proportion of new primary care physicians in NL but does not lead to long-term retention of IMGs. However, IMG retention is no worse than the retention of CMGs

Differential effects of hepatic cirrhosis on the intrinsic clearances of sorafenib and imatinib by CYPs in human liver

© 2017 Elsevier B.V. The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity. The principal findings were that liver disease impaired the microsomal oxidation of sorafenib to its major metabolites to 40–44% of control (P < 0.01), whereas the N-demethylation of imatinib was relatively unimpaired. The impairments in sorafenib biotransformation were correlated with decreased serum albumin concentrations and increased serum bilirubin concentrations in patients with liver disease, but not with the overall grade of liver disease according to the Child-Pugh system. In contrast, there was no relationship between imatinib N-demethylation and clinicopathologic factors in liver disease patients. These findings were accounted for in terms of the differential roles of CYPs 3A4 and 2C8 in the intrinsic clearance of the drugs. CYP3A4 has the major role in the intrinsic clearance of sorafenib but plays a secondary role to CYP2C8 in the intrinsic clearance of imatinib. In agreement with these findings CYP2C protein expression and CYP2C8-mediated paclitaxel 6α-hydroxylation were unimpaired in cirrhotic livers. This information could be adapted in individualized approaches such as in vivo CYP3A4 phenotyping to optimize sorafenib safety and efficacy in cancer patients with liver dysfunction

'Big Data' informed drug development: a case for acceptability

Data, which help inform various stages of drug product development, are increasingly being collected using newer, more novel platforms, such as mobile applications, and analysed computationally as much larger 'Big Data' data sets, revealing patterns relating to human behaviour and interactions. Medicine acceptability gauges the ability and willingness of patients to take their dosage forms. It has become a crucial human component of drug product design. Vouching for the age appropriateness of medicinal products, acceptability related data are now expected by regulatory bodies. Shifting from traditional paper-based to electronic data-gathering platforms will allow the pharmaceutical industry to collect real-world, real-time, clinically relevant data, capable of informing current and future drug product development, reducing time and cost, and setting foundations for patient-centric drug product design

Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids

Daptomycin is a bactericidal antibiotic of last resort for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA)1,2. Although resistance is rare, treatment failure can occur in more than 20% of cases3,4 and so there is a pressing need to identify and mitigate factors that contribute to poor therapeutic outcomes. Here, we show that loss of the Agr quorum-sensing system, which frequently occurs in clinical isolates, enhances S. aureus survival during daptomycin treatment. Wild-type S. aureus was killed rapidly by daptomycin, but Agr-defective mutants survived antibiotic exposure by releasing membrane phospholipids, which bound and inactivated the antibiotic. Although wild-type bacteria also released phospholipid in response to daptomycin, Agr-triggered secretion of small cytolytic toxins, known as phenol soluble modulins, prevented antibiotic inactivation. Phospholipid shedding by S. aureus occurred via an active process and was inhibited by the β-lactam antibiotic oxacillin, which slowed inactivation of daptomycin and enhanced bacterial killing. In conclusion, S. aureus possesses a transient defence mechanism that protects against daptomycin, which can be compromised by Agr-triggered toxin production or an existing therapeutic antibiotic

Co-Processed Excipients for Dispersible Tablets–Part 1: Manufacturability

Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr’s index ˂ 20), excellent tabletability (tensile strength > 3.0 MPa at 0.85 solid fraction), very low friability (< 1% after 15 min), rapid disintegration times (27–49 s) and produced dispersions of ideal fineness (< 250 μm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients

CEOs from Orthopaedic Centers Worldwide Meet to Discuss Common Challenges: 2010 Annual Meeting of the International Society of Orthopaedic Centers

The International Society of Orthopaedic Centers was formed in 2006 as a think tank that would bring together thought leaders in orthopaedic surgery from major orthopaedic academic centers around the world. The Society’s mission is to share knowledge and strategies, improve patient care, and foster clinical, educational, and scientific collaboration. As the Society’s agendas developed, the members recognized that many of their aims intersected with those of hospital leadership. Thus, CEOs from member centers were invited to join their physician colleagues at the 2010 meeting in Bologna, Italy in order to explore solutions to administrative challenges related to patient care, volume growth, and costs. This paper describes the dialogue that took place at the meeting

Co-Processed Excipients for Dispersible Tablets—Part 2: Patient Acceptability

Palatability and patient acceptability are critical attributes of dispersible tablet formulation. Co-processed excipients could provide improved organoleptic profile due to rational choice of excipients and manufacturing techniques. The aim of this study was to identify the most suitable co-processed excipient to use within directly compressible dispersible tablet formulations. Nine excipients, selected based on successful manufacturability, were investigated in a randomised, preference and acceptability testing in 24 healthy adult volunteers. Excipients were classified in order of preference as follows (from most preferred): SmartEx QD100 > F-Melt Type C > F-Melt Type M > MicroceLac > Ludiflash > CombiLac > Pharmaburst 500 > Avicel HFE-102 > Avicel PH-102. Broad differences were identified in terms of acceptability, with SmartEx QD100 being ‘very acceptable’, F-Melt Type C, F-Melt Type M and MicroceLac being ‘acceptable’, Ludiflash, CombiLac and Pharmaburst 500 being ‘neutral’ and Avicel products being ‘very unacceptable’ based on ratings using 5-point hedonic scales. Organoleptic differences were ascribed to different composition and physical properties of excipients, resulting in dissimilar taste and mouth-feel. Excipients with particle size in water larger than 200-250 µm were considered poorly acceptable, which supports the use of this value as a threshold for maximum particle size of dispersible formulation. The most promising co-processed excipients for directly compressible dispersible tablets were successfully identified

A Typology of Child Sponsorship Activity

Framing the debate over child sponsorship in terms of legitimacy and changing perceptions of credible international humanitarian interventions, this chapter takes exception to the tendency of child sponsorship critics to assume that sponsorship funded activity is much the same everywhere and similar today when compared to sponsorship practice in the past. Mindful of ongoing critique of child sponsorship, this chapter seeks to position those international non-governmental organisations that utilise child sponsorship to fund interventions, in a landscape of contested ideas. It argues that informed critique of child sponsorship is best achieved through a typology of funded interventions. Four key types of sponsorship funded activity are identified as emerging over time, some of which are currently deemed to be less legitimate in terms of poverty reduction and are best seen as welfare measures aimed at individual children rather than community development or advocacy activities

Active wetting of epithelial tissues

Development, regeneration and cancer involve drastic transitions in tissue morphology. In analogy with the behavior of inert fluids, some of these transitions have been interpreted as wetting transitions. The validity and scope of this analogy are unclear, however, because the active cellular forces that drive tissue wetting have been neither measured nor theoretically accounted for. Here we show that the transition between 2D epithelial monolayers and 3D spheroidal aggregates can be understood as an active wetting transition whose physics differs fundamentally from that of passive wetting phenomena. By combining an active polar fluid model with measurements of physical forces as a function of tissue size, contractility, cell-cell and cell-substrate adhesion, and substrate stiffness, we show that the wetting transition results from the competition between traction forces and contractile intercellular stresses. This competition defines a new intrinsic lengthscale that gives rise to a critical size for the wetting transition in tissues, a striking feature that has no counterpart in classical wetting. Finally, we show that active shape fluctuations are dynamically amplified during tissue dewetting. Overall, we conclude that tissue spreading constitutes a prominent example of active wetting --- a novel physical scenario that may explain morphological transitions during tissue morphogenesis and tumor progression

Variable Pathogenicity Determines Individual Lifespan in Caenorhabditis elegans

A common property of aging in all animals is that chronologically and genetically identical individuals age at different rates. To unveil mechanisms that influence aging variability, we identified markers of remaining lifespan for Caenorhabditis elegans. In transgenic lines, we expressed fluorescent reporter constructs from promoters of C. elegans genes whose expression change with age. The expression levels of aging markers in individual worms from a young synchronous population correlated with their remaining lifespan. We identified eight aging markers, with the superoxide dismutase gene sod-3 expression being the best single predictor of remaining lifespan. Correlation with remaining lifespan became stronger if expression from two aging markers was monitored simultaneously, accounting for up to 49% of the variation in individual lifespan. Visualizing the physiological age of chronologically-identical individuals allowed us to show that a major source of lifespan variability is different pathogenicity from individual to individual and that the mechanism involves variable activation of the insulin-signaling pathway