Canadians studying medicine abroad and their journey to secure postgraduate training in Canada or the United States.

BACKGROUND: From national and international workforce perspectives, Canadians studying medicine abroad (CSAs) are a growing provider group. Some were born in Canada whereas others immigrated as children. They study medicine in various countries, often attempting both American and Canadian medical licensure pathways. METHODS: Using data from the Educational Commission for Foreign Medical Graduates (ECFMG) and the Medical Council of Canada (MCC), we looked at CSAs who attempted to secure residency positions in both Canada and the United States. We detailed the CSAs' countries of birth and medical education. We tracked these individuals through their postgraduate education programs to enumerate their success rate and categorize the geographic locations of their training. RESULTS: The majority of CSAs study medicine in one of 10 countries. The remainder are disbursed across 88 other countries. Most CSAs were born in Canada (62%). Approximately 1/3 of CSA from the 2004-2016 cohort had no record of entering a residency program in Canada or the United States (U.S.). Recently graduated CSAs were most likely to secure residency training in Ontario and New York. CONCLUSION: Many CSAs attempt to secure residency training in both Canada and the U.S. Quantifying success rates may be helpful for Canadians thinking about studying medicine abroad. Understanding the educational pathways of CSAs will be useful for physician labour workforce planning.

CONTEXTE: Selon une perspective nationale et internationale des effectifs, les Canadiens qui étudient la médecine à l'étranger (CEE) représentent un groupe en croissance. Certains sont nés au Canada, alors que d'autres ont immigré durant leur enfance. Ils étudient la médecine dans divers pays, essayant souvent parallèlement d'obtenir un permis américain et canadien pour exercer la médecine. MÉTHODES: À l'aide de données de l'Educational Commission for Foreign Medical Graduates (ECFMG) et du Conseil médical du Canada (CMC), nous avons examiné les CEE qui avaient tenté d'obtenir des postes de résidence à la fois au Canada et aux États-Unis. Nous avons extrait des données quant au pays de naissance et à la formation médicale de ces CEE. Nous avons suivi ces personnes dans leurs processus de demande d'admission à des programmes de formation postdoctorale pour rapporter leur taux de succès et catégoriser les emplacements géographiques de leur formation. RÉSULTATS: Nous avons identifié 10 pays d'où provenaient la plupart de ces CEE. Les autres CEE provenaient de 88 autres pays. La plupart de ces CEE sont nées au Canada (62 %). Environ 1/3 des CEE de la cohorte de 2004 à 2016 ne possède pas de dossier d'inscription à un programme de résidence au Canada ou aux États-Unis. Les CEE récemment diplômés étaient les plus susceptibles de suivre une formation en résidence en Ontario et dans l'État de New York. CONCLUSION: De nombreux CEE ont tenté d'obtenir un poste de résidence au Canada et aux États-Unis. Quantifier les taux de succès pourrait se révéler utile pour les Canadiens qui pensent à étudier la médecine à l'étranger. Comprendre les parcours éducatifs des CEE sera utile à la planification des effectifs médicaux.

Enhanced IL-10 production in response to hepatitis C virus proteins by peripheral blood mononuclear cells from human immunodeficiency virus-monoinfected individuals.

BACKGROUND: Multiple immune evasion strategies by which HCV establishes chronic infection have been proposed, including manipulation of cytokine responses. Prior infection with HIV increases the likelihood of chronic HCV infection and accelerates development of HCV-related morbidity. Therefore, we investigated in vitro cytokine responses to HCV structural and non-structural proteins in peripheral blood mononuclear cells (PBMC) from uninfected, HIV-infected, HCV-infected and HIV/HCV-coinfected individuals. RESULTS: Intracellular flow cytometry was used to assess IL-2, IL-10, IL-12, and IFN-gamma production by freshly isolated PBMC incubated for 16 hours with recombinant HCV core, non-structural protein 3 (NS3), and NS4 proteins. Anti-HCV cellular responses were assessed in HIV/HCV-coinfected individuals by 3H-thymidine proliferation assay. Exposure to HCV antigens increased IL-10 production by PBMC, especially in uninfected and HIV-monoinfected individuals. This IL-10 response was attenuated in chronic HCV infection even with HCV/HIV-coinfection. The cells producing IL-10 in response to HCV proteins in vitro matched a PBMC subset recently shown to constitutively produce IL-10 in vivo. This subset was found at similar frequencies in uninfected, HIV-infected, HCV-infected and HIV/HCV-coinfected individuals before exposure to HCV proteins. HCV-specific T cell proliferation was detectable in only one HIV/HCV-coinfected individual who demonstrated no HCV-induced IL-10 response. CONCLUSION: This pattern suggests that selective induction of IL-10 in uninfected individuals and especially in HIV-monoinfected individuals plays a role in establishing chronic HCV infection and conversely, that attenuation of this response, once chronic infection is established, favours development of hepatic immunopathology.

Antiretroviral drug resistance mutations sustain or enhance CTL recognition of common HIV-1 Pol epitopes.

Antiretroviral drug resistance and escape from CTL are major obstacles to effective control of HIV replication. To investigate the possibility of combining drug and immune-based selective pressures against HIV, we studied the effects of antiretroviral drug resistance mutations on CTL recognition of five HIV-1 Pol epitopes presented by common HLA molecules. We found that these common drug resistance mutations sustain or even enhance the antigenicity and immunogenicity of HIV-1 Pol CTL epitopes. Variable patterns of cross-reactive and selective recognition of wild-type and corresponding variant epitopes demonstrate a relatively diverse population of CD8(+) T cells reactive against these epitopes. Variant peptides with multiple drug resistance mutations still sustained CTL recognition, and some HIV-infected individuals demonstrated strong CD8(+) T cell responses against multiple CTL epitopes incorporating drug resistance mutations. Selective reactivity against variant peptides with drug resistance mutations reflected ongoing or previous exposure to the indicated drug, but was not dependent upon the predominance of the mutated sequence in endogenous virus. The frequency and diversity of CTL reactivity against the variant peptides incorporating drug resistance mutations and the ability of these peptides to activate and expand CTL precursors in vitro indicate a significant functional interface between the immune system and antiretroviral therapy. Thus, drug-resistant variants of HIV are susceptible to immune selective pressure that could be applied to combat transmission or emergence of antiretroviral drug-resistant HIV strains and to enhance the immune response against HIV.

Factors related to loss of HIV-specific cytotoxic T lymphocyte activity.

OBJECTIVE: To identify factors associated with loss of in vitro stimulated anti-HIV cytotoxic T lymphocyte (CTL) activity. METHODS: Immunological, virological and other characteristics of individuals who sustained anti-HIV CTL activity for prolonged periods with viral replication suppressed below detectable levels were compared with those that lost anti-HIV CTL activity under the same circumstances. Forty-four individuals, all but one receiving highly active antiretroviral therapy or combination therapy, were followed for 56 months. Virus load, lymphocyte counts, CD28 expression on CD8 T cells, in vitro restimulated HIV-specific CTL and T cell proliferation were assessed at regular intervals. RESULTS: Anti-HIV CTL responses were maintained throughout by 20 individuals with consistently detectable HIV replication and in 17 of 24 individuals with sustained suppression of HIV replication. As a group, the seven who lost anti-HIV CTL were older, had weaker baseline anti-HIV CTL activity, higher historical virus loads, lower historical and contemporary CD4 T cell counts and a lower percentage of CD8 T cells expressing CD28. Multivariate analysis suggested that CD4 T cell counts and anti-HIV CTL amplitude at study onset were independently associated with CTL loss in these individuals, as was percentage of CD8 T cells expressing CD28 at study's end. There was a significant direct correlation between nadir CD4 T cell counts and duration of anti-HIV CTL persistence after suppression of viral replication. CONCLUSIONS: Most HIV-infected individuals retain CD8 anti-HIV CTL with in vitro proliferative potential, even when antigen is limited. Those who lose HIV-specific CTL responses generally show past or current evidence of severe disease progression or activity.

Lack of CD28 expression on HIV-specific cytotoxic T lymphocytes is associated with disease progression.

During HIV infection, CD8+ T cells lacking the costimulatory molecule CD28 increase in number and proportion. This accumulation is associated with disease activity and possibly with CD8+ T-cell dysfunction. In this study, CD8+CD28+ and CD8+CD28- T cells from 41 HIV-infected individuals at various stages of disease were compared in terms of HIV-specific cytotoxicity, TCR beta V repertoire diversity, and cytokine production. We found that the CD28 phenotype of anti-HIV CTL evolves in parallel with disease progression and disease activity. Absolute numbers of CD4+ T cells and CD4+/CD8+ T-cell ratios progressively decreased in 3 groups with an increasing prevalence of CD28- HIV-specific CTL. Conversely, HIV replication levels progressively increased in parallel with the prevalence of CD28- HIV-specific CTL. Repertoire diversity at the level of TCR beta V gene family expression was maintained at normal levels for both CD28+ and CD28- T cells at all stages of infection. Diversity at the level of junctional length polymorphism was more restricted in the CD8+CD28- T-cell population, but this difference remained relatively constant through different stages of infection. Both CD28+ and CD28- T cells produced IL-2 and IFN-gamma, regardless of disease stage and/or the predominant CD28 phenotype of anti-HIV CTL.

Extrapyramidal symptoms with ritonavir/indinavir plus risperidone.

OBJECTIVE: To report a case of suspected extrapyramidal symptoms (EPS) in a patient initiated on ritonavir and indinavir while taking risperidone for a tic disorder. CASE SUMMARY: A 35-year-old white man with AIDS received risperidone 2 mg twice daily for treatment of a Tourette's-like tic disorder. Ritonavir and indinavir were initiated, and 1 week later, he experienced significantly impaired swallowing, speaking, and breathing, and worsening of his existing tremors. Ritonavir and indinavir were discontinued. On the same day, the patient increased the risperidone dosage to 3 mg twice daily. Symptoms continued to worsen over the next 3 days. All investigations and laboratory parameters were unremarkable, and vital signs were stable. Risperidone was discontinued and clonazepam initiated. Three days later, the patient's symptoms were significantly improved. DISCUSSION: The symptoms described herein are consistent with neuroleptic-induced acute dystonia and potentially neuroleptic-induced parkinsonism. We believe this adverse effect occurred as a result of a drug interaction between ritonavir/indinavir and risperidone. Based on the pharmacokinetics of these medications, we hypothesize that inhibition of CYP2D6 and CYP3A4 by ritonavir and indinavir may have resulted in an accumulation of the active moiety of risperidone, which may explain the occurrence of EPS in this patient. CONCLUSIONS: This is the second published case report describing a suspected drug interaction with ritonavir, indinavir, and risperidone. Caution is warranted when risperidone is prescribed with ritonavir/indinavir, and possibly with other antiretrovirals that inhibit the same pathways.