Faculty Bibliography

BACKGROUND/UNASSIGNED:Infectious diseases (ID) physicians are important for hepatitis C virus (HCV) care delivery in Canada. Our study describes their current and intended patterns of practice, attitudes, and barriers to care. METHODS/UNASSIGNED:The study population includes 372 practicing ID physicians who are members of the Association of Medical Microbiology and Infectious Disease (AMMI) Canada. A random sample from each province was invited to participate in a web-based survey. Our outcome of interest was level of HCV care provided, and related intentions for the next 12 months. Additional survey domains included attitudes toward treatment and perceived barriers to care. RESULTS/UNASSIGNED:Of 205 invitations to complete the survey, 64 (31%) physicians responded to the full survey and 81 to an abbreviated survey on the main outcomes of interest (overall response rate 71%). After adjusting for non-response, we estimate that 38% (95% CI 29% to 46%) are prescribing direct-acting antiviral (DAA) therapy, and 17% (95% CI 9% to 24%) are interested in starting to prescribe. Of full survey respondents, 100% of prescribers and 79% of non-prescribers agreed that people who inject drugs should be offered DAA therapy. Common barriers to care include patients' competing priorities, mental health comorbidities, poor access to harm reduction services, and insufficient physician training. CONCLUSIONS/UNASSIGNED:A large proportion of Canadian ID physicians are not currently prescribing DAA therapy for HCV. While some of these physicians are interested in starting to prescribe, we need strategies to improve physician training and address other barriers to care as provincial restrictions on DAA eligibility are being eliminated.

Approximately 170 million people harbor chronic infection with hepatitis C virus (HCV) worldwide, with 3-4 million in the United States. As recently as 2013, the few treatment options available were poorly tolerated and only moderately effective. That changed when the first interferon-free direct-acting antiviral (DAA) regimen was US Food and Drug Administration-approved in December 2013. There are now 10 approved DAAs, with several more deep in the pipeline to approval. There are now interferon-free regimens available for every HCV genotype, and the application of DAA combination regimens has lifted response rates for historically difficult-to-treat patient groups to levels on par with more conventional treatment groups, including persons with HIV/HCV coinfection. This review will summarize the data behind currently recommended DAA regimens, review the data for treatment of HIV/HCV-coinfected patients, and discuss important drug-drug interactions between HCV DAAs and HIV antiretrovirals.

Yersinia enterocolitica infection rarely can cause extra-intestinal infections. We present a case of septic arthritis of the shoulder due to this organism in an elderly man with liver and cardiac disease. We review previously published cases of Y. enterocolitica septic arthritis, and discuss risk factors and management.

HIV-associated nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Pathogenesis involves direct infection of the glomerular and tubular epithelial cells leading to characteristic disorder. Recently, we have shown that HIV-1 Vpr causes hypertrophy, hyperploidy, and apoptosis. Here, we report that Vpr activates the DNA damage response resulting in the observed renal phenotype. Renal sections from the HIVAN transgenic mouse model and human biopsies both show an abundant DNA damage response.

Thymosin alpha 1 (Talpha1) has therapeutic potential in the treatment of infectious diseases and cancer. However, the exact molecular pathways for Talpha1 action are not fully understood. We found that Talpha1 induces the production of interleukin-6 (IL-6), IL-10, and IL-12 in murine bone marrow-derived macrophages (BMDMs) through IKK and MAPK pathways. Talpha1 triggers the activation of AP-1 and the phosphorylation of JNK and p38. Inhibition of p38 impairs IL-6 production in response to Talpha1. Further, TRAF6 is involved in the activation of JNK and IRAK4 is involved for the activation of IKK and PKCzeta in a Talpha1-induced system. Loss of IRAK4 largely blocked induction of IL-6. Thus, our studies define early signal events that are critical for the Talpha1-induced immune responses.

Thymosin alpha1 (T(alpha)1) is noted for its immunomodulatory activities and therapeutic potential in treatment of infectious diseases and cancer. However, the molecular mechanism of its effectiveness is not completely understood. Here, we report that T(alpha)1 induces interleukin (IL)-6 expression through the I(kappa)B kinase (IKK) and nuclear factor-(kappa)B (NF-(kappa)B) pathway. Using IKK(beta)-deficient bone-marrow-derived macrophages and mouse embryo fibroblasts (MEFs), we show that IKK(beta) is essential for IKK and NF-(kappa)B activation as well as efficient IL-6 induction. Further analysis using tumour necrosis factor receptor-associated factor 6 (TRAF6)-deficient MEFs shows that TRAF6 is crucial for activation of IKK and induction of IL-6 by Talpha1. Intriguingly, T(alpha)1 triggers protein kinase C (PKC)iota/zeta activation, which is TRAF6 dependent and involves IKK. In addition, T(alpha)1 induces the formation of a signalsome composed of TRAF6, p62 and PKC(iota)/zeta as well as IKK. Thus, our study identifies T(alpha)1 as a unique activator of the TRAF6 signal pathway and provides a cohesive interpretation of the molecular basis of the therapeutic utility of T(alpha)1.