BackgroundThe extracellular matrix protein SPARC (Secreted Protein, Acidic, Rich in Cysteine) has been linked to degeneration of the intervertebral discs and chronic low back pain (LBP). In humans, SPARC protein expression is decreased as a function of age and disc degeneration. In mice, inactivation of the SPARC gene results in the development of accelerated age-dependent disc degeneration concurrent with age-dependent behavioral signs of chronic LBP.DNA methylation is the covalent modification of DNA by addition of methyl moieties to cytosines in DNA. DNA methylation plays an important role in programming of gene expression, including in the dynamic regulation of changes in gene expression in response to aging and environmental signals.We tested the hypothesis that DNA methylation down-regulates SPARC expression in chronic LBP in pre-clinical models and in patients with chronic LBP.ResultsOur data shows that aging mice develop anatomical and behavioral signs of disc degeneration and back pain, decreased SPARC expression and increased methylation of the SPARC promoter. In parallel, we show that human subjects with back pain exhibit signs of disc degeneration and increased methylation of the SPARC promoter. Methylation of either the human or mouse SPARC promoter silences its activity in transient transfection assays.ConclusionsThis study provides the first evidence that DNA methylation of a single gene plays a role in chronic pain in humans and animal models. This has important implications for understanding the mechanisms involved in chronic pain and for pain therapy.
Purpose of Review To highlight recent trends in the epidemiology of HIV and syphilis, the impact of the COVID epidemic, our approach to care of co-infected patients, and our views on important next steps in advancing the field. Recent Findings HIV and syphilis co-infection has been on the rise in recent years although since the COVID pandemic there is a decrease in new diagnoses—it remains unclear if this represents a true decline or inadequate testing or under-reporting. Standard HIV care should include regular syphilis serology .Treatment and serological follow-up of syphilis in HIV positive and negative patients can be conducted similarly. Challenges remain in the diagnosis and management of neurosyphilis. New models for testing and prevention will be crucial next steps in controlling co-infection. Summary The intersection of HIV and syphilis infections continues to pose new and unique challenges in diagnosis, treatment, and prevention.
Objectives HIV pre-exposure prophylaxis (PrEP) is a proven tool for HIV prevention, but PrEP use in Ontario, Canada, and the effects of recent policies are unknown. We estimated the number and characteristics of PrEP users in Ontario and evaluated the impacts of policy changes between July 2015 and June 2018. Methods We obtained tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) dispensation data for Ontario from IQVIA, and applied an algorithm to identify use for PrEP. We report prevalent PrEP use for the second quarter of 2018 according to age, sex, region, prescriber specialty, and payer type, and generate “PrEP-to-need ratios” (PNR) by dividing these numbers by the estimated numbers of new HIV diagnoses. We used interventional autoregressive integrated moving average models to examine the impact of three policy changes on PrEP use: Health Canada approval (February 2016), availability of generic TDF/FTC and partial public drug coverage (September 2017), and public drug coverage for individuals aged < 25 years (January 2018). Results The estimated number of individuals receiving PrEP increased 713%, from 374 in 2015 Q3 to 3041 in 2018 Q2. Among PrEP users in 2018 Q2, 97.5% were male, 60.4% were < 40 years, 67.7% obtained PrEP from a family physician, 77.2% used private insurance, and 67.0% were in Toronto. PNRs were highest in 30–39-year-olds, males, Toronto and the Central East and West regions. Time series analyses found that Health Canada approval (p = 0.0001) and introducing generics/partial public drug coverage (p = 0.002) led to significantly increased use. Conclusions PrEP use has risen in Ontario in association with favourable policy changes, but remains far below guideline recommendations.
Pre-exposure prophylaxis (PrEP) for HIV is a proven and effective tool for preventing HIV. However, there are instances where individuals taking PrEP have contracted HIV infection. Most of these cases are due to nonadherence to the drug, while other cases of apparent PrEP failure are due to unrecognized HIV infection at baseline. Importantly, there are also now at least three well-documented cases of PrEP failing despite adequate adherence; these are cases of PrEP 'breakthrough'. This article outlines the potential mechanisms of PrEP failure, as well as how to identify and manage these patients. Finally, we provide a perspective on the future of PrEP as a key tool in preventing HIV worldwide.
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