HIV-Associated Neurocognitive Disorder: Pathogenesis and Therapeutic Opportunities

Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach

Activation of the Integrated Stress Response in HIV-Associated Neurocognitive Disorder

HIV-associated neurocognitive disorders (HAND) are comprised of a host of behavioral, cognitive, and motor disabilities and can range from more minor disorders that largely allow basic daily functioning to severe disorders, such as HIV-associated dementia. The mechanisms that ultimately result in neuronal death in HAND are not known. Presented here are data demonstrating activation of the Integrated Stress Response (ISR) in cortical autopsy tissue from HAND patients, as well as data characterizing the nature of the activation of this cellular stress response in this disease. Specifically, we have shown that there are increased levels of the molecular chaperone protein, BiP, which serves as an indicator of general ISR activation. We then present data to suggest that, of the three prongs of the ISR, the prong initiated by ATF6 appears to be active, while PERK does not appear to initiate the prong it regulates. However, intriguingly, proteins downstream of PERK, namely global pEIF2α and astrocytic ATF4 do appear to be activated, suggesting that other initiators outside of the PERK pathway may be acting on these classic components of the ISR. Finally, we show data suggesting that Nrf2, the master regulator of the endogenous antioxidant component of the ISR, may be active in the cortex of HAND patients. While the ISR is clearly a protective response, able to help individual cells protect themselves from toxic insults, it is also able to initiate cellular apoptosis, which in principle protects healthy cells from a dangerous necrotic death of neighboring cells. However, under conditions of chronic stress in the CNS, such as that seen in HAND, too many neurons may die as a result of ISR-initiated apoptosis, thereby resulting in the neurocognitive decline with which these patients are afflicted. Thus, the findings presented here provide starting points of investigation for research aimed at developing potential therapeutic targets for HAND, with some targets for which their response must be increased by therapies and other targets for which their response must be dampened by therapies

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine