Interrogating the impact of combination antiretroviral therapies on HIV-associated neurocognitive disorders.

OBJECTIVES: Although the advent of Combination Antiretroviral Therapy (cART) has greatly reduced the prevalence of HIV-Associated Dementia, the most severe form of HIV-Associated Neurocognitive Disorder (HAND), the incidence of the milder forms of HAND have risen. The explanations proposed include persistent central nervous system (CNS) viraemia and the neurotoxicity of chronic cART regimens. Nonetheless, controversies in HAND prevalence estimates, alongside a lack of consensus on the significance of CNS Penetration Effectiveness (CPE) have added to the complexity of elucidating the role of cART in HAND. The present review will evaluate the evidence underlying these explanations, as well as highlighting the need for improved trial designs and the incorporation of emerging biomarkers and neuroimaging tools. METHODS: A review of the current literature investigating cART neurotoxicity, controversies in HAND prevalence estimates, CNS Penetration Effectiveness, and neuroprotective adjuvant therapies. CONCLUSIONS: Ultimately, the inadequacy of cART in achieving complete preservation of the CNS underscores the imminent need for neuroprotective adjuvant therapies, where the efficacy of combining multiple adjuvant classes presents a potential therapeutic frontier which must be interrogated.

The rules for online clinical engagement in the COVID era.

Coronavirus disease-2019 (COVID-19) has generated a need to rapidly increase online consulting in secondary care, an area in which it has previously been underutilised. We sought to review the guidance on conducting remote consultations and found that while there is a large amount of information about the implementation of remote consultations at an organisation level, there is a paucity of high-quality papers considering the guidelines for online consultations alongside practical advice for their implementation at the individual level. We reviewed guidelines from reputable medical sources and generated practical advice to assist practitioners to perform safe and effective video consultation. Additionally, we noted reports in the literature of a lack of transparency and resulting confusion regarding the choice of telemedicine platforms. We, therefore, sought to summarise key characteristics of a number of major telemedicine platforms. We recognised a lack of clarity regarding the legal status of performing remote consultations, and reviewed advice from medico-legal sources. Finally, we address the sources of these individual uncertainties, and give recommendations on how these might be addressed systematically, so the practitioners are well trained and competent in the use of online consultations, which will inevitably play an increasingly large role in both primary and secondary care settings in the future.

LRRK2 Is Recruited to Phagosomes and Co-recruits RAB8 and RAB10 in Human Pluripotent Stem Cell-Derived Macrophages.

The Parkinson's disease-associated gene, LRRK2, is also associated with immune disorders and infectious disease and is expressed in immune subsets. Here, we characterize a platform for interrogating the expression and function of endogenous LRRK2 in authentic human phagocytes using human induced pluripotent stem cell-derived macrophages and microglia. Endogenous LRRK2 is expressed and upregulated by interferon-γ in these cells, including a 187-kDa cleavage product. Using LRRK2 knockout and G2019S isogenic repair lines, we find that LRRK2 is not involved in initial phagocytic uptake of bioparticles but is recruited to LAMP1+/RAB9+ "maturing" phagosomes, and LRRK2 kinase inhibition enhances its residency at the phagosome. Importantly, LRRK2 is required for RAB8a and RAB10 recruitment to phagosomes, implying that LRRK2 operates at the intersection between phagosome maturation and recycling pathways in these professional phagocytes.