PrEP Implementation Behaviors of Community-Based HIV Testing Staff: A Mixed-Methods Approach Using Latent Class Analysis.

BACKGROUND: Pre-exposure Prophylaxis (PrEP) is an important option for HIV prevention, but the approach has reached a limited number of people at risk of HIV infection. METHODS: A mixed-methods concurrent triangulation design was used to investigate unobserved subgroups of staff who provide community-based, publicly funded HIV testing in Florida (USA). PrEP implementation groups, or classes, were determined using latent class analysis. Generalized linear mixed models were used to estimate PrEP implementation as a function of staff characteristics. In-depth interviews based on the Consolidated Framework for Implementation Research were analyzed thematically. RESULTS: Based on fit statistics and theoretical relevance, a 3-class latent class analysis was selected. Class 1 ("Universal") staff were highly likely to talk about PrEP with their clients, regardless of client eligibility. Class 2 ("Eligibility dependent") staff were most likely to discuss PrEP if they believed their client was eligible. Class 3 ("Limited") staff sometimes spoke to clients about PrEP, but not systematically. In multivariate analyses, only race and sexual orientation remained significant predictors of the PrEP implementation group. Staff who identified as a racial or sexual minority were less likely to be in the Limited group than their heterosexual or white counterparts. Age, gender, ever having taken PrEP, and HIV status did not impact the odds of being in a specific PrEP implementation group. CONCLUSIONS: A subset of HIV testing staff differentially discuss PrEP based on perceived client eligibility; others inconsistently talk to clients about PrEP. Targeted training based on PrEP implementation groups may be beneficial.

Synergistic dopaminergic neurotoxicity of manganese and lipopolysaccharide: differential involvement of microglia and astroglia.

Overexposure to manganese is known to cause damage to basal ganglial neurons and the development of movement abnormalities. Activation of microglia and astrocytes has increasingly been associated with the pathogenesis of a variety of neurological disorders. We have recently shown that microglial activation facilitates manganese chloride (MnCl2, 10-300 microM)-induced preferential degeneration of dopamine (DA) neurons. In this study, we report that combinations of MnCl2 (1-30 microM) and endotoxin lipopolysaccharide (LPS, 0.5-2 ng/mL), at minimally effective concentrations when used alone, induced synergistic and preferential damage to DA neurons in rat primary neuron-glia cultures. Mechanistically, MnCl2 significantly potentiated LPS-induced release of tumor necrosis factor-alpha and interleukin-1 beta in microglia, but not in astroglia. MnCl2 and LPS were more effective in inducing the formation of reactive oxygen species and nitric oxide in microglia than in astroglia. Furthermore, MnCl2 and LPS-induced free radical generation, cytokine release, and DA neurotoxicity was significantly attenuated by pre-treatment with potential anti-inflammatory agents minocycline and naloxone. These results demonstrate that the combination of manganese overexposure and neuroinflammation is preferentially deleterious to DA neurons. Moreover, these findings not only shed light on the understanding of manganese neurotoxicity but may also bear relevance to the potentially multifactorial etiology of Parkinson's disease.

Microglia enhance manganese chloride-induced dopaminergic neurodegeneration: role of free radical generation.

Exposure to elevated levels of manganese has been shown to cause neuronal damage in the midbrain and the development of Parkinsonian symptoms. Activation of microglia and release of neurotoxic factors in particular free radicals are known to contribute to neurodegeneration. We have recently reported that manganese chloride (MnCl(2)) stimulates microglia to produce reactive oxygen species (ROS). The aim of this study is to determine the role of microglia in the MnCl(2)-induced degeneration of dopaminergic (DA) neurons that are particularly vulnerable to oxidative insult. MnCl(2) (10-300 microM; 7 days) was markedly more effective in damaging DA neurons in the rat mesencephalic neuron-glia cultures than the neuron-enriched (microglia-depleted) cultures. In addition, the microglia-enhanced MnCl(2) toxicity was found to be preferential to DA neurons. The microglial enhancement of DA neurotoxicity was further supported by the observation that replenishment of microglia to the neuron-enriched cultures significantly increased the susceptibility of DA neurons to the MnCl(2)-induced damage. Analysis of the temporal relationship between microglial activation and DA neurodegeneration revealed that MnCl(2)-stimulated microglial activation preceded DA neurodegeneration. Mechanistically, MnCl(2) (10-300 microM) stimulated a concentration- and time-dependent robust production of ROS and moderate production of nitric oxide but no detectable release of tumor necrosis factor-alpha and interleukin-1beta. Application of free radical scavengers including superoxide dismutase/catalase, glutathione, N-acetyl cysteine and an inhibitor of nitric oxide biosynthesis significantly protected DA neurons against the MnCl(2)-induced degeneration. These results demonstrate that microglial activation and the production of reactive nitrogen and oxygen free radicals promote the MnCl(2)-induced DA neurodegeneration.