Persistent High Burden and Mortality Associated With Advanced HIV Disease in Rural Tanzania Despite Uptake of World Health Organization "Test and Treat" Guidelines.

Background: Information about burden, characteristics, predictors, and outcomes of advanced human immunodeficiency virus disease (AHD) is scarce in rural settings of sub-Saharan Africa. Human immunodeficiency virus (HIV) infections and associated deaths remain high despite specific guidelines issued by the World Health Organization (WHO). Methods: Burden of AHD and 6-month death/loss to follow-up (LTFU) were described among 2498 antiretroviral therapy (ART)-naive nonpregnant people with HIV (PWH) aged >15 years enrolled in the Kilombero Ulanga Antiretroviral Cohort in rural Tanzania between 2013 and 2019. Baseline characteristics associated with AHD and predictors of death/LTFU among those with AHD were analyzed using multivariate logistic and Cox regression, respectively. Results: Of the PWH, 62.2% had AHD at diagnosis (66.8% before vs 55.7% after national uptake of WHO "test and treat" guidelines in 2016). At baseline, older age, male sex, lower body mass index, elevated aminotransferase aspartate levels, severe anemia, tachycardia, decreased glomerular filtration rate, clinical complaints, impaired functional status, and enrollment into care before 2018 were independently associated with AHD. Among people with AHD, incidence of mortality, and LTFU were 16 and 34 per 100 person-years, respectively. WHO clinical stage 3 or 4, CD4 counts <100 cells/µL, severe anemia, tachypnea, and liver disease were associated with death/LTFU. Conclusions: More than 50% of PWH enrolled in our cohort after test and treat implementation still had AHD at diagnosis. Increasing HIV testing and uptake and implementation of the WHO-specific guidelines on AHD for prevention, diagnosis, treatment of opportunistic infections, and reducing the risks of LTFU are urgently needed to reduce morbidity and mortality.

Correction: Synergistic activation of pro-inflammatory type-2 CD8 + T lymphocytes by lipid mediators in severe eosinophilic asthma.

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Synergistic activation of pro-inflammatory type-2 CD8+ T lymphocytes by lipid mediators in severe eosinophilic asthma.

Human type-2 CD8+ T cells are a cell population with potentially important roles in allergic disease. We investigated this in the context of severe asthma with persistent airway eosinophilia-a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines, which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.

Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D2 [PGD2]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C4, LTD4, and LTE4, are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. OBJECTIVES: We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s. METHODS: For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD2, IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants. RESULTS: Human ILC2s expressed the LT receptor CysLT1, levels of which were increased in atopic subjects. CysLTs, particularly LTE4, induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE4 enhanced the effect of PGD2, IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE4 was inhibited by montelukast, a CysLT1 antagonist. Interestingly, addition of IL-2 to LTE4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25. CONCLUSION: CysLTs, particularly LTE4, are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators.

Regeneration of neuronal cell types in Schmidtea mediterranea: an immunohistochemical and expression study.

Freshwater planarians are unique in their ability to regenerate a complete Central Nervous System (CNS) from almost any small piece of their body in just a few days. The planarian CNS contains a pair of anterior cephalic ganglia lying on top of two ventral nerve cords that extend along the length of the animal. Studies of planarian CNS regeneration have generally used pan-neural markers, which provide only a general overview of the process. Nevertheless, some reports have started to characterize the genes that are required for this process. In this study, to obtain a more detailed description of planarian neural regeneration, we monitored the regeneration of neuronal populations specifically labelled with antibodies against serotonin, allatostatin, neuropeptide F, GYRFamide and FMRFamide. We also characterized the regeneration of dopaminergic and octopaminergic cell populations by in situ hybridization. Finally, we characterized the expression pattern of a set of receptors for neurotransmitters, neuropeptides and hormones that are suggested to play a role in the regeneration process itself. Together, these data provide a more detailed description of the cellular events occurring during anterior and posterior CNS regeneration in planarians and provide the foundations for future mechanistic studies into the regeneration process in this important model system.