Serum immune markers and transition to psychosis in individuals at clinical high risk.

Individuals at clinical high risk (CHR) for psychosis have been found to have altered cytokine levels, but whether these changes are related to clinical outcomes remains unclear. We addressed this issue by measuring serum levels of 20 immune markers in 325 participants (n = 269 CHR, n = 56 healthy controls) using multiplex immunoassays, and then followed up the CHR sample to determine their clinical outcomes. Among 269 CHR individuals, 50 (18.6 %) developed psychosis by two years. Univariate and machine learning techniques were used to compare levels of inflammatory markers in CHR subjects and healthy controls, and in CHR subjects who had (CHR-t), or had not (CHR-nt) transitioned to psychosis. An ANCOVA identified significant group differences (CHR-t, CHR-nt and controls) and post-hoc tests indicated that VEGF levels and the IL-10/IL-6 ratio were significantly higher in CHR-t than CHR-nt, after adjusting for multiple comparisons. Using a penalised logistic regression classifier, CHR participants were distinguished from controls with an area-under the curve (AUC) of 0.82, with IL-6 and IL-4 levels the most important discriminating features. Transition to psychosis was predicted with an AUC of 0.57, with higher VEGF level and IL-10/IL-6 ratio the most important discriminating features. These data suggest that alterations in the levels of peripheral immune markers are associated with the subsequent onset of psychosis. The association with increased VEGF levels could reflect altered blood-brain-barrier (BBB) permeability, while the link with an elevated IL-10/IL-6 ratio points to an imbalance between anti- and pro-inflammatory cytokines.

An Emerging Syndemic of Smoking and Cardiopulmonary Diseases in People Living with HIV in Africa.

BACKGROUND: African countries have the highest number of people living with HIV (PWH). The continent is home to 12% of the global population, but accounts for 71% of PWH globally. Antiretroviral therapy has played an important role in the reduction of the morbidity and mortality rates for HIV, which necessitates increased surveillance of the threats from pernicious risks to which PWH who live longer remain exposed. This includes cardiopulmonary comorbidities, which pose significant public health and economic challenges. A significant contributor to the cardiopulmonary comorbidities is tobacco smoking. Indeed, globally, PWH have a 2-4-fold higher utilization of tobacco compared to the general population, leading to endothelial dysfunction and atherogenesis that result in cardiopulmonary diseases, such as chronic obstructive pulmonary disease and coronary artery disease. In the context of PWH, we discuss (1) the current trends in cigarette smoking and (2) the lack of geographically relevant data on the cardiopulmonary conditions associated with smoking; we then review (3) the current evidence on chronic inflammation induced by smoking and the potential pathways for cardiopulmonary disease and (4) the multifactorial nature of the syndemic of smoking, HIV, and cardiopulmonary diseases. This commentary calls for a major, multi-setting cohort study using a syndemics framework to assess cardiopulmonary disease outcomes among PWH who smoke. CONCLUSION: We call for a parallel program of implementation research to promote the adoption of evidence-based interventions, which could improve health outcomes for PWH with cardiopulmonary diseases and address the health inequities experienced by PWH in African countries.

Interaction between childhood adversity and functional polymorphisms in the dopamine pathway on first-episode psychosis.

BACKGROUND: There is consistent evidence of a cumulative relationship between childhood adversity and psychosis, with number of adversities experienced increasing the probability of psychosis onset. It is possible that genetic factors moderate the association between childhood adversity and psychosis, potentially by influencing how an individual reacts biologically and/or psychologically following exposure to adversity, in such a way as to set them off on the path to psychosis. However, identifying the specific genetic variants involved and how they interact with childhood adversity remains challenging. We examined whether the association between cumulative exposure to childhood adversity and development of psychotic disorder was moderated by the COMT Val158Met, AKT1 rs2494732 or DRD2 rs1076560 polymorphisms, known to affect dopamine levels. METHODS: Participants were 285 first-presentation psychosis cases and 256 geographically-matched controls drawn from the Genetics and Psychosis (GAP) study. Childhood adversity was assessed using the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and blood- and cheek-derived genotype data were collected. RESULTS: Our findings revealed no main effect of COMT Val158Met, AKT1 rs2494732 and DRD2 rs1076560 polymorphisms on psychosis case status or reports of childhood adversity. Individuals reporting a history of multiple adversities were more likely to be psychosis patients than controls, regardless of their genetic risk. There was no evidence of candidate genotype by childhood adversity interactions in relation to psychosis onset. CONCLUSION: These findings did not provide evidence of a possible role of COMT Val158Met, AKT1 rs2494732 or DRD2 rs1076560 genotypes in modifying the association between childhood adversity and onset of psychosis.

Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users.

BACKGROUND: Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect. METHODS: In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis. RESULTS: The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction = 8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio = 2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio = 13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio = 7.23 [95% confidence interval: 1.37, 38.12]). CONCLUSIONS: Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users.