Essential Fatty Acid Deficiency as a modifiable determinant of cognitive dysfunction among 6-18-year-old Ugandan children of varying perinatal HIV status

项目摘要/摘要 来自中低收入国家的三分之一以上的儿童有患神经认知障碍(ND)的风险 和/或由于感染发病率和营养不良的高负担而造成的重大学业问题 导致免疫功能障碍和破坏肠道(即肠道)内正常的宿主-微生物相互作用 生态失调)。虽然所有儿童都有风险，但围产期感染艾滋病毒的人神经认知功能障碍的风险 未感染艾滋病毒(PHIV)和接触艾滋病毒(HEU)的儿童通过当前和/或早期的抗逆转录病毒药物获得放大 治疗(ART)。针对感染艾滋病毒的孕妇的抗逆转录病毒疗法有效降低母婴传播的可能性 艾滋病毒的传播。然而，这种暴露增加了一系列不良风险因素的可能性。 儿童的神经发育结局，如低出生体重、代谢问题和神经毒性 他们的母亲在怀孕期间接受了抗逆转录病毒治疗。此外，艾滋病毒携带者和HEU儿童有不同的 肠道微生物区系与社区对照的比较。营养之间相互作用的程度 HIV感染者的缺陷、肠道生物失调和目前的ART或宫内/围产期ART病史 儿童造成负面反馈循环，与未暴露的艾滋病毒相比，会恶化与ND相关的结果 未感染(HUU)儿童未知。本项目解决了当前理解中的这一差距。 作为已完成和正在进行的研究的一部分，我们的团队已经建立并维护了大量的 学龄儿童和青少年(6至18岁)艾滋病毒感染者(n=255)、HEU(n=254)和HUU(n=257)儿童 乌干达。在我们现有的队列中，大多数(49.7%)感染艾滋病毒的儿童没有接受任何围产期抗逆转录病毒药物治疗 防止艾滋病毒母婴传播。绝大多数接受过围产期干预的患者 接触次优IPA(34.8%)，相对少数(15%)接触联合ART 通过他们的母亲在宫内/围产期。父项目允许此团队遵循 已建立队列三年以上，进行年度认知评估并重复 营养、肠道生态失调和免疫功能障碍的测量。数据将与已有的 对神经认知变化之间的关系进行权威性分析的可用信息 36个月随访和围产期HIV状态、早期ART状态和必需脂肪酸的结果 缺乏症。 总体影响：通过实施这一项目，我们将确定哪些儿童有恶化的风险 发展成果，以便现有的支持性护理干预措施可以针对 最大的需要。其次，被评估的神经认知风险的预测因素是潜在的可修改的、开放的 另一种干预途径，以确保所有儿童从长远来看都能在发展中茁壮成长。

PROJECT SUMMARY/ABSTRACT More than 1 in 3 children from low middle-income countries are at risk of neurocognitive disorder (ND) and/or significant scholastic problems due to high burden of infectious morbidity and malnutrition which contributes to immune dysfunction and disruption of normal host-microbe interactions in the gut (i.e., intestinal dysbiosis). While all children are at risk, the risk of neurocognitive dysfunction for perinatally HIV-infected (PHIV) and HIV-exposed uninfected (HEU) children is amplified by current and/or early life antiretroviral therapy (ART). ART for HIV-infected pregnant women effectively reduces the likelihood of mother-to-child transmission of HIV. This exposure, however, increases the likelihood of a range of risk factors for adverse neurodevelopmental outcomes such as low birth weight, metabolic problems, and neurotoxicity among children whose mothers received ART in pregnancy. Further, persons living with HIV and HEU children have different intestinal microbiomes compared to community controls. The extent to which interactions between nutritional deficiency, intestinal dysbiosis, and current ART or in utero/peripartum ART history among HIV-affected children creates a negative feedback loop that worsens ND, related outcomes relative to HIV unexposed uninfected (HUU) children is unknown. This gap in current understanding is addressed in this project. As part of completed and ongoing research, our team has established and maintained a large cohort of school-aged and adolescent (ages 6 to 18 years) PHIV (n=255), HEU (n=254) and HUU (n=257) children from Uganda. Most (49.7%) HIV exposed children in our existing cohort did not receive any peripartum ART to prevent HIV mother-to-child-transmission. The vast majority of those that received any peripartum intervention were exposed to sub-optimal IPA (34.8%) and a relative minority (15%) were exposed to combination ART through their mothers in the in utero/peripartum period. The parent project allows this team to follow the already established cohort for three more years, conduct annual assessment of cognition and repeated measures of nutrition, intestinal dysbiosis, and immune dysfunction. The data will be integrated with already available information to implement definitive analyses of relationships between change in neurocognitive outcomes over 36 months follow-up and perinatal HIV status, early ART status, and Essential Fatty Acid Deficiency. Overall Impact: By implementing this project, we will identify children who are at risk of worse developmental outcomes so that the available supportive care interventions can be directed to those in greatest need. Second, the predictors of neurocognitive risk evaluated are potentially modifiable, opening another avenue to intervene to ensure that all children are developmentally thriving in the long-term.