Neurocognitive outcomes of children exposed to and living with HIV aged 3–5 years in Kilifi, Kenya

IntroductionGlobally, 1.7 million children are living with HIV, with the majority of them residing in sub-Saharan Africa. Due to reduced rates of vertical transmission of HIV, there is an increasing population of children born to HIV-infected mothers who remain uninfected. There is a growing concern around the development of these children in the antiretroviral therapy era. This study examined the neurocognitive outcomes of children who are HIV-exposed infected (CHEI), HIV-exposed uninfected (CHEU) and HIV-unexposed uninfected (CHUU) and explored the relationship between child neurocognitive outcomes and child's biomedical and caregivers’ psychosocial factors.MethodsCHEI, CHUU and CHEU aged 3–5 years and their caregivers were recruited into the study. Neurocognitive outcomes were assessed using a validated battery of assessments. One-way analysis of variance and covariance (ANOVA and ANCOVA) were used to evaluate differences among the three groups by neurocognitive outcomes. Linear regression models were used to investigate the association between child neurocognitive outcomes and biomedical factors (nutritional status, HIV disease staging) and caregivers’ psychosocial factors [symptoms of common mental disorders (CMDs) and parenting behaviour].ResultsThe study included 153 children and their caregivers: 43 (28.1%) CHEI, 52 (34.0%) CHEU and 58 (39.9%) CHUU. ANOVA and ANCOVA revealed a significant difference in cognitive ability mean scores across the child groups. Post hoc analysis indicated that CHEU children had higher cognitive ability mean scores than the CHUU group. Better nutritional status was significantly associated with higher cognitive ability scores (β = 0.68, 95% CI [0.18–1.18], p = 0.008). Higher scores of CMDs were negatively associated with inhibitory control (β = −0.28, 95% CI [−0.53 to 0.02], p = 0.036). While comparing HIV stages 2 and 3, large effect sizes were seen in working memory (0.96, CI [0.08–1.80]) and cognitive ability scores (0.83 CI [0.01–1.63]), indicating those in stage 3 had poor performance.ConclusionsNeurocognitive outcomes were similar across CHEI, CHEU and CHUU, although subtle differences were seen in cognitive ability scores where CHEU had significantly higher cognitive mean scores than the CHUU. Well-designed longitudinal studies are needed to ascertain these findings. Nonetheless, study findings underscore the need for strategies to promote better child nutrition, mental health, and early antiretroviral therapy initiation

Somatic evolution and global expansion of an ancient transmissible cancer lineage

Made available in DSpace on 2019-10-06T15:53:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-02GPD Charitable TrustLeverhulme TrustThe canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by “metastasizing” between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage's worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer's evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.Transmissible Cancer Group Department of Veterinary Medicine University of CambridgeAnimal Management in Rural and Remote Indigenous Communities (AMRRIC)World VetsAnimal Shelter Stichting Dierenbescherming SurinameSikkim Anti-Rabies and Animal Health Programme Department of Animal Husbandry Livestock Fisheries and Veterinary Services Government of SikkimRoyal (Dick) School of Veterinary Studies Roslin Institute University of Edinburgh Easter Bush CampusConserLab Animal Preventive Medicine Department Faculty of Animal and Veterinary Sciences University of ChileCorozal Veterinary Hospital University of PanamáSt. George's UniversityNakuru District Veterinary Scheme LtdAnimal Medical CentreInternational Animal Welfare Training Institute UC Davis School of Veterinary MedicineCentro Universitário de Rio Preto (UNIRP)Department of Clinical and Veterinary Surgery São Paulo State University (UNESP)Ladybrand Animal ClinicVeterinary Clinic Sr. Dog'sWorld Vets Latin America Veterinary Training CenterNational Veterinary Research InstituteAnimal ClinicIntermunicipal Stray Animals Care Centre (DIKEPAZ)Animal Protection Society of SamoaFaculty of Veterinary Science University of ZuliaVeterinary Clinic BIOCONTROLFaculty of Veterinary Medicine School of Health Sciences University of ThessalyVeterinary Clinic El Roble Animal Healthcare Network Faculty of Animal and Veterinary Sciences University of ChileOnevetGroup Hospital Veterinário BernaUniversidade Vila VelhaVeterinary Clinic ZoovetservisÉcole Inter-états des Sciences et Médecine Vétérinaires de DakarDepartment of Small Animal Medicine Faculty of Veterinary Medicine Utrecht UniversityVetexpert Veterinary GroupVeterinary Clinic Lopez QuintanaClinique Veterinaire de Grand Fond Saint Gilles les BainsDepartment of Veterinary Sciences University of MessinaFacultad de Medicina Veterinaria y Zootecnia Universidad Autónoma del Estado de MéxicoSchool of Veterinary Medicine Universidad de las AméricasCancer Development and Innate Immune Evasion Lab Champalimaud Center for the UnknownTouray and Meyer Vet ClinicHillside Animal HospitalKampala Veterinary SurgeryAsavet Veterinary CharitiesVets Beyond BordersFaculty of Veterinary Medicine Autonomous University of YucatanLaboratorio de Patología Veterinaria Universidad de CaldasInterdisciplinary Centre of Research in Animal Health (CIISA) Faculty of Veterinary Medicine University of LisbonFour Paws InternationalHelp in SufferingVeterinary Clinic Dr José RojasDepartment of Biotechnology Balochistan University of Information Technology Engineering and Management SciencesCorozal Veterinary ClinicVeterinary Clinic VetmasterState Hospital of Veterinary MedicineJomo Kenyatta University of Agriculture and TechnologyLaboratory of Biomedicine and Regenerative Medicine Department of Clinical Sciences Faculty of Animal and Veterinary Sciences University of ChileFaculty of Veterinary and Agricultural Sciences University of MelbourneAnimal Anti Cruelty LeagueClinical Sciences Department Faculty of Veterinary Medicine BucharestDepartment of Pathology Faculty of Veterinary Medicine Ankara UniversityFaculty of Veterinary Sciences National University of AsuncionLilongwe Society for Protection and Care of Animals (LSPCA)Wellcome Sanger InstituteDepartment of Cellular and Molecular Medicine University of California San DiegoDepartment of Clinical and Veterinary Surgery São Paulo State University (UNESP)Leverhulme Trust: 102942/Z/13/

Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer

Abstract: Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for ‘selfish’ traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby ‘selfish’ positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells

Mitochondrial genetic diversity, selection and recombination in a canine transmissible cancer.

Canine transmissible venereal tumour (CTVT) is a clonally transmissible cancer that originated approximately 11,000 years ago and affects dogs worldwide. Despite the clonal origin of the CTVT nuclear genome, CTVT mitochondrial genomes (mtDNAs) have been acquired by periodic capture from transient hosts. We sequenced 449 complete mtDNAs from a global population of CTVTs, and show that mtDNA horizontal transfer has occurred at least five times, delineating five tumour clades whose distributions track two millennia of dog global migration. Negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and recombination has caused occasional mtDNA re-assortment. These findings implicate functional mtDNA as a driver of CTVT global metastatic spread, further highlighting the important role of mtDNA in cancer evolution.Wellcome Trust Investigator Award, 102942/Z/13/A Elizabeth P Murchison Leverhulme Trust Philip Leverhulme Prize Elizabeth P Murchison Royal Society Research Grant, RG130615 Elizabeth P Murchiso

Neurocognitive outcomes of children exposed to and living with HIV aged 3–5 years in Kilifi, Kenya

Introduction: Globally, 1.7 million children are living with HIV, with the majority of them residing in sub-Saharan Africa. Due to reduced rates of vertical transmission of HIV, there is an increasing population of children born to HIV-infected mothers who remain uninfected. There is a growing concern around the development of these children in the antiretroviral therapy era. This study examined the neurocognitive outcomes of children who are HIV-exposed infected (CHEI), HIV-exposed uninfected (CHEU) and HIV-unexposed uninfected (CHUU) and explored the relationship between child neurocognitive outcomes and child\u27s biomedical and caregivers’ psychosocial factors. Methods: CHEI, CHUU and CHEU aged 3–5 years and their caregivers were recruited into the study. Neurocognitive outcomes were assessed using a validated battery of assessments. One-way analysis of variance and covariance (ANOVA and ANCOVA) were used to evaluate differences among the three groups by neurocognitive outcomes. Linear regression models were used to investigate the association between child neurocognitive outcomes and biomedical factors (nutritional status, HIV disease staging) and caregivers’ psychosocial factors [symptoms of common mental disorders (CMDs) and parenting behaviour]. Results: The study included 153 children and their caregivers: 43 (28.1%) CHEI, 52 (34.0%) CHEU and 58 (39.9%) CHUU. ANOVA and ANCOVA revealed a significant difference in cognitive ability mean scores across the child groups. Post hoc analysis indicated that CHEU children had higher cognitive ability mean scores than the CHUU group. Better nutritional status was significantly associated with higher cognitive ability scores (β = 0.68, 95% CI [0.18–1.18], p = 0.008). Higher scores of CMDs were negatively associated with inhibitory control (β = −0.28, 95% CI [−0.53 to 0.02], p = 0.036). While comparing HIV stages 2 and 3, large effect sizes were seen in working memory (0.96, CI [0.08–1.80]) and cognitive ability scores (0.83 CI [0.01–1.63]), indicating those in stage 3 had poor performance. Conclusions: Neurocognitive outcomes were similar across CHEI, CHEU and CHUU, although subtle differences were seen in cognitive ability scores where CHEU had significantly higher cognitive mean scores than the CHUU. Well-designed longitudinal studies are needed to ascertain these findings. Nonetheless, study findings underscore the need for strategies to promote better child nutrition, mental health, and early antiretroviral therapy initiation

Means, SD, Cronbach’s α and correlation for the adapted FAHI (n = 103).

<p>Means, SD, Cronbach’s α and correlation for the adapted FAHI (n = 103).</p

Factor loadings of adapted FAHI using subscale scores.

<p>Factor loadings of adapted FAHI using subscale scores.</p

Factor loadings of adapted FAHI subscale items.

<p>Factor loadings of adapted FAHI subscale items.</p