The neurodevelopmental outcomes of perinatally HIV-infected children on different antiretroviral treatment (ART) strategies

Thesis (PhD)--Stellenbosch University, 2019.ENGLISH ABSTRACT: At the commencement of this study, it was apparent that antiretroviral therapy (ART) improved neurodevelopmental outcomes of children infected with HIV. Little was known about the long-term outcomes in infants who commenced early ART, or whether there would be consequences of temporary ART interruption. We conducted a prospective, longitudinal, observational study to determine the neurodevelopmental outcomes of children perinatally infected with HIV on different ART strategies from the Children with HIV Early antiRetroviral treatment (CHER) trial. We compared the outcomes of children whose ART was deferred to children who started early ART but with planned interruption of treatment. We also assessed the neurodevelopmental outcomes at 11months of age in a cohort of children perinatally infected with HIV, who started ART within the first few weeks of life. The Griffiths mental development scales (GMDS) were used to assess neurodevelopment at 11, 20, 30, 42 and 60 months, and the Beery-Buktenica developmental tests of visual motor integration were performed at 60 months. HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children from similar neighbourhoods were enrolled for comparison. Mixed model repeated measures were used to compare groups over time. We found that children whose ART was deferred, had worse locomotor and general development in the first year of life compared to those who started treatment early and whilst asymptomatic with planned interruption. However, by five years of age the GMDS scores were similar. Children who started very early ART at a median age of 6 days, had similar GMDS scores at 11 months of age to the early treatment arm on CHER, who had started ART at median of 8 weeks. During the study we noted that children developed HIV encephalopathy, despite being on ART, including some with viral suppression. These children were followed for a median or 6.2 years and most recovered. This suggested a temporary insult, possibly due to inflammation associated with immune reconstitution that then resolved over time. An important finding was the visual perceptual deficit noted in HIV-infected children, compared to uninfected controls at 5 years of age. This study demonstrated that initiation of ART at a young age in an asymptomatic HIV- infected cohort had encouraging neurodevelopmental outcome at 5 years, apart from visual perception which was noted regardless of ART treatment strategy. Planned treatment interruption did not affect neurodevelopmental outcome by 5 years of age, but this was with careful clinical surveillance. Longer-term outcomes in older children would continue to provide further knowledge on ART treatment strategies.AFRIKAANSE OPSOMMING: Met die aanvang van hierdie studie, was dit duidelik dat antiretrovirale terapie (ART) die neurologiese ontwikkelings uitkomste van kinders met HIV besmetting verbeter het. Daar was 'n gebrek aan inligting oor die langtermyn uitkomste van kinders wat vroeë ART behandeling gekry het, en of daar gevolge sou wees vir tydelike onderbreking van ART. Ons het 'n voornemende, langtermyn, observasionele studie na die neurologiese ontwikkelings uitkomste van kinders wat perinataal met MIV besmet was, en op verskillende ART behandelings strategieë, gedoen om die uitslae te vergelyk met die van kinders met MIV en wat op vroeë antiretrovirale behandeling is. Ons het die uitkomste van kinders wie se ART behandeling uitgestel is vergelyk met die van kinders wat ART behandeling vroeg begin het en beplande onderbreking van behandeling ondergaan het, in die Children with HIV early antiretroviral treatment (CHER) studie. Ons het ook die neurologiese ontwikkeling uitkomste op 11 maande van ouderdom in 'n groep van kinders wat perinataal met MIV besmet was, en wat ART binne die eerste paar weke van die lewe begin het, geassesseer. Die Griffiths Mental Development Scales (GMDS) is gebruik om die neurologiese ontwikkeling van kinders op 11, 20, 30, 42 en 60 maande te bepaal, en die Beery- Buktenica ontwikkelings toetse van visuele motoriese integrasie is uitgevoer op 60 maande. MIV-blootgestelde onbesmette (HEU) en MIV-onbesmette (HU) kinders van soortgelyke buurte is ingeskryf vir 'n vergelyking. 'n Gemengde model herhaal maatreëls is gebruik om groepe oor ‘n tydperk te vergelyk. Ons het gevind dat kinders wie se ART uitgestel is, slegter lokomotoriese en algemene ontwikkeling getoon het in die eerste jaar, in vergelyking met diegene wat behandeling vroeg begin het wanneer hulle asimptomaties was en wat beplande onderbreking van behandeling ondergaan het. Tog op vyf jaar van ouderdom was die GMDS tellings soortgelyk. Kinders wat vroeë ART behandeling by 'n gemiddelde ouderdom van 6 dae begin, het soortgelyke GMDS tellings op 11 maande van ouderdom gehad as die van die vroeë behandeling arm op CHER, wat ART by mediaan van 8 weke begin het. Tydens die studie is opgemerk dat kinders MIV enkefalopatie ontwikkel, ten spyte daarvan dat hulle op ART behandeling was, insluitend 'n paar wat virale onderdrukking gehad het. Hierdie kinders is opgevolg vir 'n mediaan van 6,2 jaar en die meeste van hulle het herstel. Hierdie was 'n aanduiding van tydelike skade, waarskynlik weens inflammasie, gepaartgaande met immuun-herstel, wat daarna met verloop van tyd opgeklaar het 'n Belangrike bevinding was die opmerking van 'n visuele perseptuele gebrek in kinders wat met MIV besmet is, in vergelyking met die onbesmette kontroles op 5 jaar van ouderdom. Hierdie studie het getoon dat die aanvang van ART behandeling op 'n jong ouderdom, in 'n asimptomatiese MIV-besmette groep, bemoedigende neurologiese uitkomste op 5 jaar getoon het. Die bevinding is tenspyte van visuele persepsie wat ongeag die ART behandelings strategie opgemerk was. Beplande behandeling onderbreking het geen invloed op die neurologiese uitkomste teen die ouderdom van 5 jaar aangedui nie, maar hierdie met noukeurige kliniese toesig. Die langer termyn uitkomste in ouer kinders sal voortaan verdere kennis verskaf oor ART behandelings strategieë.Doctora

isiXhosa Translation of the Patient Health Questionnaire (PHQ-9):A Pilot Study of Psychometric Properties [Stage 1]

Depression is a debilitating illness, and stigma associated with it often prevents people from seeking support. Easy-to-administer and culturally-specific diagnostic tools can allow for early screening for depression in primary care clinics, especially in resource-limited settings. In this pilot study, we will produce the first open-access isiXhosa-language version of the nine-item Patient Health Questionnaire (PHQ-9), a well-validated measure of depression incidence and severity, using a transcultural translation framework. We will validate this isiXhosa PHQ-9 in a small sample of adolescents living with HIV in Cape Town, South Africa who speak isiXhosa at home. Participants have previously completed the ASEBA Youth Self Report (YSR) form, and responses from the YSR will be used as a gold standard to validate the isiXhosa PHQ-9. If validated through this Registered Report, this isiXhosa PHQ-9 may be an invaluable culturally-specific tool for clinicians serving Xhosa people in identifying clinical or sub-clinical depression

CLAD: A Complex and Long Activities Dataset with Rich Crowdsourced Annotations

This paper introduces a novel activity dataset which exhibits real-life and diverse scenarios of complex, temporally-extended human activities and actions. The dataset presents a set of videos of actors performing everyday activities in a natural and unscripted manner. The dataset was recorded using a static Kinect 2 sensor which is commonly used on many robotic platforms. The dataset comprises of RGB-D images, point cloud data, automatically generated skeleton tracks in addition to crowdsourced annotations. Furthermore, we also describe the methodology used to acquire annotations through crowdsourcing. Finally some activity recognition benchmarks are presented using current state-of-the-art techniques. We believe that this dataset is particularly suitable as a testbed for activity recognition research but it can also be applicable for other common tasks in robotics/computer vision research such as object detection and human skeleton tracking

Diffusion tensor imaging point to ongoing functional impairment in HIV-infected children at age 5, undetectable using standard neurodevelopmental assessments

Background Perinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts. Methods DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard–Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter. Results 38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5. Conclusion Even directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study

Middle Ear Function in Human Immunodeficiency Virus (HIV)-Infected South African Children

Abstract Children with human immunodeficiency virus (HIV) infection are more likely to have hearing loss and are more susceptible to middle ear infections. The purpose of this study was to quantitatively measure middle ear function, using tympanometry

Multimodal magnetic resonance neuroimaging measures characteristic of early cART-treated pediatric HIV: A feature selection approach

Children with perinatally acquired HIV (CPHIV) have poor cognitive outcomes despite early combination antiretroviral therapy (cART). While CPHIV-related brain alterations can be investigated separately using proton magnetic resonance spectroscopy

Multi-phase quantitative compositional mapping by LA-ICP-MS: Analytical approach and data reduction protocol implemented in XMapTools

Mapping of trace element signatures is an expanding tool in geoscience and material sciences, which allows the study of solid materials, and processes that may not be captured by major elements. Developments in laser-ablation inductively-coupled-plasma mass-spectrometry (LA-ICP-MS) capabilities in the last decade now provide the necessary spatial resolution for in situ element mapping. The acquisition of two-dimensional, fully quantitative and geologically meaningful data with LA-ICP-MS is still a challenging task, and a particular obstacle is the calibration of inhomogeneous phases, such as chemically zoned minerals. This work presents a novel approach to data reduction and image generation for multi-element mapping employing LA-ICP- quadrupole MS (LA-ICP-QMS), implemented in the free and open-source software XMapTools. Three geological applications are presented to illustrate the benefits of the procedures. Garnet from an eclogitic sample (Lato Hills, Togo) and plagioclase, K-feldspar, biotite from a migmatite sample (El Oro Complex, Ecuador) were mapped multiple times at different spatial resolutions to test the calibration quality and chemical detection capabilities. Rutile in a metapelite sample (Val Malenco, Italian Alps) was mapped, and Zr-in-rutile thermometry shows a temperature range of 510 to 550 °C within a single grain. The accuracy of the LA-ICP-MS method was verified by comparison with zoned major and minor element maps (garnet, plagioclase) and Ti-in-biotite geothermometry maps obtained by electron probe microanalysis (EPMA). A spatial resolution of up to 5 μm is achieved with LA-ICP-QMS, which is similar to the resolution reported for LA-ICP time-of-flight mass spectrometry (LA-ICP-TOFMS), albeit at significantly lower acquisition speed. Maps with lower spatial resolution offer better chemical detection power as demonstrated by lower per-pixel limit of detection (LOD) map calculation. Moreover, such maps are also recorded faster. The pixel allocation strategy and the instrumental conditions also have a direct impact on map quality. We recommend that maps are interpolated to square pixels, where a pixel consists of multiple sweeps to gain an improved detection power. Benchmarks using an emulated LA-ICP-MS mapping show that the spot size, together with scan direction, can lead to a shift in composition depending on the feature size of chemical patterns. This is verified by mapping a thin 10 μm annulus in garnet visible in REE and such compositional shifts can have a significant impact on e.g., diffusion modelling. The new software solution provides a multi-standard and variable composition calibration of LA-ICP-MS maps with single pixel LOD filtering at 95% confidence, allowing the user to quantify inhomogeneous materials of major and trace elements simultaneously with improved accuracy