Multimodal neuroimaging of vestibular and postural networks: Investigating the pathophysiology of idiopathic dizziness in older adults

Successful ageing - the preservation of good performance into old age, is an aspiration for many and a challenge for society. Modifiable factors which account for ageing-related functional decline should thus be identified and reduced. As life expectancy increases, brain ageing and its functional consequences become an increasingly important target for research and intervention. Cerebral small vessel disease, largely driven by vascular risk factors, has emerged as a strong contributor to cognitive and balance decline in late life. Though the early effects of cerebral small vessel disease on cognition are increasingly better understood, its symptomatic effects on other functional systems are not well characterised. In this thesis, I investigated the long recognised, but pathophysiologically enigmatic syndrome of dizziness in older adults, not accounted for by neurological disease or vestibular dysfunction. I considered the hypothesis that this ‘idiopathic dizziness’ is secondary to cerebral small vessel disease through its deleterious effects on white matter networks which subserve vestibular perceptual processes and/or the control of balance. I first defined the functional anatomy of the core human vestibular cortex by its functional connectivity (Chapter 3). I related the resulting anatomical subregions to behavioural and task neuroimaging data to define a vestibular network involved in self-motion perception. I proceeded to characterise the syndrome of idiopathic dizziness using clinical, cognitive and behavioural (vestibular function, balance and gait) data from patients and controls (Chapter 4). I combined this data with structural and diffusion magnetic resonance imaging data to investigate the pathophysiology of idiopathic dizziness. I found that frontal white matter tracts relevant to the control of balance had lower integrity in patients with idiopathic dizziness than controls. These findings occurred in the context of excess vascular risk, and markers of cerebral small vessel disease. Additionally, I found vestibular function and perception were normal in patients with idiopathic dizziness. The results suggest disrupted balance control may underpin idiopathic dizziness in cerebral small vessel disease. I proceeded to investigate whether neural correlates of balance control were altered in idiopathic dizziness as a model for mild balance impairment in cerebral small vessel disease (Chapter 5). To do this, I applied electroencephalography during quiet standing and related brain activity to spontaneous sway. I showed idiopathic dizziness was linked to altered cortical activity in relation to balance control, and this cortical activity was influenced by the burden of cerebral small vessel disease. Additionally, patients with idiopathic dizziness uniquely engaged a low frequency postural connectivity network, consistent with a different mode of postural control. Overall, the results within this thesis show a relationship between idiopathic dizziness and vascular injury to frontal tracts involved in the control of balance in cerebral small vessel disease. Small vessel disease may disrupt the cortical control of balance as a basis for symptoms in this syndrome.Open Acces

Multiphysics simulation of added carbon particles within fluidized bed anode zinc-electrode

Batteries will continue to encounter the problem of dendrite formation until a suitable solution is identified to address the problem. Dendrite formation can short circuit batteries cells, reduce their life span, voltages and cause mechanical abrasion to the cells. Batteries electrodes are part of the approaches that can be used to address these problems but depending on the fabrication of these electrodes and dimensions. Before fabricating and incorporating a real anode reactor to a fabricated ZnBr2 cell system, it was necessary to model the behaviour with injected carbon particles in between 254 microns to 354 microns and simulate the geometry in COMSOL to observe their interaction with the electrolyte. This study investigates the performances of a designed anode reactor and to observe within the reactor the effect of having a uniform and non-uniform current density distribution before the fabrication, physically charge and incorporating it to the anode-side of ZnBr2 cell system

Vestibular loss disrupts visual reactivity in the alpha EEG rhythm

The alpha rhythm is a dominant electroencephalographic oscillation relevant to sensory-motor and cognitive function. Alpha oscillations are reactive, being for example enhanced by eye closure, and suppressed following eye opening. The determinants of inter-individual variability in reactivity in the alpha rhythm (e.g. changes with amplitude following eye closure) are not fully understood despite the physiological and clinical applicability of this phenomenon, as indicated by the fact that ageing and neurodegeneration reduce reactivity. Strong interactions between visual and vestibular systems raise the theoretical possibility that the vestibular system plays a role in alpha reactivity. To test this hypothesis, we applied electroencephalography in sitting and standing postures in 15 participants with reduced vestibular function (bilateral vestibulopathy, median age = 70 years, interquartile range = 51-77 years) and 15 age-matched controls. We found participants with reduced vestibular function showed less enhancement of alpha electroencephalography power on eye closure in frontoparietal areas, compared to controls. In participants with reduced vestibular function, video head impulse test gain - as a measure of residual vestibulo-ocular reflex function - correlated with reactivity in alpha power across most of the head. Greater reliance on visual input for spatial orientation ('visual dependence', measured with the rod-and-disc test) correlated with less alpha enhancement on eye closure only in participants with reduced vestibular function, and this was partially moderated by video head impulse test gain. Our results demonstrate for the first time that vestibular function influences alpha reactivity. The results are partly explained by the lack of ascending peripheral vestibular input but also by central reorganisation of processing relevant to visuo-vestibular judgements

Oxidative stress-related biomarkers in multiple sclerosis:a review

Aim: To provide an up-to-date review of oxidative stress biomarkers in multiple sclerosis and thus identify candidate molecules with greatest promise as biomarkers of diagnosis, disease activity or prognosis. Method: A semi-systematic literature search using PubMed and other databases. Results: Nitric oxide metabolites, superoxide dismutase, catalase, glutathione reductase, inducible nitric oxide synthase, protein carbonyl, 3-nitrotyrosine, isoprostanes, malondialdehyde and products of DNA oxidation have been identified across multiple studies as having promise as diagnostic, therapeutic or prognostic markers in MS. Conclusion: Heterogeneity of study design, particularly patient selection, limits comparability across studies. Further cohort studies are needed, and we would recommend promising markers be incorporated into future clinical trials to prospectively validate their potential

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.Peer reviewe

Hearing loss prevalence and years lived with disability, 1990–2019: findings from the Global Burden of Disease Study 2019

Background Hearing loss affects access to spoken language, which can affect cognition and development, and can negatively affect social wellbeing. We present updated estimates from the Global Burden of Disease (GBD) study on the prevalence of hearing loss in 2019, as well as the condition's associated disability. Methods We did systematic reviews of population-representative surveys on hearing loss prevalence from 1990 to 2019. We fitted nested meta-regression models for severity-specific prevalence, accounting for hearing aid coverage, cause, and the presence of tinnitus. We also forecasted the prevalence of hearing loss until 2050. Findings An estimated 1·57 billion (95% uncertainty interval 1·51–1·64) people globally had hearing loss in 2019, accounting for one in five people (20·3% [19·5–21·1]). Of these, 403·3 million (357·3–449·5) people had hearing loss that was moderate or higher in severity after adjusting for hearing aid use, and 430·4 million (381·7–479·6) without adjustment. The largest number of people with moderate-to-complete hearing loss resided in the Western Pacific region (127·1 million people [112·3–142·6]). Of all people with a hearing impairment, 62·1% (60·2–63·9) were older than 50 years. The Healthcare Access and Quality (HAQ) Index explained 65·8% of the variation in national age-standardised rates of years lived with disability, because countries with a low HAQ Index had higher rates of years lived with disability. By 2050, a projected 2·45 billion (2·35–2·56) people will have hearing loss, a 56·1% (47·3–65·2) increase from 2019, despite stable age-standardised prevalence. Interpretation As populations age, the number of people with hearing loss will increase. Interventions such as childhood screening, hearing aids, effective management of otitis media and meningitis, and cochlear implants have the potential to ameliorate this burden. Because the burden of moderate-to-complete hearing loss is concentrated in countries with low health-care quality and access, stronger health-care provision mechanisms are needed to reduce the burden of unaddressed hearing loss in these settings

Global, regional, and national sex-specific burden and control of the HIV epidemic, 1990-2019, for 204 countries and territories: the Global Burden of Diseases Study 2019

Background: The sustainable development goals (SDGs) aim to end HIV/AIDS as a public health threat by 2030. Understanding the current state of the HIV epidemic and its change over time is essential to this effort. This study assesses the current sex-specific HIV burden in 204 countries and territories and measures progress in the control of the epidemic. Methods: To estimate age-specific and sex-specific trends in 48 of 204 countries, we extended the Estimation and Projection Package Age-Sex Model to also implement the spectrum paediatric model. We used this model in cases where age and sex specific HIV-seroprevalence surveys and antenatal care-clinic sentinel surveillance data were available. For the remaining 156 of 204 locations, we developed a cohort-incidence bias adjustment to derive incidence as a function of cause-of-death data from vital registration systems. The incidence was input to a custom Spectrum model. To assess progress, we measured the percentage change in incident cases and deaths between 2010 and 2019 (threshold >75% decline), the ratio of incident cases to number of people living with HIV (incidence-to-prevalence ratio threshold <0·03), and the ratio of incident cases to deaths (incidence-to-mortality ratio threshold <1·0). Findings: In 2019, there were 36·8 million (95% uncertainty interval [UI] 35·1–38·9) people living with HIV worldwide. There were 0·84 males (95% UI 0·78–0·91) per female living with HIV in 2019, 0·99 male infections (0·91–1·10) for every female infection, and 1·02 male deaths (0·95–1·10) per female death. Global progress in incident cases and deaths between 2010 and 2019 was driven by sub-Saharan Africa (with a 28·52% decrease in incident cases, 95% UI 19·58–35·43, and a 39·66% decrease in deaths, 36·49–42·36). Elsewhere, the incidence remained stable or increased, whereas deaths generally decreased. In 2019, the global incidence-to-prevalence ratio was 0·05 (95% UI 0·05–0·06) and the global incidence-to-mortality ratio was 1·94 (1·76–2·12). No regions met suggested thresholds for progress. Interpretation: Sub-Saharan Africa had both the highest HIV burden and the greatest progress between 1990 and 2019. The number of incident cases and deaths in males and females approached parity in 2019, although there remained more females with HIV than males with HIV. Globally, the HIV epidemic is far from the UNAIDS benchmarks on progress metrics. Funding: The Bill & Melinda Gates Foundation, the National Institute of Mental Health of the US National Institutes of Health (NIH), and the National Institute on Aging of the NIH

Estimating global injuries morbidity and mortality : methods and data used in the Global Burden of Disease 2017 study

Background: While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods: In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results: GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions: GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future

Subnational mapping of HIV incidence and mortality among individuals aged 15–49 years in sub-Saharan Africa, 2000–18 : a modelling study

Background: High-resolution estimates of HIV burden across space and time provide an important tool for tracking and monitoring the progress of prevention and control efforts and assist with improving the precision and efficiency of targeting efforts. We aimed to assess HIV incidence and HIV mortality for all second-level administrative units across sub-Saharan Africa. Methods: In this modelling study, we developed a framework that used the geographically specific HIV prevalence data collected in seroprevalence surveys and antenatal care clinics to train a model that estimates HIV incidence and mortality among individuals aged 15–49 years. We used a model-based geostatistical framework to estimate HIV prevalence at the second administrative level in 44 countries in sub-Saharan Africa for 2000–18 and sought data on the number of individuals on antiretroviral therapy (ART) by second-level administrative unit. We then modified the Estimation and Projection Package (EPP) to use these HIV prevalence and treatment estimates to estimate HIV incidence and mortality by second-level administrative unit. Findings: The estimates suggest substantial variation in HIV incidence and mortality rates both between and within countries in sub-Saharan Africa, with 15 countries having a ten-times or greater difference in estimated HIV incidence between the second-level administrative units with the lowest and highest estimated incidence levels. Across all 44 countries in 2018, HIV incidence ranged from 2 ·8 (95% uncertainty interval 2·1–3·8) in Mauritania to 1585·9 (1369·4–1824·8) cases per 100 000 people in Lesotho and HIV mortality ranged from 0·8 (0·7–0·9) in Mauritania to 676· 5 (513· 6–888·0) deaths per 100 000 people in Lesotho. Variation in both incidence and mortality was substantially greater at the subnational level than at the national level and the highest estimated rates were accordingly higher. Among second-level administrative units, Guijá District, Gaza Province, Mozambique, had the highest estimated HIV incidence (4661·7 [2544·8–8120·3]) cases per 100000 people in 2018 and Inhassunge District, Zambezia Province, Mozambique, had the highest estimated HIV mortality rate (1163·0 [679·0–1866·8]) deaths per 100 000 people. Further, the rate of reduction in HIV incidence and mortality from 2000 to 2018, as well as the ratio of new infections to the number of people living with HIV was highly variable. Although most second-level administrative units had declines in the number of new cases (3316 [81· 1%] of 4087 units) and number of deaths (3325 [81·4%]), nearly all appeared well short of the targeted 75% reduction in new cases and deaths between 2010 and 2020. Interpretation: Our estimates suggest that most second-level administrative units in sub-Saharan Africa are falling short of the targeted 75% reduction in new cases and deaths by 2020, which is further compounded by substantial within-country variability. These estimates will help decision makers and programme implementers expand access to ART and better target health resources to higher burden subnational areas