Using near infrared spectroscopy (NIRS) to assess workload and inhibitory control in real and simulated driving environments

Both mental workload and inhibitory control have previously been found to relate to road traffic collisions and these factors are also believed to be highly dependent on the prefrontal cortex. Driving simulators create a safe environment in which to manipulate these factors and examine human behaviours. However, the validity of simulators is often called in to question and previous simulator validation research has a number of common methodological issues. As such, there were two main aims of this thesis. The first was to examine the efficacy of functional near infrared spectroscopy in measuring changes in prefrontal cortex activation as a result of mental workload and inhibitory control manipulations in simulated driving scenarios. The second aim was to examine the similarities and differences in driving behaviour, eye movements and prefrontal cortex activation in real and simulated driving environments. In Experiment One mental workload was examined using a simulated driving task which used different road types to manipulate workload in a medium fidelity driving simulator. Results showed changes in subjective workload ratings with changes in road types, with dual carriageway roads having the lowest mental workload followed by A-roads, city centre routes and suburb roads, which had the highest workload demands. Increases in mental workload were accompanied by reductions in speed and mean fixation duration and increases in accelerations, horizontal spread of search, skin conductance responses and the concentration of oxygenated haemoglobin in the prefrontal cortex. In Experiments Two and Three, inhibitory control was examined in both a high and medium fidelity simulator. Inhibition was manipulated by using different hazard types and by changing the role of the participant to active or passive. Results showed changes in prefrontal cortex activation with changes in hazard type in the high fidelity simulator. Although the same pattern of results was found in the medium fidelity simulator the magnitude of change was lower and results were not statistically significant. Subjective ratings of risk and mental workload also showed an increased magnitude of change from everyday to hazardous driving in the high fidelity simulator suggesting that it may be a more useful tool for comparing hazardous scenarios than the medium fidelity simulator. Results also revealed greater activation for active than passive participants for oxygenated haemoglobin. In Experiment Four, driving behaviour and eye movements were compared between real world and simulated driving at both high and medium fidelities using the same road definitions as in Experiment One. Results showed that participants had reduced speeds and spread of search and increased accelerations and mean fixation durations in the car. However, changes in driving behaviours and eye movements in all environments were consistent with the patterns seen in Experiment One. More specifically, there were increases in acceleration and spread of search and reductions in speed and fixation duration with increased mental workload. These results demonstrate relative validity for both simulators. Behavioural equivalence was found between the high and medium fidelity simulator for all eye movement and speed measures and two (right and absolute) of the five acceleration signatures. Finally, Experiment Five compared the similarities and differences in driver behaviour and prefrontal cortex activation as measured using functional near infrared spectroscopy in on-road and high fidelity simulated driving. Results showed reduced speed and increased acceleration in the car compared to the simulator but as with Experiments One and Four there were increases in acceleration and reductions in speed with increased workload in both environments, showing support for relative validity for driver behaviour measures. Prefrontal cortex activation did not show meaningful patterns of activation in either environments or across changes in road types. It was concluded that functional near infrared spectroscopy is a valuable neuroimaging technique that can be used to detect mental workload changes and prefrontal cortex responses to hazardous situations in controlled, simulated environments. However, it is currently not an effective technique for determining these changes in mental workload in real world driving where experimental control is reduced. With respect to simulator validation, driver behaviour and eye movements differ numerically between on-road and simulated driving but show the same direction of change with changes in road demands. As such, there is relative validity for both medium and high fidelity simulated driving and behavioural equivalence between the two levels of simulator fidelity

Establishment of the Ivermectin Research for Malaria Elimination Network: updating the research agenda.

The potential use of ivermectin as an additional vector control tool is receiving increased attention from the malaria elimination community, driven by the increased importance of outdoor/residual malaria transmission and the threat of insecticide resistance where vector tools have been scaled-up. This report summarizes the emerging evidence presented at a side meeting on "Ivermectin for malaria elimination: current status and future directions" at the annual meeting of the American Society of Tropical Medicine and Hygiene in New Orleans on November 4, 2014. One outcome was the creation of the "Ivermectin Research for Malaria Elimination Network" whose main goal is to establish a common research agenda to generate the evidence base on whether ivermectin-based strategies should be added to the emerging arsenal to interrupt malaria transmission

Ivermectin as a novel complementary malaria control tool to reduce incidence and prevalence: a modelling study.

BACKGROUND: Ivermectin is a potential new vector control tool to reduce malaria transmission. Mosquitoes feeding on a bloodmeal containing ivermectin have a reduced lifespan, meaning they are less likely to live long enough to complete sporogony and become infectious. We aimed to estimate the effect of ivermectin on malaria transmission in various scenarios of use. METHODS: We validated an existing population-level mathematical model of the effect of ivermectin mass drug administration (MDA) on the mosquito population and malaria transmission against two datasets: clinical data from a cluster- randomised trial done in Burkina Faso in 2015 wherein ivermectin was given to individuals taller than 90 cm and entomological data from a study of mosquito outcomes after ivermectin MDA for onchocerciasis or lymphatic filariasis in Burkina Faso, Senegal, and Liberia between 2008 and 2013. We extended the existing model to include a range of complementary malaria interventions (seasonal malaria chemoprevention and MDA with dihydroartemisinin-piperaquine) and to incorporate new data on higher doses of ivermectin with a longer mosquitocidal effect. We consider two ivermectin regimens: a single dose of 400 μg/kg (1 × 400 μg/kg) and three consecutive daily doses of 300 μg/kg per day (3 × 300 μg/kg). We simulated the effect of these two doses in a range of usage scenarios in different transmission settings (highly seasonal, seasonal, and perennial). We report percentage reductions in clinical incidence and slide prevalence. FINDINGS: We estimate that MDA with ivermectin will reduce prevalence and incidence and is most effective in areas with highly seasonal transmission. In a highly seasonal moderate transmission setting, three rounds of ivermectin only MDA at 3 × 300 μg/kg (rounds spaced 1 month apart) and 70% coverage is predicted to reduce clinical incidence by 71% and prevalence by 34%. We predict that adding ivermectin MDA to seasonal malaria chemoprevention in this setting would reduce clinical incidence by an additional 77% in children younger than 5 years compared with seasonal malaria chemoprevention alone; adding ivermectin MDA to MDA with dihydroartemisinin-piperaquine in this setting would reduce incidence by an additional 75% and prevalence by an additional 64% (all ages) compared with MDA with dihydroartemisinin-piperaquine alone. INTERPRETATION: Our modelling predictions suggest that ivermectin could be a valuable addition to the malaria control toolbox, both in areas with persistently high transmission where existing interventions are insufficient and in areas approaching elimination to prevent resurgence. FUNDING: Imperial College Junior Research Fellowship

Prefrontal cortex activation and young driver behaviour: a fNIRS study

Road traffic accidents consistently show a significant over-representation for young, novice and particularly male drivers. This research examines the prefrontal cortex activation of young drivers and the changes in activation associated with manipulations of mental workload and inhibitory control. It also considers the explanation that a lack of prefrontal cortex maturation is a contributing factor to the higher accident risk in this young driver population. The prefrontal cortex is associated with a number of factors including mental workload and inhibitory control, both of which are also related to road traffic accidents. This experiment used functional near infrared spectroscopy to measure prefrontal cortex activity during five simulated driving tasks: one following task and four overtaking tasks at varying traffic densities which aimed to dissociate workload and inhibitory control. Age, experience and gender were controlled for throughout the experiment. The results showed that younger drivers had reduced prefrontal cortex activity compared to older drivers. When both mental workload and inhibitory control increased prefrontal cortex activity also increased, however when inhibitory control alone increased there were no changes in activity. Along with an increase in activity during overtaking manoeuvres, these results suggest that prefrontal cortex activation is more indicative of workload in the current task. There were no differences in the number of overtakes completed by younger and older drivers but males overtook significantly more than females. We conclude that prefrontal cortex activity is associated with the mental workload required for overtaking. We additionally suggest that the reduced activation in younger drivers may be related to a lack of prefrontal maturation which could contribute to the increased crash risk seen in this population

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Using near infrared spectroscopy (NIRS) to assess workload and inhibitory control in real and simulated driving environments

Both mental workload and inhibitory control have previously been found to relate to road traffic collisions and these factors are also believed to be highly dependent on the prefrontal cortex. Driving simulators create a safe environment in which to manipulate these factors and examine human behaviours. However, the validity of simulators is often called in to question and previous simulator validation research has a number of common methodological issues. As such, there were two main aims of this thesis. The first was to examine the efficacy of functional near infrared spectroscopy in measuring changes in prefrontal cortex activation as a result of mental workload and inhibitory control manipulations in simulated driving scenarios. The second aim was to examine the similarities and differences in driving behaviour, eye movements and prefrontal cortex activation in real and simulated driving environments. In Experiment One mental workload was examined using a simulated driving task which used different road types to manipulate workload in a medium fidelity driving simulator. Results showed changes in subjective workload ratings with changes in road types, with dual carriageway roads having the lowest mental workload followed by A-roads, city centre routes and suburb roads, which had the highest workload demands. Increases in mental workload were accompanied by reductions in speed and mean fixation duration and increases in accelerations, horizontal spread of search, skin conductance responses and the concentration of oxygenated haemoglobin in the prefrontal cortex. In Experiments Two and Three, inhibitory control was examined in both a high and medium fidelity simulator. Inhibition was manipulated by using different hazard types and by changing the role of the participant to active or passive. Results showed changes in prefrontal cortex activation with changes in hazard type in the high fidelity simulator. Although the same pattern of results was found in the medium fidelity simulator the magnitude of change was lower and results were not statistically significant. Subjective ratings of risk and mental workload also showed an increased magnitude of change from everyday to hazardous driving in the high fidelity simulator suggesting that it may be a more useful tool for comparing hazardous scenarios than the medium fidelity simulator. Results also revealed greater activation for active than passive participants for oxygenated haemoglobin. In Experiment Four, driving behaviour and eye movements were compared between real world and simulated driving at both high and medium fidelities using the same road definitions as in Experiment One. Results showed that participants had reduced speeds and spread of search and increased accelerations and mean fixation durations in the car. However, changes in driving behaviours and eye movements in all environments were consistent with the patterns seen in Experiment One. More specifically, there were increases in acceleration and spread of search and reductions in speed and fixation duration with increased mental workload. These results demonstrate relative validity for both simulators. Behavioural equivalence was found between the high and medium fidelity simulator for all eye movement and speed measures and two (right and absolute) of the five acceleration signatures. Finally, Experiment Five compared the similarities and differences in driver behaviour and prefrontal cortex activation as measured using functional near infrared spectroscopy in on-road and high fidelity simulated driving. Results showed reduced speed and increased acceleration in the car compared to the simulator but as with Experiments One and Four there were increases in acceleration and reductions in speed with increased workload in both environments, showing support for relative validity for driver behaviour measures. Prefrontal cortex activation did not show meaningful patterns of activation in either environments or across changes in road types. It was concluded that functional near infrared spectroscopy is a valuable neuroimaging technique that can be used to detect mental workload changes and prefrontal cortex responses to hazardous situations in controlled, simulated environments. However, it is currently not an effective technique for determining these changes in mental workload in real world driving where experimental control is reduced. With respect to simulator validation, driver behaviour and eye movements differ numerically between on-road and simulated driving but show the same direction of change with changes in road demands. As such, there is relative validity for both medium and high fidelity simulated driving and behavioural equivalence between the two levels of simulator fidelity