Child Health and Infection with Low Density (CHILD) malaria: a protocol for a randomised controlled trial to assess the long-term health and socioeconomic impacts of testing and treating low-density malaria infection among children in Tanzania.

INTRODUCTION: As malaria declines, low-density malaria infections (LMIs) represent an increasing proportion of infections and may have negative impacts on child health and cognition, necessitating development of targeted and effective solutions. This trial assesses the health, cognitive and socioeconomic impact of two strategies for detecting and treating LMI in a low transmission setting. METHODS AND ANALYSIS: The study is a 3-arm open-label individually randomised controlled trial enrolling 600 children aged 6 months to 10 years in Bagamoyo district, Tanzania. Children are randomised to one of three arms: active case detection with molecular (ACDm) testing by high volume quantitative PCR (qPCR), passive case detection also with molecular testing (PCDm) and a control of standard PCD using rapid diagnostics tests (RDTs). Over the 2-year trial, ACDm participants receive malaria testing using RDT and qPCR three times annually, and malaria testing by RDT only when presenting with fever. PCDm and PCD participants receive malaria testing by RDT and qPCR or RDT only, respectively, when presenting with fever. RDT or qPCR positive participants with uncomplicated malaria are treated with artemether lumefantrine. The primary outcome is cumulative incidence of all-cause sick visits. Secondary outcomes include fever episodes, clinical failure after fever episodes, adverse events, malaria, non-malarial infection, antibiotic use, anaemia, growth faltering, cognition and attention, school outcomes, immune responses, and socioeconomic effects. Outcomes are assessed through monthly clinical assessments and testing, and baseline and endline neurodevelopmental testing. The trial is expected to provide key evidence and inform policy on health, cognitive and socioeconomic impact of interventions targeting LMI in children. ETHICS AND DISSEMINATION: Study is approved by Tanzania NatHREC and institutional review boards at University of California San Francisco and Ifakara Health Institute. Findings will be reported on ClinicalTrials.gov, in peer-reviewed journals and through stakeholder meetings. TRIAL REGISTRATION NUMBER: NCT05567016.

Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia.

Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease characterised in most cases by progressive and debilitating motor dysfunction. Degeneration of cerebellar white matter pathways have been previously reported, alongside indications of cerebello-cerebral functional alterations. In this work, we examine resting-state functional connectivity changes within cerebello-cerebral circuits, and their associations with disease severity (Scale for the Assessment and Rating of Ataxia [SARA]), psychomotor function (speeded and paced finger tapping), and white matter integrity (diffusion tensor imaging) in 35 adults with FRDA and 45 age and sex-matched controls. Voxel-wise seed-based functional connectivity was assessed for three cerebellar cortical regions (anterior lobe, lobules I-V; superior posterior lobe, lobules VI-VIIB; inferior posterior lobe, lobules VIIIA-IX) and two dentate nucleus seeds (dorsal and ventral). Compared to controls, people with FRDA showed significantly reduced connectivity between the anterior cerebellum and bilateral pre/postcentral gyri, and between the superior posterior cerebellum and left dorsolateral PFC. Greater disease severity correlated with lower connectivity in these circuits. Lower anterior cerebellum-motor cortex functional connectivity also correlated with slower speeded finger tapping and less fractional anisotropy in the superior cerebellar peduncles, internal capsule, and precentral white matter in the FRDA cohort. There were no significant between-group differences in inferior posterior cerebellar or dentate nucleus connectivity. This study indicates that altered cerebello-cerebral functional connectivity is associated with functional status and white matter damage in cerebellar efferent pathways in people with FRDA, particularly in motor circuits.

Validation of a digit symbol substitution test for use in supervised and unsupervised assessment in mild Alzheimer's disease.

INTRODUCTION: The Digit-Symbol-Substitution Test (DSST) is used widely in neuropsychological investigations of Alzheimer's Disease (AD). A computerized version of this paradigm, the DSST-Meds, utilizes medicine-date pairings and has been developed for administration in both supervised and unsupervised environments. This study determined the utility and validity of the DSST-Meds for measuring cognitive dysfunction in early AD. METHOD: Performance on the DSST-Meds was compared to performance on the WAIS Coding test, and a computerized digit symbol coding test (DSST-Symbols). The first study compared supervised performance on the three DSSTs versions in cognitively unimpaired (CU) adults (n = 104). The second compared supervised DSST performance between CU (n = 60) and mild-symptomatic AD (mild-AD, n = 79) groups. The third study compared performance on the DSST-Meds between unsupervised (n= 621) and supervised settings. RESULTS: In Study 1, DSST-Meds accuracy showed high correlations with the DSST-Symbols accuracy (r = 0.81) and WAIS-Coding accuracy (r = 0.68). In Study 2, when compared to CU adults, the mild-AD group showed lower accuracy on all three DSSTs (Cohen's d ranging between 1.39 and 2.56) and DSST-Meds accuracy was correlated moderately with Mini-Mental State Examination scores (r = 0.44, p < .001). Study 3 observed no difference in DSST-meds accuracy between supervised and unsupervised administrations. CONCLUSION: The DSST-Meds showed good construct and criterion validity when used in both supervised and unsupervised contexts and provided a strong foundation to investigate the utility of the DSST in groups with low familiarity to neuropsychological assessment.

A Comparison of Tick Collection Materials and Methods in Southeastern Virginia.

In field studies of tick ecology, observed patterns may be biased by sampling methods. Results can vary by species, life stage, and habitat, and understanding these biases will improve comparisons of data across studies as well as assessment of human disease risk. A direct comparison of flagging versus dragging was conducted in southeastern Virginia. Transects were surveyed over a 6-wk period to identify differences in species and life stage collected, as well as differences between corduroy and denim material and inspection method for drags. Flagging collected more Ixodes affinis Neumann (Acari: Ixodidae) adults and Amblyomma americanum L. (Acari: Ixodidae) adults than dragging. Ground inspection was more efficient than tree inspection for collection of I. affinis adults, with no significant difference in inspection method for any other species or life stage. Corduroy was found to be more effective than denim in collecting nymphal A. americanum, although this may be an artifact of three large samples for corduroy collection of these ticks. There was no significant difference in Ixodes scapularis Say (Acari: Ixodidae) collection in any comparison. Dragging, tree inspection, and denim were not found to be more efficient in any scenario. This is the first comparison of flagging and dragging conducted in the southeastern United States. The community composition of ticks in this region greatly differs from regions where studies of these commonly used sampling techniques have been conducted. As the distributions of ticks continue to change over time, it will be important to evaluate best practices annually.

Comparative population genetics of Amblyomma maculatum and Amblyomma americanum in the mid-Atlantic United States.

The Gulf Coast tick, Amblyomma maculatum, is undergoing a northward expansion along the United States East Coast, most recently establishing populations in Virginia, Maryland, and Delaware. This expansion has human health implications, as A. maculatum is the primary natural vector of the bacterium Rickettsia parkeri, which causes a spotted fever-type rickettsiosis. Newly established populations of A. maculatum in Virginia tend to have high prevalence of R. parkeri, compared to lower infection rates in the historical range. The factors contributing to high R. parkeri prevalence in Virginia are not known. Investigating connectivity between sites colonized with A. maculatum can help determine whether sites with higher prevalence are isolated or well-connected through migration, thus serving as a source of infected individuals. We characterized 16S rRNA haplotypes of A. maculatum and, for comparison, the congeneric Amblyomma americanum collected from sites where these species co-occur. We then explored connectivity and genetic structure among Virginia populations using pairwise ΦST and AMOVA analyses. Our study identified one recently restored native grassland site with low A. maculatum haplotype diversity and strong evidence of a founder effect, whereas most sites are haplotypically diverse but with no clear genetic structure or connectivity between sites. These findings contrast with high connectivity and a slight mainland/island structure among A. americanum populations. Our results suggest that A. maculatum populations occasionally arise following long-distance drop-offs of few individual ticks in suitable habitat, but no clear migration patterns were observed. The distinct population genetic patterns between species might result from differences in host utilization.