Connectivity precedes function in the development of the visual word form area

What determines the cortical location at which a given functionally specific region will arise in development? We tested the hypothesis that functionally specific regions develop in their characteristic locations because of pre-existing differences in the extrinsic connectivity of that region to the rest of the brain. We exploited the visual word form area (VWFA) as a test case, scanning children with diffusion and functional imaging at age 5, before they learned to read, and at age 8, after they learned to read. We found the VWFA developed functionally in this interval and that its location in a particular child at age 8 could be predicted from that child's connectivity fingerprints (but not functional responses) at age 5. These results suggest that early connectivity instructs the functional development of the VWFA, possibly reflecting a general mechanism of cortical development.National Institutes of Health (U.S.) (Grant F32HD079169)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant F32HD079169)National Institutes of Health (U.S.) (Grant R01HD067312)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant R01HD067312

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Increasing the acceptability of HIV counseling and testing with three C's: Convenience, confidentiality and credibility

Agencies engaged in humanitarian efforts to prevent the further spread of HIV have emphasized the importance of voluntary counseling and testing (VCT), and most high-prevalence countries now have facilities that offer testing free of charge. The utilization of these services is disappointingly low, however, despite high numbers reporting that they would like to be tested. Explanations of this discrepancy typically rely on responses to hypothetical questions posed in terms of psychological or social barriers; often, the explanation is that people fear learning that they are infected with a disease that they understand to be fatal and stigmatizing. Yet when we offered door-to-door rapid blood testing for HIV as part of a longitudinal study in rural Malawi, the overwhelming majority agreed to be tested and to receive their results immediately. Thus, in this paper, we ask: why are more people not getting tested? Using an explanatory research design, we find that rural Malawians are responsive to door-to-door HIV testing for the following reasons: it is convenient, confidential, and the rapid blood test is credible. Our study suggests that attention to these factors in VCT strategies may mitigate the fear of HIV testing, and ultimately increase uptake in rural African settings.Sub-Saharan Africa Malawi HIV/AIDS Voluntary counseling and testing (VCT) Rapid blood test Home-based testing

Behavioral disinhibition and sexual risk behavior among adolescents and young adults in Malawi.

While behavioral factors such as early age of sexual debut, inconsistent use of condoms and multiple sexual partners have been studied in Africa, less is known about how characteristics such as impulsivity and externalizing behaviors relate to HIV-related sexual risk-taking in that region. The purpose of this study was to develop a culturally adapted behavioral disinhibition index in a sample of adolescents and young adults in Malawi. We then sought to examine the relationship between the index and sexual risk behavior as measured by multiple sexual partners and number of lifetime sexual partners.Cross-sectional data were collected from 2342 participants in rural Malawi aged 15 to 29 years. We constructed a disinhibitory behavior score (DBS) using questions assessing disinhibitory behaviors. Bivariate analyses were conducted to assess the relationships among the individual DBS component behaviors. We utilized multivariable logistic regression to determine the association of the DBS with multiple sexual partners, and negative binomial regression to model the relationship between the DBS and number of lifetime sexual partners.Nearly all the DBS component behaviors were significantly associated in the bivariate analyses. The DBS was associated with having multiple sexual partners (OR 1.97; 95% CI 1.57-2.48) in the multivariable logistic regression analysis. Further, negative binomial regression results demonstrated that the DBS was associated with an increased number of lifetime sexual partners (OR 1.11; 95% CI 1.07-1.16).HIV preventive programs in Africa should take into consideration disinhibitory behaviors that may be associated with sexual risk-taking. The DBS can be used as a simple tool to identify those who may be more likely to engage in these behaviors and provide useful information regarding which groups of individuals particularly need to be targeted for behavior change interventions

Frequency distribution of the number of lifetime sexual partners.

<p>Frequency distribution of the number of lifetime sexual partners.</p

Frequency distribution of disinhibitory behavior scores.

<p>Frequency distribution of disinhibitory behavior scores.</p

Odds ratios and 95% confidence intervals of unadjusted associations among components of the DBS.

<p>Odds ratios and 95% confidence intervals of unadjusted associations among components of the DBS.</p