First Probe of Sub-GeV Dark Matter beyond the Cosmological Expectation with the COHERENT CsI Detector at the SNS.

The COHERENT Collaboration searched for scalar dark matter particles produced at the Spallation Neutron Source with masses between 1 and 220 MeV/c^{2} using a CsI[Na] scintillation detector sensitive to nuclear recoils above 9 keV_{nr}. No evidence for dark matter is found and we thus place limits on allowed parameter space. With this low-threshold detector, we are sensitive to coherent elastic scattering between dark matter and nuclei. The cross section for this process is orders of magnitude higher than for other processes historically used for accelerator-based direct-detection searches so that our small, 14.6 kg detector significantly improves on past constraints. At peak sensitivity, we reject the flux consistent with the cosmologically observed dark-matter concentration for all coupling constants α_{D}<0.64, assuming a scalar dark-matter particle. We also calculate the sensitivity of future COHERENT detectors to dark-matter signals which will ambitiously test multiple dark-matter spin scenarios.

Measurement of Electron-Neutrino Charged-Current Cross Sections on

Using an 185-kg NaI[Tl] array, COHERENT has measured the inclusive electron-neutrino charged-current cross section on ^{127}I with pion decay-at-rest neutrinos produced by the Spallation Neutron Source at Oak Ridge National Laboratory. Iodine is one the heaviest targets for which low-energy (≤50 MeV) inelastic neutrino-nucleus processes have been measured, and this is the first measurement of its inclusive cross section. After a five-year detector exposure, COHERENT reports a flux-averaged cross section for electron neutrinos of 9.2_{-1.8}^{+2.1}×10^{-40} cm^{2}. This corresponds to a value that is ∼41% lower than predicted using the MARLEY event generator with a measured Gamow-Teller strength distribution. In addition, the observed visible spectrum from charged-current scattering on ^{127}I has been measured between 10 and 55 MeV, and the exclusive zero-neutron and one-or-more-neutron emission cross sections are measured to be 5.2_{-3.1}^{+3.4}×10^{-40} and 2.2_{-0.5}^{+0.4}×10^{-40} cm^{2}, respectively.

Measurement of the Coherent Elastic Neutrino-Nucleus Scattering Cross Section on CsI by COHERENT.

We measured the cross section of coherent elastic neutrino-nucleus scattering (CEvNS) using a CsI[Na] scintillating crystal in a high flux of neutrinos produced at the Spallation Neutron Source at Oak Ridge National Laboratory. New data collected before detector decommissioning have more than doubled the dataset since the first observation of CEvNS, achieved with this detector. Systematic uncertainties have also been reduced with an updated quenching model, allowing for improved precision. With these analysis improvements, the COHERENT Collaboration determined the cross section to be (165_{-25}^{+30})×10^{-40} cm^{2}, consistent with the standard model, giving the most precise measurement of CEvNS yet. The timing structure of the neutrino beam has been exploited to compare the CEvNS cross section from scattering of different neutrino flavors. This result places leading constraints on neutrino nonstandard interactions while testing lepton flavor universality and measures the weak mixing angle as sin^{2}θ_{W}=0.220_{-0.026}^{+0.028} at Q^{2}≈(50 MeV)^{2}.

Post-traumatic stress disorder prevalence and sleep quality in fire victims and rescue workers in southern Brazil: a cross-sectional study.

OBJECTIVES: This survey was conducted to evaluate the prevalence of post-traumatic stress disorder (PTSD) and the sleep quality in victims and rescue team of the third deadliest nightclub fire in the world. STUDY DESIGN: A cross-sectional study. METHODS: Participants were victims and rescue workers exposed to a fire at a nightclub, which occurred in January 2013 in Southern Brazil. The Pittsburgh Sleep Quality Index (PSQI), composed of seven subjective sleep variables (including daytime dysfunction), and PTSD Checklist - Civilian version (PCL-C) were applied to all people who sought medical attention at the local reference center in the first year after the event. Comprehensive information was obtained concerning sociodemographic factors, health status, and sleep complaints. RESULTS: A total of 370 individuals, 190 victims and 180 rescue workers, were included. Participants were 70% male, with an average age of 29 years. The prevalence of PTSD was 31.9%, ranging from 24.4% for rescue workers to 38.9% for victims. The prevalence of poor sleep quality was 65.9%, ranging from 56.1% for rescue workers to 75.3% for victims. Most of the participants with PTSD (91.5%) had PSQI scores >5 (poor sleepers), against 54.0% of the non-PTSD individuals. All seven PSQI subscores showed significant differences between PTSD and non-PTSD individuals, especially daytime dysfunction. Sex, shift work, previous psychiatric disease, and sleep quality remained associated with PTSD in adjusted models, with a prevalence ratio (95% CI) of 1.76 (1.28-2.43) in females, 1.73 (1.17-2.55) in shift workers, 1.36 (1.03-1.80) in individuals with psychiatric disease history, and 5.42 (2.55-11.52) in poor sleepers. CONCLUSIONS: The presence of daytime dysfunction increased by at least tenfold the prevalence of PTSD in this sample. Considering that daytime dysfunction was shown to be strongly associated with PTSD, sleep-related issues should be addressed in the assessment of individuals exposed to traumatic events, both victims and rescuers. Factors like shift work and female sex were also associated with PTSD, especially among victims.

First Measurement of Coherent Elastic Neutrino-Nucleus Scattering on Argon.

We report the first measurement of coherent elastic neutrino-nucleus scattering (CEvNS) on argon using a liquid argon detector at the Oak Ridge National Laboratory Spallation Neutron Source. Two independent analyses prefer CEvNS over the background-only null hypothesis with greater than 3σ significance. The measured cross section, averaged over the incident neutrino flux, is (2.2±0.7)×10^{-39} cm^{2}-consistent with the standard model prediction. The neutron-number dependence of this result, together with that from our previous measurement on CsI, confirms the existence of the CEvNS process and provides improved constraints on nonstandard neutrino interactions.

Tungsten accumulates in the intervertebral disc and vertebrae stimulating disc degeneration and upregulating markers of inflammation and pain.

Tungsten is incorporated in many industrial goods, military applications and medical devices due to its ability to impart flexibility, strength and conductance to materials. Emerging evidence has questioned the safety of tungsten exposure as studies have demonstrated it can promote tumour formation, induce pulmonary disease and alter immune function. Although tungsten is excreted from the body it can accumulate in certain organs such as the brain, colon, liver, kidneys, spleen and bones, where most of the bioaccumulation occurs. Whether prolonged tungsten exposure leads to accumulation in other tissues is unknown. The present study demonstrated that mice exposed to 15 ppm sodium tungstate for 4 weeks in their drinking water showed comparable accumulation in both the bony vertebrae and intervertebral discs (IVDs). Lumbar IVD height was significantly reduced in tungsten-exposed mice and accompanied by decreased proteoglycan content and increased fibrosis. In addition to catabolic enzymes, tungsten also increased the expression of the inflammatory cytokines IL-1ß and tumour necrosis factor (TNF)-α as well as the neurotrophic factors nerve growth factor (NGF) and brain-derived nerve factor (BDNF) in IVD cells. Tungsten significantly increased the presence of nociceptive neurons at the endplates of IVDs as observed by the expression of calcitonin gene-related peptide (CGRP) and anti-protein gene product 9.5 (PGP9.5) in endplate vessels. The present study provided evidence that tungsten may enhance disc degeneration and fibrosis as well as increase the expression of markers for pain. Therefore, tungsten toxicity may play a role in disc degeneration disease.

A longitudinal, observational study of the features of transitional healthcare associated with better outcomes for young people with long-term conditions.

BACKGROUND: Most evidence about what works in transitional care comes from small studies in single clinical specialties. We tested the hypothesis that exposures to nine recommended features of transitional healthcare were associated with better outcomes for young people with long-term conditions during transition from child-centred to adult-oriented health services. METHODS: This is a longitudinal, observational cohort study in UK secondary care including 374 young people, aged 14-18.9 years at recruitment, with type 1 diabetes (n = 150), cerebral palsy (n = 106) or autism spectrum disorder with an associated mental health problem (n = 118). All were pre-transfer and without significant learning disability. We approached all young people attending five paediatric diabetes centres, all young people with autism spectrum disorder attending four mental health centres, and randomly selected young people from two population-based cerebral palsy registers. Participants received four home research visits, 1 year apart and 274 participants (73%) completed follow-up. Outcome measures were Warwick Edinburgh Mental Wellbeing Scale, Mind the Gap Scale (satisfaction with services), Rotterdam Transition Profile (Participation) and Autonomy in Appointments. RESULTS: Exposure to recommended features was 61% for 'coordinated team', 53% for 'age-banded clinic', 48% for 'holistic life-skills training', 42% for 'promotion of health self-efficacy', 40% for 'meeting the adult team before transfer', 34% for 'appropriate parent involvement' and less than 30% for 'written transition plan', 'key worker' and 'transition manager for clinical team'. Three features were strongly associated with improved outcomes. (1) 'Appropriate parent involvement', example association with Wellbeing (b = 4.5, 95% CI 2.0-7.0, p = 0.001); (2) 'Promotion of health self-efficacy', example association with Satisfaction with Services (b = - 0.5, 95% CI - 0.9 to - 0.2, p = 0.006); (3) 'Meeting the adult team before transfer', example associations with Participation (arranging services and aids) (odds ratio 5.2, 95% CI 2.1-12.8, p < 0.001) and with Autonomy in Appointments (average 1.7 points higher, 95% CI 0.8-2.6, p < 0.001). There was slightly less recruitment of participants from areas with greater socioeconomic deprivation, though not with respect to family composition. CONCLUSIONS: Three features of transitional care were associated with improved outcomes. Results are likely to be generalisable because participants had three very different conditions, attending services at many UK sites. Results are relevant for clinicians as well as for commissioners and managers of health services. The challenge of introducing these three features across child and adult healthcare services, and the effects of doing so, should be assessed.

A longitudinal, observational study examining the relationships of patient satisfaction with services and mental well-being to their clinical course in young people with Type 1 diabetes mellitus during transition from child to adult health services.

AIM: We hypothesized that participant well-being and satisfaction with services would be positively associated with a satisfactory clinical course during transition from child to adult health care. METHODS: Some 150 young people with Type 1 diabetes mellitus from five diabetes units in England were recruited to a longitudinal study of transition. Each young person was visited at home four times by a research assistant; each visit was 1 year apart. Satisfaction with services (Mind the Gap; MTG) and mental well-being (Warwick-Edinburgh Mental Well-being Scale; WEMWBS) were captured. Change in HbA1c , episodes of ketoacidosis, clinic and retinal screening attendance were used to assess clinical course. In total, 108 of 150 (72%) young people had sufficient data for analysis at visit 4. RESULTS: Mean age at entry was 16 years. By visit 4, 81.5% had left paediatric healthcare services. Median HbA1c increased significantly (P = 0.01) from 69 mmol/mol (8.5%) at baseline to 75 mmol/mol (9.0%) at visit 4. WEMWBS scores were comparable with those in the general population at baseline and were stable over the study period. MTG scores were also stable. By visit 4, some 32 individuals had a 'satisfactory' and 76 a 'suboptimal' clinical course. There were no significant differences in average WEMWBS and MTG scores between the clinical course groups (P = 0.96, 0.52 respectively); nor was there a significant difference in transfer status between the clinical course groups. CONCLUSIONS: The well-being of young people with diabetes and their satisfaction with transition services are not closely related to their clinical course. Investigating whether innovative psycho-educational interventions can improve the clinical course is a research priority.

The clinical utility of genetic testing of tissues from pregnancy losses.

OBJECTIVE: To map the current testing being undertaken following pregnancy loss across the UK and to examine the clinical utility in terms of identifying a cause for the loss and in identifying couples at risk of an unbalanced liveborn child. DESIGN: Retrospective audit. SETTING: UK, for the year 2014. POPULATION: An audit of 6465 referrals for genetic testing of tissue samples following pregnancy loss. METHODS: Data were obtained by questionnaire from 15 UK regional genetics laboratories. MAIN OUTCOME MEASURES: Data were analysed with respect to gestational age, the presence of identified fetal anomalies, methodologies used, abnormality rates and the presence of a parental balanced rearrangement. RESULTS: Of 6465 referrals a genetic cause was identified in 22% of cases (before 12 weeks' gestation, in 47%; at 12-24 weeks, in 14%; after 24 weeks, in 6%). In 0.4% of cases a balanced parental rearrangement was identified where there was a risk of an affected liveborn child in a future pregnancy. Eighty percent of genetic imbalances identified were aneuploidy or triploidy and could be identified by quantitative fluorescence polymerase chain reaction alone. There was significant variation across the UK in acceptance criteria, testing strategies and thus level of resolution of testing. CONCLUSIONS: Genetic testing of tissues following pregnancy loss identifies a probable cause of fetal demise in 22% of cases, but it is of low clinical utility in identifying couples at risk of a future unbalanced liveborn child. A comprehensive multidisciplinary review is needed to develop proposals for an affordable and equitable service. TWEETABLE ABSTRACT: UK audit of genetic testing of fetal loss shows variation in access to and resolution of analysis.

Obstetric and gynecologic ultrasound curriculum and competency assessment in residency training programs: consensus report.

Ultrasound imaging has become integral to the practice of obstetrics and gynecology. With increasing educational demands and limited hours in residency programs, dedicated time for training and achieving competency in ultrasound has diminished substantially. The American Institute of Ultrasound in Medicine assembled a multi-Society Task Force to develop a consensus-based, standardized curriculum and competency assessment tools for obstetric and gynecologic ultrasound training in residency programs. The curriculum and competency-assessment tools were developed based on existing national and international guidelines for the performance of obstetric and gynecologic ultrasound examinations and thus are intended to represent the minimum requirement for such training. By expert consensus, the curriculum was developed for each year of training, criteria for each competency assessment image were generated, the pass score was established at or close to 75% for each, and obtaining a set of five ultrasound images with pass score in each was deemed necessary for attaining each competency. Given the current lack of substantial data on competency assessment in ultrasound training, the Task Force expects that the criteria set forth in this document will evolve with time. The Task Force also encourages use of ultrasound simulation in residency training and expects that simulation will play a significant part in the curriculum and the competency-assessment process. Incorporating this training curriculum and the competency-assessment tools may promote consistency in training and competency assessment, thus enhancing the performance and diagnostic accuracy of ultrasound examination in obstetrics and gynecology. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Psychiatric comorbidity in alcohol use disorders: results from the German S3 guidelines.

Alcohol use disorders (AUD) have a high comorbidity with mental disorders. Vice versa, alcohol consumption plays an important role in affective disorders, anxiety disorders, ADHD, schizophrenic psychosis, and other mental disorders. In developing the current interdisciplinary, evidence-based treatment guideline on screening, diagnostics, and treatment of AUD, available research on comorbid mental diseases in AUD has been compiled to generate recommendations for treatment. The guideline was prepared under the responsibility of the German Association for Psychiatry, Psychotherapy, and Psychosomatics (DGPPN) and the German Association for Addiction Research and Therapy (DG-Sucht). To meet the methodological criteria for the highest quality guidelines ("S3-criteria") as defined by the Association of Scientific Medical Societies in Germany (AWMF), the following criteria were employed: (1) a systematic search, selection, and appraisal of the international literature; (2) a structured process to reach consensus; and (3) inclusion of all relevant representatives of future guideline users. After assessing and grading the available literature, the expert groups generated several recommendations for the screening, diagnosis, and treatment of comorbid mental disorders. These recommendations were subdivided into psycho-, pharmaco-, and combination therapies. These are the first guidelines ever to make specific treatment recommendations for comorbid mental diseases in AUD. The recommendations extend to different treatment approaches including diagnostics and settings to present available effective and state-of-the-art treatment approaches to clinicians. Hitherto, many clinical constellations have not been addressed in research. Therefore, recommendations for future research are specified.

Development of the MapMe intervention body image scales of known weight status for 4-5 and 10-11 year old children.

Background: Parents tend to visually assess children to determine their weight status and typically underestimate child body size. A visual tool may aid parents to more accurately assess child weight status and so support strategies to reduce childhood overweight. Body image scales (BIS) are visual images of people ranging from underweight to overweight but none exist for children based on UK criteria. Our aim was to develop sex- and age-specific BIS for children, based on British growth reference (UK90) criteria. Methods: BIS were developed using 3D surface body scans of children, their associated weight status using UK90 criteria from height and weight measurements, and qualitative work with parents and health professionals. Results: Height, weight and 3D body scans were collected (211: 4-5 years; 177: 10-11 years). Overall, 12 qualitative sessions were held with 37 participants. Four BIS (4-5-year-old girls and boys, 10-11-year-old girls and boys) were developed. Conclusions: This study has created the first sex- and age-specific BIS, based on UK90 criteria. The BIS have potential for use in child overweight prevention and management strategies, and in future research. This study also provides a protocol for the development of further BIS appropriate to other age groups and ethnicities.

How well do services for young people with long term conditions deliver features proposed to improve transition?

BACKGROUND: For young people with long-term conditions, transition from child to adult-oriented health services is a critical period which, if not managed well, may lead to poor outcomes. There are features of transition services which guidance and research suggest improve outcomes. We studied nine such features, calling them 'proposed beneficial features': age-banded clinic; meet adult team before transfer; promotion of health self-efficacy; written transition plan; appropriate parent involvement; key worker; coordinated team; holistic life-skills training; transition manager for clinical team. We aimed to describe the extent to which service providers offer these nine features, and to compare this with young people's reported experience of them. METHODS: A longitudinal, mixed methods study followed 374 young people as their care moved from child to adult health services. Participants had type 1 diabetes, cerebral palsy or autism spectrum disorder with additional mental health difficulties. Data are reported from the first two visits, one year apart. RESULTS: Three hundred four (81.3%) of the young people took part in the second visit (128 with diabetes, 91 with autism, 85 with cerebral palsy). Overall, the nine proposed beneficial features of transition services were poorly provided. Fewer than half of services stated they provided an age-banded clinic, written transition plan, transition manager for clinical team, a protocol for promotion of health self-efficacy, or holistic life-skills training. To varying degrees, young people reported that they had not experienced the features which services said they provided. For instance, the agreement for written transition plan, holistic life-skills training and key worker, was 30, 43 and 49% respectively. Agreement was better for appropriate parent involvement, age-banded clinic, promotion of health self-efficacy and coordinated team at 77, 77, 80 and 69% respectively. Variation in the meaning of the features as experienced by young people and families was evident from qualitative interviews and observations. CONCLUSIONS: UK services provide only some of the nine proposed beneficial features for supporting healthcare transition of young people with long term conditions. Observational studies or trials which examine the influence of features of transition services on outcomes should ensure that the experiences of young people and families are captured, and not rely on service specifications.

Social determinants of emotional well-being in new refugees in the UK.

OBJECTIVES: Refugees are most vulnerable to mental health problems of all migrant groups, and an understanding of the role of postdisplacement social factors in refugee emotional well-being can help to shape the future interventions for this group. We aimed to investigate the effect of social determinants, such as employment, language ability and accommodation, on mental health in refugees in the UK. STUDY DESIGN: This prospective longitudinal cohort study was set in the UK. The study population of new UK refugees was drawn from an existing data set of the Longitudinal Survey of New Refugees (n = 5678), in which all new UK refugees (2005-2007) were sent a postal questionnaire at four time points across 2 years. METHODS: Ordered logistic regression models were used to evaluate associations between social determinants and the dependent variables, emotional well-being or change in emotional well-being, using a question from the Short Form-36 Health Survey Questionnaire. RESULTS: Refugees who were unemployed in the UK, could not speak English well or were unsatisfied with their accommodation had significantly higher odds of poorer emotional well-being in the cross-sectional analysis (P < 0.05 at all time points measured). CONCLUSIONS: Postdisplacement social factors, including language ability, employment status and accommodation satisfaction, were important determinants of refugee emotional well-being. Changes in these social determinants have the potential to improve refugee mental health, making them legitimate, modifiable targets for important public health interventions. Accounting for this, further research into how to improve refugee well-being is crucial given the increase in refugee numbers around the developed world.

Longitudinal study of the associations between change in sedentary behavior and change in adiposity during childhood and adolescence: Gateshead Millennium Study.

BACKGROUND: Sedentary time (ST) has been reported to have a range of negative health effects in adults, however, the evidence for such effects among children and adolescents is sparse. The primary aim of the study was to examine associations between changes in sedentary behavior (time and fragmentation) and changes in adiposity across childhood and adolescence. METHODS: Participants were recruited as part of the Gateshead Millennium Study. Measures were taken at age 7 (n=502), 9 (n=506), 12 (n=420) and 15 years (n=306). Participants wore an ActiGraph GT1M and accelerometer epochs were 'sedentary' when recorded counts were ⩽25 counts per 15 s. ST was calculated and fragmentation (SF) was assessed by calculating the number of sedentary bouts per sedentary hour. Associations of changes in ST and SF with changes in adiposity (body mass index (BMI), and fat mass index (FMI)) were examined using bivariate linear spline models. RESULTS: Increasing ST by 1% per year was associated with an increase in BMI of 0.08 kg m-2 per year (95% CI: 0.06-0.10; P<0.001) and FMI of 0.15 kg m-2 per year (0.11-0.19; P<0.001). Change in SF was associated with BMI and FMI (P<0.001). An increase of 1 bout per sedentary hour per year (that is, sedentary time becoming more fragmented) was associated with an increase in BMI of 0.07 kg m-2 per year (0.06-0.09; P<0.001) and an increase in FMI of 0.14 kg m-2 per year (0.10-0.18; P<0.001) over the 8 years period. However, an increase in SF between 9-12 years was associated with a 0.09 kg m-2 per year decrease in BMI (-0.18-0.00; P=0.046) and 0.11 kg m-2 per year decrease in FMI (-0.22-0.00; P=0.049). CONCLUSIONS: Increased ST and increased SF from 7-15 years were associated with increased adiposity. This is the first study to show age-specific associations between change in objectively measured sedentary behavior and adiposity after adjustment of moderate-to-vigorous-intensity physical activity in children and adolescents. The study suggests that, targeting sedentary behavior for obesity prevention may be most effective during periods in which we see large increases in ST.

The 'bother' of obstructed defecation.

OBJECTIVE: To examine the relationship of visual analog scale (VAS) 'bother' scores for obstructed defecation (OD) with demographic data, physical examination and sonographic findings of the posterior compartment. METHODS: All patients seen at a urogynecology clinic between January and October 2013 were included. Patients were diagnosed with OD if they had any of the following: incomplete bowel emptying, straining with bowel movement or need for digitation. Patients used a VAS to rate OD bother on a scale of 0-10 (0, no bother; 10, worst imaginable bother). For each patient, a comprehensive history was obtained, the International Continence Society Pelvic Organ Prolapse Quantification was performed and four-dimensional translabial ultrasound volumes were recorded on maximal Valsalva maneuver. Linear and multiple regression models were used to correlate bother VAS scores with demographic, clinical and sonographic findings. RESULTS: Among 265 patients included in the analysis, 61% had OD symptoms with a mean VAS bother score of 5.6. OD bother scores were associated with a history of previous prolapse surgery (P = 0.0001), previous hysterectomy (P = 0.0006), descent of the posterior compartment (Bp; P = 0.004) and hiatal dimensions (Pb and Gh + Pb; P = 0.006 and P = 0.004). OD bother was associated with the following sonographic findings: true rectocele (P = 0.01), depth of rectocele (P = 0.04), descent of rectal ampulla (P = 0.02), enterocele (P = 0.03) and rectal intussusception (P < 0.0001). CONCLUSIONS: VAS bother scores are associated with both clinical and sonographic measures of posterior compartment descent. Rectal intussusception was most likely to result in highly bothersome symptoms of OD. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Twelve tips for applying the science of learning to health professions education.

Findings from the science of learning have clear implications for those responsible for teaching and curricular design. However, this data has been historically siloed from educators in practice, including those in health professions education. In this article, we aim to bring practical tips from the science of learning to health professions educators. We have chosen to organize the tips into six themes, highlighting strategies for 1) improving the processing of information, 2) promoting effortful learning for greater retention of knowledge over time, 3) applying learned information to new and varied contexts, 4) promoting the development of expertise, 5) harnessing the power of emotion for learning, and 6) teaching and learning in social contexts. We conclude with the importance of attending to metacognition in our learners and ourselves. Health professions education can be strengthened by incorporating these evidence-based techniques.

Genomic architecture of human neuroanatomical diversity.

Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here, based on our analyses of neuroimaging and whole-genome genotyping data from 1765 subjects, we show that up to 54% of this heritability is captured by large numbers of single-nucleotide polymorphisms of small-effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.

Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents.

Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54,837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10(-)(7)), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.

Activation, activity and inactivation of factor VIII in factor VIII products.

INTRODUCTION: Factor VIII (FVIII) products used in haemophilia A treatment show inter-and intra-product and inter-assay differences in specific activity. The mechanistic basis of these differences remains unclear. AIM: The aim of this study was to mechanistically compare the functional properties of an in-house excipient-free full-length FVIII standard and pharmacologic recombinant products containing full-length (products A and B) or B-domainless (C and D) FVIII. METHODS: Factor VIII protein concentration was quantitated by ELISA. Product potency determinations (APTT, intrinsic tenase assays) and kinetic analyses detailing these products' activations by thrombin and FXa, their spontaneous and activated protein C (APC) catalysed inactivation and their performances in coagulation proteome reconstructions were studied +/- von Willebrand factor (VWF). Computational models were developed to facilitate interpretation of empirical data. RESULTS: Factor VIII protein content per manufacturer activity unit was highest for product C with the other three products similar to the standard. Potency estimates, done five different ways, varied 20-30% in inter- and intra-assay comparisons, with product B consistently showing lower specific activity. Kinetic analyses showed the five FVIII species to differ somewhat in maximum rate of activation, the maximum level of activity achieved, the rate of spontaneous or APC catalysed inactivation and the magnitude of the effect of VWF on these parameters. When evaluated both computationally and empirically in the context of tissue factor initiated thrombin generation, product C appears the most dissimilar. CONCLUSION: Assessments of FVIII activation/inactivation dynamics report larger differences between FVIII products than standard functional assays. However, all FVIII products promote a 'normal' thrombin generation response to TF.