Negative Associations between Corpus Callosum Midsagittal Area and IQ in a Representative Sample of Healthy Children and Adolescents

Documented associations between corpus callosum size and cognitive ability have heretofore been inconsistent potentially owing to differences in sample characteristics, differing methodologies in measuring CC size, or the use of absolute versus relative measures. We investigated the relationship between CC size and intelligence quotient (IQ) in the NIH MRI Study of Normal Brain Development sample, a large cohort of healthy children and adolescents (aged six to 18, n = 198) recruited to be representative of the US population. CC midsagittal area was measured using an automated system that partitioned the CC into 25 subregions. IQ was measured using the Wechsler Abbreviated Scale of Intelligence (WASI). After correcting for total brain volume and age, a significant negative correlation was found between total CC midsagittal area and IQ (r = −0.147; p = 0.040). Post hoc analyses revealed a significant negative correlation in children (age<12) (r = −0.279; p = 0.004) but not in adolescents (age $\geq$ 12) (r = −0.005; p = 0.962). Partitioning the subjects by gender revealed a negative correlation in males (r = −0.231; p = 0.034) but not in females (r = 0.083; p = 0.389). Results suggest that the association between CC and intelligence is mostly driven by male children. In children, a significant gender difference was observed for FSIQ and PIQ, and in males, a significant age-group difference was observed for FSIQ and PIQ. These findings suggest that the correlation between CC midsagittal area and IQ may be related to age and gender

The role of Allied Health Professions and Nursing Research Internships in developing a research culture: a mixed-methods exploration of stakeholder perspectives

Background: Developing research capability and capacity within the healthcare professions is a challenge throughout diverse international settings. Within England, the National Institute for Health Research aimed to address these challenges through the Integrated Clinical Academic (ICA) research careers escalator for nurses, midwives and allied health professionals. Poor academic progression has been identified in the advanced stages of the pathway, though progression from the earlier entry point (Internship) has not previously been investigated. A national evaluation of four completed Internship cohorts was undertaken to explore stakeholder perspectives and progression beyond the Internship programme. Methods A mixed methods project used sequential qualitative and quantitative data collection phases commencing with two stakeholder focus groups (n = 10); the findings informed the development of an online survey distributed to previous cohorts of interns (n = 104), their managers (n = 12) and academic mentors (n = 36). Eight semi-structured interviews subsequently explored the challenges and opportunities afforded by the internships. Thematic analysis was used to review qualitative data from focus groups and interviews, with survey data analysed and displayed using descriptive statistics. Synthesis of data from each phase is displayed within the four level evaluation framework outlined within the New World Kirkpatrick® Training Evaluation Model. Results Important regional differences exist yet the internships are highly valued by all stakeholders. Representation varied between different professions, with nursing and some service-based professions poorly represented. All interns successfully completed the programme (n = 104), with evidence of positive impacts on interns, colleagues and patient care. Balancing research commitments with clinical activity was challenging; middle managers were seen as gatekeepers to programme success. Progression to the next stage of the ICA pathway is highly competitive and was achieved by only a quarter of interns; access to mentors outside of the funded programme is vital for a successful transition. Conclusions The Internship programme succeeds in providing a range of important early experiences in research, though progression beyond the programme is challenging due, in part, to a widening gap between Internship and the next level of the ICA framework. Vital mentorship support to bridge this gap is threatened by a lack of time and funding; therefore, the pursuit of a clinical-academic career will continue to be elusive for many nurses and allied health professionals. A partnership approach to clinical academic support at institutional level is needed with several international models offering alternative strategies for consideration

Intellectual ability in tuberous sclerosis complex correlates with predicted effects of mutations on TSC1 and TSC2 proteins.

BACKGROUND: Tuberous sclerosis complex is a multisystem genetic disease, caused by mutation in the TSC1 or TSC2 genes, associated with many features, including intellectual disability (ID). We examined psychometric profiles of patients with TSC1 or TSC2 mutations and tested whether different mutation types were associated with different degrees of intellectual ability. METHODS: One hundred subjects with known TSC1/TSC2 mutations were assessed using a range of IQ or developmental quotient (DQ) measures. Effects of mutations on TSC1/TSC2 proteins were inferred from sequence data and published biochemical studies. RESULTS: Most individuals with TSC1 mutations fell on a normal distribution identical to the general population, with ∼10% showing profound ID. Of individuals with TSC2 mutations, 34% showed profound ID, and the remainder a pattern of IQ/DQ more variable and shifted to the left than in TSC1 or the general population. Truncating TSC1 mutations were all predicted to be subject to nonsense-mediated mRNA decay. Mutations predicted to result in unstable protein were associated with less severe effects on IQ/DQ. There was a statistically significant negative correlation between length of predicted aberrant C-terminal tails arising from frameshift mutations in TSC1 and IQ/DQ; for TSC2 a positive but not statistically significant correlation was observed. CONCLUSION: We propose a model where (i) IQ/DQ correlates inversely with predicted levels and/or deleterious biochemical effects of mutant TSC1 or TSC2 protein, and (ii) longer aberrant C-terminal tails arising from frameshift mutations are more detrimental for TSC1 and less for TSC2. Predictions of the model require replication and biochemical testing.We thank the Tuberous Sclerosis Association, the Wales Gene Park, the National Research Foundation of South Africa and the Struengmann Fund for financial support. We thank Prof Chris Smith for helpful comments on the manuscript.This is the author accepted manuscript. The final version is available from the British Medical Journal via http://dx.doi.org/10.1136/jmedgenet-2015-10315

Negative associations between corpus callosum midsagittal area and IQ in a representative sample of healthy children and adolescents.

Documented associations between corpus callosum size and cognitive ability have heretofore been inconsistent potentially owing to differences in sample characteristics, differing methodologies in measuring CC size, or the use of absolute versus relative measures. We investigated the relationship between CC size and intelligence quotient (IQ) in the NIH MRI Study of Normal Brain Development sample, a large cohort of healthy children and adolescents (aged six to 18, n = 198) recruited to be representative of the US population. CC midsagittal area was measured using an automated system that partitioned the CC into 25 subregions. IQ was measured using the Wechsler Abbreviated Scale of Intelligence (WASI). After correcting for total brain volume and age, a significant negative correlation was found between total CC midsagittal area and IQ (r = -0.147; p = 0.040). Post hoc analyses revealed a significant negative correlation in children (ag

The Social context of motorcycle riding and the key determinants influencing rider behavior: A qualitative investigation

Objective: Given the increasing popularity of motorcycle riding and heightened risk of injury or death associated with being a rider, this study explored rider behaviour as a determinant of rider safety and, in particular, key beliefs and motivations which influence such behaviour. To enhance the effectiveness of future education and training interventions, it is important to understand riders’ own views about what influences how they ride. Specifically, this study sought to identify key determinants of riders’ behaviour in relation to the social context of riding including social and identity-related influences relating to the group (group norms and group identity) as well as the self (moral/personal norm and self-identity). ----- ----- Method: Qualitative research was undertaken via group discussions with motorcycle riders (n = 41). Results: The findings revealed that those in the group with which one rides represent an important source of social influence. Also, the motorcyclist (group) identity was associated with a range of beliefs, expectations, and behaviours considered to be normative. Exploration of the construct of personal norm revealed that riders were most cognizant of the “wrong things to do” when riding; among those issues raised was the importance of protective clothing (albeit for the protection of others and, in particular, pillion passengers). Finally, self-identity as a motorcyclist appeared to be important to a rider’s self-concept and was likely to influence their on-road behaviour. ----- ----- Conclusion: Overall, the insight provided by the current study may facilitate the development of interventions including rider training as well as public education and mass media messages. The findings suggest that these interventions should incorporate factors associated with the social nature of riding in order to best align it with some of the key beliefs and motivations underpinning riders’ on-road behaviours

Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts

STUDY QUESTION: Is cord blood DNA methylation associated with having been conceived by medically assisted reproduction? SUMMARY ANSWER: This study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation. WHAT IS KNOWN ALREADY: Medically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes. STUDY DESIGN, SIZE, DURATION: We investigated the association of DNA methylation and medically assisted reproduction using a case-control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls). MAIN RESULTS AND THE ROLE OF CHANCE: The ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling. LIMITATIONS, REASONS FOR CAUTIONS: While insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction. WIDER IMPLICATIONS OF THE FINDINGS: Newborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health. STUDY FUNDING/COMPETING INTERESTS(S): This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union's Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A

A life in progress: motion and emotion in the autobiography of Robert M. La Follette

This article is a study of a La Follette’s Autobiography, the autobiography of the leading Wisconsin progressive Robert M. La Follette, which was published serially in 1911 and, in book form, in 1913. Rather than focusing, as have other historians, on which parts of La Follette’s account are accurate and can therefore be trusted, it explains instead why and how this major autobiography was conceived and written. The article shows that the autobiography was the product of a sustained, complex, and often fraught series of collaborations among La Follette’s family, friends, and political allies, and in the process illuminates the importance of affective ties as well as political ambition and commitment in bringing the project to fruition. In the world of progressive reform, it argues, personal and political experiences were inseparable

Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer

The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1-/-, and A1cf-/- mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC