Single Center Neurosurgical Outcomes and Trends in Endoscopic Endonasal Resection of 297 Sellar/Suprasellar Tumors Stratified by Duration of Neurosurgical Career.

INTRODUCTION: Endoscopic endonasal transsphenoidal surgery (EETS) is a common treatment for sellar and suprasellar tumors. While endoscopic training has improved over the years and formal fellowship training is now broadly available, the operative nuances of EETS conjectures the existence a learning curve as a neurosurgeon matures with experience. We aim to evaluate operative outcomes of three different experience levels of neurosurgeons over time at a single institution. METHODS: We reviewed all adult patients who underwent EETS at Loyola University Medical Center by three early career, one mid-career, and two late career neurosurgeons from 2007 to 2023. A comparative assessment of patient demographics, tumor features, and surgical outcomes was done using metrics such as length of surgery, rates of gross total resection (GTR) and symptomatic improvement (SI), new postoperative steroid dependence, and development of diabetes insipidus (DI). T-tests and Chi-Square were used to statistically evaluate the study cohorts. RESULTS: A total of 297 patients underwent EETS. One hundred and three (35%) were operated on by an early career, 122 (41%) by a mid-career, and 72 (24%) by a late career neurosurgeon. Late-career surgeons had shorter operation times (144 vs. 180 minutes with early and mid-career, p=0.029) and increased GTR rates (p=0.008). There were no significant differences between the SI rates amongst various surgeon experience levels. Although not statistically significant, early-career neurosurgeons had lower rates of new postoperative steroid dependence. Patients of early career surgeons experienced significantly less DI (15% vs 40%, p=0.004). CONCLUSION: Late-career neurosurgeons had shorter operation lengths, achieved higher rates of GTR, and their patients experienced significantly higher rates of DI. Overall outcomes remained stable throughout the course of 16 years between different surgeon experience levels.

Cerebral arterial vasospasm complicating supratentorial meningioma resection: illustrative cases.

BACKGROUND: Cerebral arterial vasospasm is a rare complication after supratentorial meningioma resection. The pathophysiology of this condition may be similar to vasospasm after aneurysmal subarachnoid hemorrhage, and treatment options may be similar. OBSERVATIONS: The authors present two cases of cerebral vasospasm after supratentorial meningioma resection and perform a systematic literature review of similar cases. LESSONS: Cerebral arterial vasospasm after supratentorial meningioma resection may be associated with significant morbidity due to cerebral ischemia if not addressed in a timely manner. Treatment paradigms may be adopted from the management of arterial vasospasm associated with subarachnoid hemorrhage.

Infant excitation/inhibition balance interacts with executive attention to predict autistic traits in childhood.

BACKGROUND: Autism is proposed to be characterised by an atypical balance of cortical excitation and inhibition (E/I). However, most studies have examined E/I alterations in older autistic individuals, meaning that findings could in part reflect homeostatic compensation. To assess the directionality of effects, it is necessary to examine alterations in E/I balance early in the lifespan before symptom emergence. Recent explanatory frameworks have argued that it is also necessary to consider how early risk features interact with later developing modifier factors to predict autism outcomes. METHOD: We indexed E/I balance in early infancy by extracting the aperiodic exponent of the slope of the electroencephalogram (EEG) power spectrum ('1/f'). To validate our index of E/I balance, we tested for differences in the aperiodic exponent in 10-month-old infants with (n = 22) and without (n = 27) neurofibromatosis type 1 (NF1), a condition thought to be characterised by alterations to cortical inhibition. We then tested for E/I alterations in a larger heterogeneous longitudinal cohort of infants with and without a family history of neurodevelopmental conditions (n = 150) who had been followed to early childhood. We tested the relevance of alterations in E/I balance and our proposed modifier, executive attention, by assessing whether associations between 10-month aperiodic slope and 36-month neurodevelopmental traits were moderated by 24-month executive attention. Analyses adjusted for age at EEG assessment, sex and number of EEG trials. RESULTS: Infants with NF1 were characterised by a higher aperiodic exponent, indicative of greater inhibition, supporting our infant measure of E/I. Longitudinal analyses showed a significant interaction between aperiodic slope and executive attention, such that higher aperiodic exponents predicted greater autistic traits in childhood, but only in infants who also had weaker executive functioning abilities. LIMITATIONS: The current study relied on parent report of infant executive functioning-type abilities; future work is required to replicate effects with objective measures of cognition. CONCLUSIONS: Results suggest alterations in E/I balance are on the developmental pathway to autism outcomes, and that higher executive functioning abilities may buffer the impact of early cortical atypicalities, consistent with proposals that stronger executive functioning abilities may modify the impact of a wide range of risk factors.

Depressive symptoms during early adulthood and the development of physical multimorbidity in the UK: an observational cohort study.

BACKGROUND: An understanding of whether early-life depression is associated with physical multimorbidity could be instrumental for the development of preventive measures and the integrated management of depression. We therefore aimed to map out the cumulative incidence of physical multimorbidity over adulthood, and to determine the association between the presence of depressive symptoms during early adulthood and the development of physical multimorbidity in middle age. METHODS: In this observational cohort study, we used pooled data from the 1958 National Child Development Study (NCDS) and the 1970 British Cohort Study (BCS). Cohort waves were pooled in each decade of adult life available (when cohort members were aged 26 years in the BCS and 23 years in the NCDS [baseline]; 34 years in the BCS and 33 years in the NCDS [age 34 BCS/33 NCDS]; 42 years in the BCS and NCDS [age 42 BCS/NCDS]; and 46 years in the BCS and 50 years in the NCDS [age 46 BCS/50 NCDS]). We included participants who had completed the nine-item Malaise Inventory at baseline, and did not have a history of physical multimorbidity, any physical multimorbidity at baseline, or the presence of depressive symptoms before the development of physical multimorbidity. The presence of depressive symptoms was determined using the nine-item Malaise Inventory (cutoff score ≥4). Physical multimorbidity was defined as having at least two measures of any of the following ten self-reported groups of long-term conditions: asthma or bronchitis; backache; bladder or kidney conditions; cancer; cardiovascular conditions; convulsions or epilepsy; diabetes; hearing conditions; migraine; and stomach, bowel, or gall conditions. Cumulative incidence (with 95% CI) of physical multimorbidity was calculated for each decade considered after baseline, with physical multimorbidity being assessed as both a dichotomous and categorical variable. The association between depressive symptoms and the development of physical multimorbidity was assessed using adjusted relative risk ratios (with 95% CIs). FINDINGS: Analyses included 15 845 participants, of whom 4001 (25·25%; 95% CI 24·57-25·93) had depressive symptoms at baseline and 11 844 (74·75%; 74·07-75·42) did not. The cumulative incidence of physical multimorbidity (dichotomous) ranged over the study period from 2263 (18·44%; 95% CI 17·75-18·14) of 12 273 participants at age 34 BCS/33 NCDS, to 4496 (42·90%; 41·95-43·85) of 10 481 participants at age 46 BCS/50 NCDS, and was consistently higher in participants with depressive symptoms at baseline. The adjusted relative risk of physical multimorbidity was higher in participants with depressive symptoms than in those without and remained stable over the study period (adjusted relative rate ratio 1·67, 95% CI 1·50-1·87, at age 34 BCS/33 NCDS; 1·63, 1·48-1·79, at age 42 BCS/NCDS; and 1·58, 1·43-1·73, at age 46 BCS/50 NCDS). INTERPRETATION: The presence of depressive symptoms during early adulthood is associated with an increased risk of the development of physical multimorbidity in middle age. Although further research about the drivers of this relationship is needed, these results could help to enhance the integrated management of individuals with depressive symptoms and the development of preventive strategies to reduce the effect and burden of physical multimorbidity. FUNDING: UK Medical Research Council and Guy's Charity.

Understanding usual care in randomised controlled trials of complex interventions: A multi-method approach.

BACKGROUND: Evaluations of complex interventions compared to usual care provided in palliative care are increasing. Not describing usual care may affect the interpretation of an intervention's effectiveness, yet how it can be described remains unclear. AIM: To demonstrate the feasibility of using multi-methods to describe usual care provided in randomised controlled trials (RCTs) of complex interventions, shown within a feasibility cluster RCT. DESIGN: Multi-method approach comprising usual care questionnaires, baseline case note review and focus groups with ward staff completed at study end. Thematic analysis of qualitative data, descriptive statistics of quantitative data, followed by methodological triangulation to appraise approach in relation to study aim. SETTING/PARTICIPANTS: Four general medical wards chosen from UK hospitals. Purposive sampling of healthcare professionals for usual care questionnaires, and focus groups. Review of 20 patients' notes from each ward who died during admission or within 100 days of discharge. RESULTS: Twenty-three usual care questionnaires at baseline, two focus groups comprising 20 healthcare professionals and 80 case note reviews. Triangulation of findings resulted in understanding the usual care provided to the targeted population in terms of context, structures, processes and outcomes for patients, families and healthcare professionals. Usual care was described, highlighting (1) similarities and embedded practices, (2) heterogeneity and (3) subtle changes in care during the trial within and across sites. CONCLUSIONS: We provide a feasible approach to defining usual care that can be practically adopted in different settings. Understanding usual care enhances the reliability of tested complex interventions, and informs research and policy priorities.

Using a cross-cohort comparison design to test the role of maternal smoking in pregnancy in child mental health and learning: evidence from two UK cohorts born four decades apart.

BACKGROUND: Maternal smoking in pregnancy is associated with low birth weight (LBW), child conduct problems, hyperactivity and lower cognitive attainment, but associations may reflect measured and unmeasured confounding. Cross-cohort designs can aid causal inference through comparison of associations across populations with different confounding structures. We compared associations between maternal smoking in pregnancy and child conduct and hyperactivity problems, cognition and LBW across two cohorts born four decades apart. METHODS: Two national UK cohorts born in 1958 (n = 12 415) and 2000/01 (n = 11 800) were compared. Maternal smoking in pregnancy and child birth weight was assessed at or shortly after birth. Parents rated children's conduct problems and hyperactivity, and children completed standardized tests of reading and mathematics. RESULTS: Maternal smoking in pregnancy was less common and more strongly associated with social disadvantage in 2000/01 compared with 1958 (interactions P < 0.001). Maternal smoking in pregnancy was robustly and equivalently associated with infant LBW in both cohorts [interactions: boys odds ratio (OR) = 1.01 (0.89, 1.16), P = 0.838; girls OR = 1.01 (0.91, 1.17), P = 0.633]. Maternal smoking was more strongly associated with conduct problems, hyperactivity and reading in the 2000/01 cohort (interactions P < 0.001). CONCLUSIONS: Marked cross-cohort change in associations between maternal smoking and child conduct problems, hyperactivity and reading highlights the likely role of confounding factors. In contrast, association with LBW was unaffected by change in prevalence of maternal smoking and patterns of confounding. The study highlights the utility of cross-cohort designs in helping triangulate conclusions about the role of putative causal risk factors in observational epidemiology.

The Regulation of Monoamine Oxidase A Gene Expression by Distinct Variable Number Tandem Repeats.

The monoamine oxidase A (MAOA) uVNTR (upstream variable number tandem repeat) is one of the most often cited examples of a gene by environment interaction (GxE) in relation to behavioral traits. However, MAOA possesses a second VNTR, 500 bp upstream of the uVNTR, which is termed d- or distal VNTR. Furthermore, genomic analysis indicates that there are a minimum of two transcriptional start sites (TSSs) for MAOA, one of which encompasses the uVNTR within the 5' untranslated region of one of the isoforms. Through expression analysis in semi-haploid HAP1 cell lines genetically engineered in order to knockout (KO) either the uVNTR, dVNTR, or both VNTRs, we assessed the effect of the two MAOA VNTRs, either alone or in combination, on gene expression directed from the different TSSs. Complementing our functional analysis, we determined the haplotype variation of these VNTRs in the general population. The expression of the two MAOA isoforms was differentially modulated by the two VNTRs located in the promoter region. The most extensively studied uVNTR, previously considered a positive regulator of the MAOA gene, did not modulate the expression of what it is considered the canonical isoform, while we found that the dVNTR positively regulated this isoform in our model. In contrast, both the uVNTR and the dVNTR were found to act as negative regulators of the second less abundant MAOA isoform. The haplotype analysis for these two VNTRs demonstrated a bias against the presence of one of the potential variants. The uVNTR and dVNTR differentially affect expression of distinct MAOA isoforms, and thus, their combined profiling offers new insights into gene-regulation, GxE interaction, and ultimately MAOA-driven behavior.

Tutorial: The practical application of longitudinal structural equation mediation models in clinical trials.

The study of mediation of treatment effects, or how treatments work, is important to understanding and improving psychological and behavioral treatments, but applications often focus on mediators and outcomes measured at a single time point. Such cross-sectional analyses do not respect the implied temporal ordering that mediation suggests. Clinical trials of treatments often provide repeated measures of outcomes and, increasingly, of mediators as well. Repeated measurements allow the application of various types of longitudinal structural equation mediation models. These provide flexibility in modeling, including the ability to incorporate some types of measurement error and unmeasured confounding that can strengthen the robustness of findings. The usual approach is to identify the most theoretically plausible model and apply that model. In the absence of clear theory, we put forward the option of fitting a few theoretically plausible models, providing a type of sensitivity analysis for the mediation hypothesis. In this tutorial, we outline how to fit several longitudinal mediation models, including simplex, latent growth and latent change models. This will allow readers to learn about one type of model that is of interest, or about several alternative models, so that they can take this sensitivity approach. We use the Pacing, Graded Activity, and Cognitive Behavioral Therapy: A Randomized Evaluation (PACE) trial of rehabilitative treatments for chronic fatigue syndrome (ISRCTN 54285094) as a motivating example and describe how to fit and interpret various longitudinal mediation models using simulated data similar to those in the PACE trial. The simulated data set and Mplus code and output are provided. (PsycINFO Database Record

A multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin compared with standard therapy for the treatment of transverse myelitis in adults and children (STRIVE).

BACKGROUND: Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord that affects adults and children and that causes motor, sensory and autonomic dysfunction. There is a prolonged recovery phase, which may continue for many years. Neuromyelitis optica (NMO) is an uncommon relapsing inflammatory central nervous system condition in which TM can be the first presenting symptom. As TM and NMO affect many patients in the prime of their working life, the disorder can impose a significant demand on health resources. There are currently no robust controlled trials in children or adults to inform the optimal treatment of TM. However, treatment with intravenous immunoglobulin (IVIG) is being effectively used in the management of a range of neurological conditions. Although other interventions such as plasma exchange (PLEX) in addition to intravenous (IV) methylprednisolone therapy can be beneficial in TM, PLEX is costly and technically challenging to deliver in the acute setting. IVIG is more readily accessible and less costly. OBJECTIVE: To evaluate whether additional and early treatment with IVIG is of extra benefit in TM compared with standard therapy with IV steroids. DESIGN: A multicentre, single-blind, parallel-group randomised controlled trial of IVIG compared with standard therapy for the treatment of TM in adults and children. PARTICIPANTS: Patients aged ≥ 1 year diagnosed with either acute first-onset TM or first presentation of NMO. Target recruitment was 170 participants (85 participants per arm). INTERVENTIONS: Participants were randomised 1 : 1 to treatment with IV methylprednisolone only or treatment with IV methylprednisolone plus 2 g/kg of IVIG in divided doses within 5 days of the first commencement of steroid therapy. MAIN OUTCOME MEASURES: Primary outcome measure - American Spinal Injury Association (ASIA) Impairment Scale at 6 months post randomisation, with a good outcome defined by a two-grade change. Secondary and tertiary outcome measures - ASIA motor and sensory scales, Expanded Disability Status Scale, health outcome, quality of life, Client Service Receipt Inventory and International Spinal Cord Injury Pain, Bladder and Bowel Basic Data Sets. RESULTS: In total, 26 participants were screened and two were randomised into the study. With the limited sample size, treatment effect could not be determined. However, we identified barriers to accrual that included strict inclusion criteria, the short enrolment window, challenges associated with the use of the ASIA Impairment Scale as an outcome measure and estimation of the incidence of TM. CONCLUSIONS: The study did not reach the end point and the effect of IVIG in TM/NMO could not be determined. Investigators should be aware of the potential challenges associated with carrying out a rare disease trial with a short enrolment window. The study question is one that still necessitates investigation. Preliminary work to ameliorate the effect of the barriers encountered in this study is vital. TRIAL REGISTRATION: EudraCT 2014-002335-34, ClinicalTrials.gov NCT02398994 and Current Controlled Trials ISRCTN12127581. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 31. See the NIHR Journals Library website for further project information. Funding was also received from Biotest AG, Germany (supply of IVIG) and the Transverse Myelitis Society (excess research cost to facilitate study initiation).

Prenatal anxiety, maternal stroking in infancy, and symptoms of emotional and behavioral disorders at 3.5 years.

Animal findings of long-term effects of maternal behaviors mediated via altered GR gene expression will, if translated into humans, have far reaching implications for our understanding of child and adolescent psychopathology. We have previously shown that mothers' self-reported stroking of their infants modifies associations between prenatal depression and anxiety and child outcomes at 29 weeks and 2.5 years. Here, we examine whether the effect of early maternal stroking is evident at 3.5 years, and in a much larger sample than in previous publications. A general population sample of 1233 first-time mothers completed anxiety measures at 20 weeks gestation, 865 reported on infant stroking at 9 weeks, and 813 on child symptoms at 3.5 years. Maternal stroking moderated the association between pregnancy-specific anxiety and internalizing (p = 0.010) and externalizing (p = 0.004) scores, such that an effect of PSA to increase symptoms was markedly reduced for mothers who reported high levels of stroking. There was no effect of maternal stroking on general anxiety. The findings confirm the previously reported effect of maternal stroking, and in a much larger sample. They indicate that there are long-term effects of early maternal stroking, modifying associations between prenatal anxiety and child emotional and behavioral symptoms.

Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial.

BACKGROUND: Cognitive behaviour therapy (CBT) added to specialist medical care (SMC), or graded exercise therapy (GET) added to SMC, are more effective in reducing fatigue and improving physical function than both adaptive pacing therapy (APT) plus SMC and SMC alone for chronic fatigue syndrome. We investigate putative treatment mechanisms. METHODS: We did a planned secondary mediation analysis of the PACE trial comparing SMC alone or SMC plus APT with SMC plus CBT and SMC plus GET for patients with chronic fatigue syndrome. 641 participants were recruited from six specialist chronic fatigue syndrome clinics in the UK National Health Service between March 18, 2005, and Nov 28, 2008. We assessed mediation using the product of coefficients method with the 12 week measure of the mediators and the 52 week measure of the outcomes. The primary outcomes were fatigue measured by the Chalder fatigue scale and physical function measured by the physical function subscale of the SF-36. We included confounder covariates and used treatment by mediator interaction terms to examine differences in mediator-outcome relations by treatment group. FINDINGS: The largest mediated effect for both CBT and GET and both primary outcomes was through fear avoidance beliefs with an effect of larger magnitude for GET (standardised effects ×10, CBT vs APT, fatigue -1.22, 95% CI -0.52 to -1.97, physical function 1.54, 0.86 to 2.31; GET vs APT, fatigue -1.86, -0.80 to -2.89, physical function 2.35, 1.35 to 3.39). Increase in exercise tolerance (6 min walk distance) was a potent mediator of the effect of GET (vs APT, fatigue -1.37, 95% CI -0.76 to -2.21, physical function 1.90, 1.10 to 2.91), but not CBT. INTERPRETATION: Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET. Changes in both beliefs and behaviour mediated the effects of both CBT and GET, but more so for GET. The results support a treatment model in which both beliefs and behaviour play a part in perpetuating fatigue and disability in chronic fatigue syndrome. FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, and Institute of Psychiatry, Psychology, and Neuroscience, King's College London.

Gut permeability in autism spectrum disorders.

OBJECTIVE: To test whether gut permeability is increased in autism spectrum disorders (ASD) by evaluating gut permeability in a population-derived cohort of children with ASD compared with age- and intelligence quotient-matched controls without ASD but with special educational needs (SEN). PATIENTS AND METHODS: One hundred thirty-three children aged 10-14 years, 103 with ASD and 30 with SEN, were given an oral test dose of mannitol and lactulose and urine collected for 6 hr. Gut permeability was assessed by measuring the urine lactulose/mannitol (L/M) recovery ratio by electrospray mass spectrometry-mass spectrometry. The ASD group was subcategorized for comparison into those without (n = 83) and with (n = 20) regression. RESULTS: There was no significant difference in L/M recovery ratio (mean (95% confidence interval)) between the groups with ASD: 0.015 (0.013-0.018), and SEN: 0.014 (0.009-0.019), nor in lactulose, mannitol, or creatinine recovery. No significant differences were observed in any parameter for the regressed versus non-regressed ASD groups. Results were consistent with previously published normal ranges. Eleven children (9/103 = 8.7% ASD and 2/30 = 6.7% SEN) had L/M recovery ratio > 0.03 (the accepted normal range cut-off), of whom two (one ASD and one SEN) had more definitely pathological L/M recovery ratios > 0.04. CONCLUSION: There is no statistically significant group difference in small intestine permeability in a population cohort-derived group of children with ASD compared with a control group with SEN. Of the two children (one ASD and one SEN) with an L/M recovery ratio of > 0.04, one had undiagnosed asymptomatic celiac disease (ASD) and the other (SEN) past extensive surgery for gastroschisis.

Psychopathology in children before and after surgery for extratemporal lobe epilepsy.

AIM: To establish the rates and types of psychiatric disorder in children before and after surgery for extratemporal epilepsy. Relationships between psychiatric morbidity and demographic/clinical variables were examined. METHOD: A retrospective case note review of 71 children undergoing extratemporal focal resection for drug resistant epilepsy in a specialist epilepsy surgery programme between 1997 and 2008. Psychiatric diagnoses were derived from pre- and postoperative assessments according to DSM-IV criteria. RESULTS: Seventy-one children (38 males, 33 females) were eligible for this study. Mean age (SD) at surgery was 9 (5) years. Frontal resections were performed in 73% of the children, parietal in 17%, and occipital in 10%. Mental health problems were present in 37 of 71 (52%) children pre- and/or postoperatively. A similar proportion of children had psychiatric diagnoses pre- and postoperatively: 31 of 71 (44%) and 32 of 71 (45%) respectively. INTERPRETATION: Psychopathology is common in children with extratemporal epilepsy. In this sample, the impact of surgery on psychiatric symptoms was not predictable: some children were unchanged, others improved, and others acquired new psychiatric diagnoses postoperatively. Given the high rates of psychiatric disorder in this group of patients, detection and treatment of mental health needs may be important.

Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts.

Genetic influences have an important role in the ageing process. The genetic factors that influence success in bodily ageing may also contribute to the successful ageing of cognitive abilities. A comparative genomics approach found longevity genes conserved between yeast Saccharomyces cerevisiae and nematode Caenorhabditis elegans. We hypothesised that these longevity genes influence variance in cognitive ability and age-related cognitive decline in humans. Here, we investigated six of these genes that have human orthologs and show expression in the brain. We tested AFG3L2 (MIM: 604581, AFG3 ATPase family gene 3-like 2 (yeast)), FRAP1 (MIM: 601231, a FK506 binding protein 12-rapamycin associated protein), MAT1A, MAT2A (MIM: 610550 and 601468, methionine adenosyltransferases I alpha and II alpha, respectively), SYNJ1 and SYNJ2 (MIM: 604297 and 609410, synaptojanin-1 and synaptojanin-2, respectively) in approximately 1000 healthy older Scots: the Lothian Birth Cohort 1936 (LBC1936). They were tested on general cognitive ability at age 11 years. At a mean age of 70 years, they re-sat the same general cognitive ability test and underwent an additional battery of diverse cognitive tests. In all, 70 tag and functional SNPs in the six longevity genes were genotyped and tested for association with cognition and cognitive ageing in LBC1936. Suggestive associations were detected between SNPs in SYNJ2, MAT1A, AFG3L2 and SYNJ1 and a general memory factor and general cognitive ability at age 11 and 70 years. Replication studies for cognitive ability associations were performed in 2506 samples from the Cognitive Ageing Genetics in England and Scotland consortium. A meta-analysis replicated the SYNJ2 association with cognitive abilities (lowest P=0.00077). SYNJ2 is a novel gene in which variation is potentially associated with cognitive abilities.

Influence of environmental factors in higher risk of sudden infant death syndrome linked with parental mental illness.

CONTEXT: Since national risk reduction campaigns have been conducted, sudden infant death syndrome (SIDS) has become increasingly concentrated among disadvantaged families, including those affected by mental illness. However, causal mechanisms specific to this group are poorly understood. OBJECTIVES: To estimate relative risk and compare risk factor prevalence in infants with and without parental psychiatric inpatient history, and to explore effect modification after the 1992 Swedish risk reduction campaign. DESIGN: National birth cohort. Parental psychiatric admissions, maternal prenatal smoking, obstetric and social risk factors, and cause-specific infant death were ascertained via linkage between national registers. SETTING: The Swedish population, 1978 through 2004. PARTICIPANTS: All singleton live births (N = 2.5 million). MAIN OUTCOME MEASURE: Incidence of SIDS. RESULTS: Risk of SIDS was higher with a history of parental inpatient care, especially if both parents were admitted with any mental illness (odds ratio, 6.8; 95% confidence interval, 4.7-10.0), or if the mother (6.5; 4.9-8.7) or both parents (9.5; 5.5-16.4) had an alcohol/drug disorder. A 2-fold higher risk was also seen if the mother or father was admitted with any psychiatric illness other than alcohol or other drug disorders. Elevated risk persisted even if the last maternal inpatient episode had occurred 5 or more years before the infant's birth. After the national campaign, risk factor prevalence (especially maternal antenatal smoking) remained high in this population, and relative risks therefore increased. During 1992 through 2004, smoking and individual social adversity measures jointly accounted for approximately half the excess risk linked with maternal psychiatric inpatient history, whereas the confounding effects of obstetric factors were minimal. CONCLUSIONS: Tailored approaches are needed to ensure that standard safety advice is effectively communicated to these vulnerable families. In particular, mentally ill pregnant women should be encouraged and better supported to stop smoking. Families with 2 affected parents require particularly strong support. A clearer understanding is needed as to why high risk factor prevalence persists among these parents.

CMIP and ATP2C2 modulate phonological short-term memory in language impairment.

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 x 10(-7) at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 x 10(-5) at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.

Estimating intervention effects in a complex multi-level smoking prevention study.

This paper illustrates how to estimate cumulative and non-cumulative treatment effects in a complex school-based smoking intervention study. The Instrumental Variable method is used to tackle non-compliance and measurement error for a range of treatment exposure measures (binary, ordinal and continuous) in the presence of clustering and dropout. The results are compared to more routine analyses. The empirical findings from this study provide little encouragement for believing that poorly resourced school-based interventions can bring about substantial long-lasting reductions in smoking behaviour but that novel components such as a computer game might have some short-term effect.

A flexible model for multivariate interval-censored survival times with complex correlation structure.

We focus on the analysis of multivariate survival times with highly structured interdependency and subject to interval censoring. Such data are common in developmental genetics and genetic epidemiology. We propose a flexible mixed probit model that deals naturally with complex but uninformative censoring. The recorded ages of onset are treated as possibly censored ordinal outcomes with the interval censoring mechanism seen as arising from a coarsened measurement of a continuous variable observed as falling between subject-specific thresholds. This bypasses the requirement for the failure times to be observed as falling into non-overlapping intervals. The assumption of a normal age-of-onset distribution of the standard probit model is relaxed by embedding within it a multivariate Box-Cox transformation whose parameters are jointly estimated with the other parameters of the model. Complex decompositions of the underlying multivariate normal covariance matrix of the transformed ages of onset become possible. The new methodology is here applied to a multivariate study of the ages of first use of tobacco and first consumption of alcohol without parental permission in twins. The proposed model allows estimation of the genetic and environmental effects that are shared by both of these risk behaviours as well as those that are specific.

The Autism Diagnostic Observation Schedule: revised algorithms for improved diagnostic validity.

Autism Diagnostic Observation Schedule (ADOS) Modules 1-3 item and domain total distributions were reviewed for 1,630 assessments of children aged 14 months to 16 years with an autism spectrum disorder (ASD) or with heterogeneous non-spectrum disorders. Children were divided by language level and age to yield more homogeneous cells. Items were chosen that best differentiated between diagnoses and were arranged into domains on the basis of multi-factor item-response analysis. Reflecting recent research, the revised algorithm now consists of two new domains, Social Affect and Restricted, Repetitive Behaviors (RRB), combined to one score to which thresholds are applied, resulting in generally improved predictive value.

The Croydon Assessment of Learning Study: prevalence and educational identification of mild mental retardation.

BACKGROUND: Mild mental retardation is an enduring and impairing condition. Its prevalence has varied widely across different studies from .5 to over 8%, with higher rates in completely ascertained samples. The current study estimates the prevalence of low IQ in the mental retardation range (intellectual disability) in a population sample and examines the factors that relate to educational identification. METHOD: A total of 2,730 children in school years 8 and 9 attending local authority schools were assessed in school with the group-administered Cognitive Abilities Test (CAT). A sample of 304 pupils at high, moderate and low risk of mild mental retardation was selected for in-depth study. This included the individually measured full-scale IQ (WISC-III(UK)), the Wechsler Quicktest of attainments, the Strengths and Difficulties Questionnaire from parents and teachers and an abbreviated version of the Social Communication Questionnaire. RESULTS: Of those selected for the in-depth study, 204 (67%) participated, with a greater proportion from the low risk group. A range of prevalence estimates were calculated using different imputation methods and assumptions about individuals not screened. Rates of pupils with WISC IQ < 70 varied from 5.8% to 10.6%. There were no significant gender differences. In contrast to the high prevalence estimates using the WISC, the proportion of pupils scoring in the lowest stanine on the CAT was as expected. Only 15% of those with IQ < 70 had a statement of special educational needs or attended a school for moderate learning difficulties. Behaviour, particularly social communication problems, predicted educational identification. CONCLUSIONS: The current study produced a high estimate of the prevalence of mild intellectual disability based on the WISC but not on the CAT. The findings highlight that the majority of mild intellectual disability in the UK would not be detected using registers. Cases that are detected by registers are more behaviourally disturbed than others.