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Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multicenter structural magnetic resonance imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male), and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. Increases were observed in different brain regions in males and females, with larger effect sizes in females. BSC correlated with ADOS-2 Calibrated Severity Score in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared with cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multi-center magnetic resonance structural imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male) and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Increases were observed in different brain regions in males and females, with larger effect sizes in females. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. BSC correlated with ADOS-2 CSS in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared to cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.

Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of the relationship between factors influencing clinical heterogeneity and their relationship to brain anatomy. To this end, we performed a large-scale examination of cortical morphometry in ASD, with a specific focus on the impact of three potential sources of heterogeneity: sex, age and full-scale intelligence (FIQ). To examine these potentially subtle relationships, we amassed a large multi-site dataset that was carefully quality controlled (yielding a final sample of 1327 from the initial dataset of 3145 magnetic resonance images; 491 individuals with ASD). Using a meta-analytic technique to account for inter-site differences, we identified greater cortical thickness in individuals with ASD relative to controls, in regions previously implicated in ASD, including the superior temporal gyrus and inferior frontal sulcus. Greater cortical thickness was observed in sex specific regions; further, cortical thickness differences were observed to be greater in younger individuals and in those with lower FIQ, and to be related to overall clinical severity. This work serves as an important step towards parsing factors that influence neuroanatomical heterogeneity in ASD and is a potential step towards establishing individual-specific biomarkers.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the efficacy of intranasal oxytocin in improving social interaction and communication deficit, and other clinical outcomes in autism spectrum disorders (ASD), and to examine its safety.

Background.Mentalizing deficits are a hallmark of the autism spectrum condition (ASC) and a potential endophenotype for atypical social cognition in ASC. Differences in performance and neural activation on the ‘Reading the Mind in the Eyes’ task (the Eyes task) have been identified in individuals with ASC in previous studies.Method.Performance on the Eyes task along with the associated neural activation was examined in adolescents with ASC (n = 50), their unaffected siblings (n = 40) and typically developing controls (n = 40). Based on prior literature that males and females with ASC display different cognitive and associated neural characteristics, analyses were stratified by sex. Three strategies were applied to test for endophenotypes at the level of neural activation: (1) identifying and locating conjunctions of ASC–control and sibling–control differences; (2) examining whether the sibling group is comparable to the ASC or intermediate between the ASC and control groups; and (3) examining spatial overlaps between ASC–control and sibling–control differences across multiple thresholds.Results.Impaired behavioural performance on the Eyes task was observed in males with ASC compared to controls, but only at trend level in females; and no difference in performance was identified between sibling and same-sex control groups in both sexes. Neural activation showed a substantial endophenotype effect in the female groups but this was only modest in the male groups.Conclusions.Behavioural impairment on complex emotion recognition associated with mental state attribution is a phenotypic, rather than an endophenotypic, marker of ASC. However, the neural response during the Eyes task is a potential endophenotypic marker for ASC, particularly in females.

This review summarizes the published work on the prevalence and incidence rates of autism spectrum disorder (ASD) in Chinese populations. The authors searched MEDLINE, Web of Science and the PsycINFO database and identified seven studies that were published in the English language. In mainland China, Li and colleagues reported an autism prevalence rate of 2.38/10,000 but admitted the possibility of underestimation. A higher prevalence of 11/10,000 was reported by Zhang and Ji based on a survey that was conducted in Tianjin, China. In Taiwan, Chien and colleagues reported that the cumulative prevalence of ASD increased from 1.79 to 28.72/10,000 from 1996 to 2005 and the annual incidence rate increased from 0.91 to 4.41/10,000 per year from 1997 to 2005. Another study based on the Taiwan national health insurance database reported a high prevalence rate of 122.8/10,000 for the year 2007. Two studies based on the Taiwan national disability registry data reported an increasing trend of ASD for the period 2000-2007 and 2004-2010, respectively. In Hong Kong, Wong and colleagues estimated that the incidence of ASD was 5.49/10,000 and the average prevalence over the 1986-2005 period was 16.1/10,000. We identified 12 studies through the searching of Chinese databases. The prevalences among these studies varied from 2.8 to 29.5/10,000. While existing data appear to suggest, it remains unclear whether there is a true rise in the prevalence of ASD in ethnic Chinese population across geographic sites. More collaborative research on this topic should be conducted in the future.

Atypical activation during the Embedded Figures Task has been demonstrated in autism, but has not been investigated in siblings or related to measures of clinical severity. We identified atypical activation during the Embedded Figures Task in participants with autism and unaffected siblings compared with control subjects in a number of temporal and frontal brain regions. Autism and sibling groups, however, did not differ in terms of activation during this task. This suggests that the pattern of atypical activation identified may represent a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings. We also found that reduced activation in autism relative to control subjects in regions including associative visual and face processing areas was strongly correlated with the clinical severity of impairments in reciprocal social interaction. Behavioural performance was intact in autism and sibling groups. Results are discussed in terms of atypical information processing styles or of increased activation in temporal and frontal regions in autism and the broader phenotype. By separating the aspects of atypical activation as markers of familial risk for the condition from those that are autism-specific, our findings offer new insight into the factors that might cause the expression of autism in families, affecting some children but not others.

BACKGROUND: Studies of antisocial populations have found that they show deficits in recognition of facial affect. Such deficits are also found in other populations with clinical conditions such as autism spectrum disorders, schizophrenia and obsessive compulsive disorder. AIMS: We aimed to investigate the hypothesis that facial affect recognition in the Scottish prison population would differ from matched controls. In addition, we aimed to investigate any relationship between facial affect recognition deficits and offence history. METHODS: A sample of serving convicted prisoners, drawn from a larger study, was assessed for ability to recognise facial affect. Other variables were also measured and a self-report offending history obtained. RESULTS: 127 prisoners were assessed in 11 prisons. Male prisoners were significantly worse than age, sex and IQ-matched controls at recognising negative facial emotions, specifically anger, fear, sadness and disgust. Within the sample of prisoners, deficits in fear recognition were associated with a history of previous prison sentences but not previous convictions. With respect to offending history, sex offenders were relatively better at recognising sadness and worse at recognising surprise than the other offenders. These relationships remain after controlling for IQ. CONCLUSIONS: Scottish convicted prisoners show deficits in recognising negative facial emotions in a pattern consistent with other antisocial populations. We also demonstrated a relationship between particular patterns of deficit and types of offending history not previously described.

Background Autism is a highly heritable condition, and common variants explain approximately 50% of the genetic variance of autism. Individuals with autism typically have difficulties with social interactions, which may be due to altered social cognition. Variants in the Oxytocin Receptor (OXTR) have been implicated in both autism and social cognition. Functional neuroimaging studies on the brain’s response to social tasks in individuals with autism have yielded mixed findings. This may not be surprising as autism is a heterogeneous neurodevelopmental condition, with varied genetic and biological aetiologies. In the current study we combine genetics and functional neuroimaging to investigate the biological basis of differences in social cognition in autism. Methods Participants were adolescents (12-18 years old): 41 (11 females) were diagnosed with high-functioning autism or Asperger syndrome (autism group) and 33 (17 females) were typically developing (control group). Participants provided buccal DNA samples and these were genotyped for 7 Single Nucleotide Polymorphisms (SNPs) in the OXTR; of these, 2 had little variance in the sample and were excluded from further analysis. The remaining 5 SNPs were rs2254298, rs53576, rs2268491, rs2228485, and rs7632287. The participants were scanned using a Siemens 3-T TimTrio scanner (Siemens Healthcare, Germany) while completing the adolescent version of the ‘Reading the Mind in the Eyes’ Test. We conducted a whole brain analysis (controlling for sex and age) and examined the effect of genotype, diagnosis and the interaction between genotype and diagnosis on brain activation during the Eyes test. Analyses were conducted for each SNP separately. Results Examining brain activation when making a mental state decision, versus deciding the sex of the portrayed character (baseline condition), we found 3 SNPs with significant effects. For rs2254298 and rs53576 a region overlapping with the Inferior Parietal Lobule (IPL) showed hyperactivation during the mental state condition depending on genotype (F(1,60)=11.97, p value(FWE-corr)=0.010 and F(1,60)=11.97, p value(FWE-corr)=0.006, respectively) and on the interaction between genotype and diagnosis (F(1,60)=11.97, p value (FWE-corr)=0.009 and F(1,60)=11.97, p value (FWE-corr)=0.034, respectively). Increased activation in a region overlapping with the IPL was also found for rs2268491, but this was associated with the interaction only (F(1,60)=11.93, p value (FWE-corr)=0.009). For 2 (rs2228485, rs7632287) of the 5 SNPs, no cluster survived the family-wise correction (FWE) set at 0.05. Discussion The current study provides preliminary evidence that brain activation in response to a social task may be associated with both diagnostic status and common variation in the OXTR. Importantly, the IPL has been previously implicated in the affect sharing system. An imaging genetics approach might lend itself to increasingly accurate understanding of the heterogeneous autism phenotype.

Summary Background Many UK hospitals have set-up specialised chest pain clinics to deal promptly and efficiently with cases of possible cardiac chest pain. It is possible that a proportion of patients attending these clinics will have a respiratory cause for their chest pain, or respiratory disease in addition to their cardiac pain. This study aimed to determine the prevalence of airflow obstruction, ischaemic heart disease and dual pathology in such patients. Methods Spirometry was performed on patients referred to a rapid access chest pain clinic over a 12-month period (target population of 400 patients). The main outcome measure was the prevalence of airflow obstruction (defined using spirometry), ischaemic heart disease and dual pathology. Results 405 subjects participated in the study. Abnormal spirometry was detected in 21% of patients (n = 85). Airflow obstruction was the predominant lung function abnormality and was detected in 60 patients. Ischaemic heart disease was diagnosed in 21% of patients (n = 85). Dual pathology was found in 4% of patients (n = 17). Conclusions Previous studies have reported a link between impaired lung function and future cardiovascular morbidity and mortality. This study suggests that airflow obstruction is an important alternative differential diagnosis in patients referred to a rapid access chest pain clinic. The identification of abnormal spirometry may help to better risk-stratify patients for future cardiovascular events and allow interventions to be instituted.

ResumenAntecedentes.En pacientes con autismo se han descrito anomalías estructurales cerebrales, pero los estudios realizados son de pequeño tamaño y contradictorios. Quisimos identificar qué regiones cerebrales de los pacientes con autismo pueden considerarse diferentes de las de los controles sanos.Métodos.Se realizó una búsqueda sistemática de estudios de resonancia magnética del tamaño de diversas regiones cerebrales. Se recogieron datos y se combinaron por medio de un metaanálisis de efectos aleatorios. Se investigaron los efectos sobre la variabilidad de la edad y del CI por medio de meta-regresión.Resultados.El cerebro completo, los hemisferios cerebrales, el cerebelo y el núcleo caudado tenían mayor volumen, pero el área del cuerpo calloso estaba reducida. La edad y el CI modificaron los lóbulos del vérmix cerebeloso VI-VII, y la edad, la amígdala.Conclusiones.El autismo podría deberse a anomalías de regiones específicas del cerebro y a una falta de integración global debida al aumento de tamaño del cerebro. Los resultados contradictorios en la literatura se deben en parte a la edad y al CI de las poblaciones del estudio. Algunas regiones muestran alteraciones de las trayectorias de crecimiento.

Summary Aim To assess and compare health status among chronic obstructive pulmonary disease (COPD) patients presenting for treatment in six countries and in two healthcare settings using a generic health status instrument. Methods A population based cross-sectional survey was conducted among 2703 patients and their physicians (1381 in primary and 1322 in specialty care) in five EU countries and the USA. Information was collected on demographic and clinical characteristics, exacerbations and health status estimated using EQ-5D. Results The mean EQ-5D score for COPD patients was similar between primary and specialty settings in all countries except Italy. Approximately, half of the patients indicated some impairment in health status on mobility, usual activities, pain/discomfort and anxiety/depression domains of EQ-5D. Approximately, 5% of patients in EU countries except UK had health status valued as worse than death based on valuations of the general population. Patients suffering from severe breathlessness, experiencing ⩾3 exacerbations in the previous year, categorised as severe according to GOLD criteria, and experiencing day-time and night-time symptoms had significantly impaired health status. Conclusion COPD patients classified as moderate/severe in clinical practice have worse health status compared to mild patients. This impairment is similar in primary and specialty setting across western countries.

To explore the cost-effectiveness of fluticasone propionate (FP) for the treatment of chronic obstructive pulmonary disease (COPD), we estimated costs and quality-adjusted life-years (QALYs) over 3 years, based on an economic appraisal of a previously reported clinical trial (Inhaled Steroids in Obstructive Lung Disease in Europe [ISOLDE]).Seven hundred forty-two patients enrolled in the ISOLDE trial who received either FP or placebo had data available on health-care costs and quality of life over the period of the study. The SF-36-based utility scores for quality of life were used to calculate QALYs. A combined imputation and bootstrapping procedure was employed to handle missing data and to estimate statistical uncertainty in the estimated cumulative costs and QALYs over the study period. The imputation approach was based on propensity scoring and nesting this approach within the bootstrap ensured that multiple imputations were performed such that statistical estimates included imputation uncertainty.Complete data were available on mortality within the follow-up period of the study and a nonsignificant trend toward improved survival of 0.06 (95% confidence interval [CI]-0.01 to 0.15) life-years was observed. In an analysis based on a propensity scoring approach to missing data we estimated the incremental costs of FP versus placebo to be 1021 sterling pound(95% CI 619-1338 sterling pound) with an additional effect of 0.11 QALYs (CI 0.04-0.20). Cost-effectiveness estimates for the within-trial period of 17,700 sterling pound per life-year gained (6900 sterling pound to infinity) and 9500 sterling pound per QALY gained (CI 4300-26,500 sterling pound) were generated that include uncertainty due to the imputation process. An alternative imputation approach did not materially affect these estimates.Previous analyses of the ISOLDE study showed significant improvement on disease-specific health status measures and a trend toward a survival advantage for treatment with FP. This analysis shows that joint considerations of quality of life and survival result in a substantial increase in QALYs favoring treatment with FP. Based on these data, the inhaled corticosteroid FP appears cost-effective for the treatment of COPD. Confirmation or refutation of this result may be achieved once the Towards a Revolution in COPD Health (TORCH) study reports, a large randomized controlled trial powered to detect mortality changes associated with the use of FP alone, or in combination with salmeterol, which is also collecting resource use and utility data suitable for estimating cost-effectiveness.

SummaryThe economic consequences of chronic obstructive pulmonary disease (COPD) are considerable, although the factors that best predict costs are largely unknown. This study used a population-based cohort to identify the clinical factors during an index year that were most predictive of increased direct medical costs in the subsequent year, and to develop a predictive model that described the cost variations in COPD.The medical records of 2116 patients enrolled in one regional health system who had COPD and healthcare resource utilisation data for 1998 and 1999, were abstracted for information about symptoms, smoking history, chronic illnesses, and pulmonary function data. All inpatient, outpatient and pharmacy utilisation data for each subject for 1999 were extracted from the database. Total costs for each individual were transformed to a log scale. Potential causes of cost variability (predictor variables) were defined and classified into sets (or domains). Multiple linear regression models were fitted for each domain.The study demonstrated that severity of airflow obstruction, as assessed by FEV1% predicted, is a significant but weak predictor of future healthcare resource utilisation—prior hospitalisation and home oxygen use, the presence of comorbid conditions and symptoms of dyspnoea are better predictors of costs. Those interested in the economic benefits of new COPD treatments and disease management programs need to carefully account for these factors.

The existence of an endophenotype of autism spectrum condition (ASC) has been recently suggested by several commentators. It can be estimated by finding differences between controls and people with ASC that are also present when comparing controls and the unaffected siblings of ASC individuals. In this work, we used a multivariate methodology applied on magnetic resonance images to look for such differences. The proposed procedure consists of combining a searchlight approach and a support vector machine classifier to identify the differences between three groups of participants in pairwise comparisons: controls, people with ASC and their unaffected siblings. Then we compared those differences selecting spatially collocated as candidate endophenotypes of ASC., This work was partly supported by the University of Granada under the Genil PYR2012-10 project (CEI BioTIC GENIL CEB09-0010) and the University of Liège. The study was also funded by a Clinical Scientist Fellowship from the UK Medical Research Council (MRC (G0701919)) to Michael Spencer and by the UK National Institute for Health Research Cambridge Biomedical Research Centre.

Background Reduced activity during cognitively demanding tasks has been reported in the default mode network in typically developing controls and individuals with autism. However, no study has investigated the default mode network (DMN) in first-degree relatives of those with autism (such as siblings) and it is not known whether atypical activation of the DMN is specific to autism or whether it is also present in unaffected relatives. Here we use functional magnetic resonance imaging to investigate the pattern of task-related deactivation during completion of a visual search task, the Embedded Figures Task, in teenagers with autism, their unaffected siblings and typically developing controls. Findings We identified striking reductions in deactivation during the Embedded Figures Task in unaffected siblings compared to controls in brain regions corresponding to the default mode network. Adolescents with autism and their unaffected siblings similarly failed to deactivate regions, including posterior cingulate and bilateral inferior parietal cortex. Conclusions This suggests that a failure to deactivate these regions is a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings.

Rightward cerebral lateralization has been suggested to be involved in the neuropathology of autism spectrum conditions. We investigated functional and neuroanatomical asymmetry, in terms of handedness and corpus callosum measurements in male adolescents with autism, their unaffected siblings and controls, and their associations with executive dysfunction and symptom severity. Adolescents with autism did not differ from controls in functional asymmetry, but neuroanatomically showed the expected pattern of stronger rightward lateralization in the posterior and anterior midbody based on their hand-preference. Measures of symptom severity were related to rightward asymmetry in three subregions (splenium, posterior midbody and rostral body). We found the opposite pattern for the isthmus and rostrum with better cognitive and less severe clinical scores associated with rightward lateralization.

The TOwards a Revolution in COPD Health (TORCH) study was a 3-yr multicentre trial of 6,112 patients randomised to salmeterol (Salm), fluticasone propionate (FP), a Salm/FP combination (SFC) or placebo (P). Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed. For four regions, 3-yr all-cause hospitalisation, medication and outpatient care costs were calculated. The sample was restricted to the 21 countries (n = 4,237) in which European quality of life five-dimension (EQ-5D) data were collected in order to estimate the number of quality-adjusted life years (QALYs). Regression models were fitted to survival, study medication cost, other medication cost and EQ-5D data in order to estimate total cost, number of QALYs and cost per QALY, adjusted for missing data and region. SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars (USD) compared with P (95% confidence interval 21,400–123,500 USD). Estimates for Salm versus P (197,000 USD) and FP versus P (78,000 USD) were less favourable. The US estimates were greater than those from other regions; for SFC versus P, the cost per QALY was 77,100 (46,200–241,700) USD compared to 24,200 (15,200–56,100) USD in Western Europe. Compared with P, SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone, and is, therefore, preferred to these monotherapies on the grounds of cost-effectiveness.

Adolescents with mild intellectual impairment are known to have an increased risk of schizophrenia compared to the general population. However, little is known regarding the association between potential risk markers for later schizophrenia within this population. We therefore set out to examine the association between schizotypal traits and progressive grey matter loss in adolescents with mild intellectual impairment. Ninety-eight adolescents receiving educational assistance were divided into two groups based on their degree of schizotypal features, measured using the Structured Interview for Schizotypy (SIS). Each participant received two structural magnetic resonance imaging scans approximately 16 months apart. Changes over time in the voxel-wise presentation of tissue were evaluated using tensor based morphometry. Those with marked schizotypal features exhibited significantly greater grey matter losses in the left medial temporal lobe than those without. Three focal locations were identified, two within the left amygdala and one in the left parahippocampal gyrus. Thus, adolescents with cognitive impairment and schizotypal features show changes in brain structure over time, changes that are consistent with those identified in other high risk populations. Medial temporal grey matter loss may therefore represent a common neuroanatomical substrate of risk for schizophrenia, common to familial, prodromal and cognitive high risk groups.

BackgroundThere is evidence to suggest that among young people with mild intellectual disability there are those whose cognitive difficulties may predict the subsequent manifestation of a schizophrenic phenotype. It is suggested that they may be detectable by simple means.AimsTo gain adequate cooperation from educational services, parents and students so as to recruit a sufficiently large sample to test the above hypothesis, and to examine the hypothesis in the light of the findings.MethodThe sample was screened with appropriate instruments, and groups hypothesised as being likely or not likely to have the phenotype were compared in terms of psychopathology and neuropsychology.ResultsSimple screening methods detect a sample whose psychopathological and neuropsychological profile is consistent with an extended phenotype of schizophrenia.ConclusionsDifficulties experienced by some young people with mild and borderline intellectual disability are associated with enhanced liability to schizophrenia. Clinical methods can both identify those with this extended phenotype and predict those in whom psychosis will occur.

Cognitive performance and the relationship between theory of mind (TOM), weak central coherence and executive function were investigated in a cohort of young people with additional learning needs. Participants were categorized by social communication questionnaire score into groups of 10 individuals within the autistic spectrum disorder (ASD) range, 14 within the pervasive developmental disorder range and 18 with few autistic traits. The ASD group were significantly poorer than the other groups on a test of cognitive flexibility. In the ASD group only, there was a strong relationship between executive performance and TOM which remained after controlling for IQ. Our findings suggest that the relationship between cognitive traits may more reliably distinguish autism than the presence of individual deficits alone.

White matter development during adolescents is crucial for a mature integration of neural networks in the brain. Autism spectrum condition (ASC), characterized by social and communication difficulties and rigid behaviour may interact with white matter development observed during adolescence. Changes in white matter development may link autistic symptoms to its genetic underpinnings and explain a 10-fold increase in susceptibility to ASC among siblings of individuals with ASC. We used diffusion tensor imaging to study an association between age and white matter integrity measures, fractional anisotropy (FA) and mean diffusivity (MD), in adolescents with ASC, their siblings and age-matched healthy controls. Diffusion-weighted data were acquired with 64-direction protocol with 3mm slices and TR of 6600ms and tract-based spatial statistics analysis was performed. The control subjects showed robust signs of increase in white matter integrity correlated with age. In contrast, individuals with ASC showed significantly lower negative correlation between MD and age in a broad area centred in the right superior longitudinal fasciculus (rSLF). When the three eigenvalues constituting a tensor ellipsoid were considered separately, siblings of individuals with ASC showed a diminished negative correlation between the second eigenvalue and age also centred in the rSLF. Adolescents with ASC and their siblings experience alterations in white matter development in comparison to age-matched healthy controls, which are similar in direction yet different in scale for the two affected groups. The alterations are observed in the area associated with flexibility of behaviour and may explain both symptoms of ASC and increased susceptibility to ASC.

BackgroundStructural brain abnormalities have been described in autism but studies are often small and contradictory. We aimed to identify which brain regions can reliably be regarded as different in autism compared to healthy controls.MethodA systematic search was conducted for magnetic resonance imaging studies of regional brain size in autism. Data were extracted and combined using random effects meta-analysis. The modifying effects of age and IQ were investigated using meta-regression.ResultsThe total brain, cerebral hemispheres, cerebellum and caudate nucleus were increased in volume, whereas the corpus callosum area was reduced. There was evidence for a modifying effect of age and IQ on the cerebellar vermal lobules VI–VII and for age on the amygdala.ConclusionsAutism may result from abnormalities in specific brain regions and a global lack of integration due to brain enlargement. Inconsistencies in the literature partly relate to differences in the age and IQ of study populations. Some regions may show abnormal growth trajectories.

Intellectual disability, a common but under-researched condition, is strongly associated with autism spectrum disorders (ASD). Although studies have investigated the neural correlates of intelligence quotient (IQ) and ASD in intellectually unimpaired subjects, these issues have not been addressed in intellectually impaired subjects. We studied 63 intellectually disabled adolescents receiving additional learning support and 72 controls using whole brain tissue volumes extracted from native space and voxel-based morphometry (VBM) in normalised space. We applied a qualitative and quantitative review of VBM preprocessing and modified the optimised method to establish optimum co-registration of the brains in normalised space. We report tissue density differences at cluster level with adjustment for underlying smoothness. Individuals with intellectual disability had smaller total white matter and total brain tissue volumes than controls, as well as reduced grey matter density in the right cerebellar hemisphere and left temporo-parietal cortex, and reduced white matter density in the posterior corpus callosum. Intellectually disabled subjects were additionally subgrouped according to their degree of reported autistic features. Reduced grey matter density was detected in the thalamus of subjects with autistic features scoring within the pervasive developmental disorder range as compared to subjects below the threshold for ASD, and increased white matter density was detected in the left superior temporal gyrus of subjects scoring above the threshold for autism as compared to subjects below the threshold for ASD.

To develop a Markov model that allows the cost effectiveness of interventions in patients with chronic obstructive pulmonary disease (COPD) to be estimated, and to apply the model to investigate the cost effectiveness of an inhaled corticosteroid/long-acting beta(2)-adrenoceptor agonist (beta(2)-agonist) combination (salmeterol/fluticasone propionate) versus usual care.A Markov model consisting of four mutually exclusive disease states was constructed (mild, moderate and severe disease, and death). The transition probabilities of disease progression (for smokers and ex-smokers) and death were derived from the published medical literature. The model outputs were costs, exacerbations, survival, QALYs and cost effectiveness. The model was made fully probabilistic to reflect the joint uncertainty in the model parameters. Efficacy data for the combination of inhaled salmeterol/fluticasone propionate 50/500microg twice daily in poorly reversible COPD patients with a history of exacerbations were obtained from the 1-year TRISTAN (TRial of Inhaled STeroids ANd long-acting beta-agonists) study and applied to the model, based on patient profiles representative of COPD clinical trials.According to the model, the mean life expectancy with usual care alone (placebo group) was 8.95 years, which decreased to 4.08 QALYs once adjusted for quality and discounted, at a lifetime discounted cost of Can 16,415 dollars per patient (year 2002 values). Assuming that salmeterol/fluticasone propionate reduced exacerbation frequency only (base case analysis), the estimated mean survival time remained unchanged but there was an increase in the number of QALYs (4.21) for an estimated lifetime cost of Can 25,780 dollars, resulting in a cost-effectiveness ratio of Can 74,887 dollars per QALY (95% CI 21,985, 128,671) versus usual care. If a survival benefit was assumed for salmeterol/fluticasone propionate, the incremental cost per QALY was Can11,125 dollars (95% CI 8710, dominated) versus usual care. If the combination achieved around a 10% improvement in forced expiratory volume in 1 second, leading to delayed progression to more severe disease states, the benefits translated into an incremental cost per QALY of Can 49,928 dollars (95% CI 37 269, 66,006) versus usual care.This Markov model allows, for the first time, a means of estimating the long-term cost effectiveness and cost utility of interventions for COPD. Initial evidence suggests that for patients with poorly reversible COPD and a documented history of frequent COPD exacerbations, the addition of salmeterol (a long-acting beta(2)-agonist) to fluticasone propionate (an inhaled corticosteroid) is potentially cost effective from the Canadian healthcare payer's perspective. However, the precision of this estimate will be improved when additional data are available from clinical trials such as the ongoing TORCH (TOwards a Revolution in COPD Health) study.

Objective: To describe the early psychiatric and neurological features of variant Creutzfeldt-Jakob disease. Design: Cohort study. Setting: National surveillance system for Creutzfeldt-Jakob disease in the United Kingdom. Participants: The first 100 cases of variant Creutzfeldt-Jakob disease identified in the United Kingdom. Main outcome measures: The timing and nature of early psychiatric and neurological symptoms in variant Creutzfeldt-Jakob disease. Results: The early stages of variant Creutzfeldt-Jakob disease are dominated by psychiatric symptoms, but neurological symptoms precede psychiatric symptoms in 15% of cases and are present in combination with psychiatric symptoms in 22% of cases from the onset of disease. Common early psychiatric features include dysphoria, withdrawal, anxiety, insomnia, and loss of interest. No common early neurological features exist, but a significant proportion of patients do exhibit neurological symptoms within 4 months of clinical onset, including poor memory, pain, sensory symptoms, unsteadiness of gait, and dysarthria. Conclusions: Although the diagnosis of variant Creutzfeldt-Jakob disease may be impossible in the early stages of the illness, particular combinations of psychiatric and neurological features may allow early diagnosis in an appreciable proportion of patients.

Summary Background Prion diseases are associated with the accumulation of an abnormal isoformof cellular prion protein (PrP Sc ), which is the principal constituent of prions. Prions replicate in lymphoreticular tissues before neuroinvasion, suggesting that lymphoreticular biopsy samples may allow early diagnosis by detection of PrP Sc . Variant Creutzfeldt-Jakob disease (variant CJD) is difficult to distinguish from common psychiatric disorders in its early stages and definitive diagnosis has relied on neuropathology. We studied lymphoreticular tissues from a necropsy series and assessed tonsillar biopsy samples as a diagnostic investigation for human prion disease. Methods Lymphoreticular tissues (68 tonsils, 64 spleens, and 40 lymph nodes) were obtained at necropsy from patients affected by prion disease and from neurological and normal controls. Tonsil biopsy sampling was done on 20 patients with suspected prion disease. Tissues were analysed by western blot to detect and type PrP Sc , by PrP immunohistochemistry, or both. Findings All lymphoreticular tissues obtained at necropsy from patients with neuropathologically confirmed variant CJD, but not from patients with other prion diseases or controls, were positive for PrP Sc . In addition, PrP Sc typing revealed a consistent pattern (designated type 4t) different from that seen in variant CJD brain (type 4) or in brain from other CJD subtypes (types 1–3). Tonsil biopsy tissue was positive in all eight patients with an adequate biopsy sample and whose subsequent course has confirmed, or is highly consistent with, a diagnosis of variant CJD and negative in all patients subsequently confirmed to have other diagnoses. Interpretation We found that if, in the appropriate clinical context, a tonsil biopsy sample was positive for PrPSc, variant CJD could be diagnosed, which obviates the need for a brain biopsy sample to be taken. Our results also show that variant CJD has a different pathogenesis to sporadic CJD.

A 16 year old boy with epilepsy and learning difficulties is reported. At 3 years of age he was diagnosed with common acute lymphoblastic leukaemia, and received therapy according to the UK protocol, UKALL VIII. This included prophylactic CNS radiotherapy and chemotherapy. He did not develop CNS leukaemia, and complete remission was achieved. At age 7, he began to experience lethargy and learning difficulties, especially problems with hand-writing, concentration and memory. Furthermore, he began experiencing atypical absence seizures, which were provoked by concentration at times of tiredness. EEG showed bilateral non-specific abnormalities, with some epileptiform features. Over the following 9 years, several anti-epileptic drugs were prescribed. Although with the changes in therapy initial remissions have been achieved, the seizures have, each time, continued to relapse. At age 12, EEG was very abnormal, showing frequent generalized slow or sharp waves. At age 13, MRI revealed multiple discrete small high-intensity lesions in the subcortical white matter of both hemispheres. Problems with lethargy, concentration and memory persist and although multiple anti-epileptic drugs have been prescribed, seizures continue to occur almost daily.

Abstract 3027 Introduction: Bortezomib (Velcade®) is effective and well tolerated in patients with relapsed/refractory multiple myeloma (MM). Although it is often administered in combination with dexamethasone (VelDex) in the relapsed setting, there are little data on VelDex in this patient population. The international, non-interventional, Electronic Velcade Observational Study (eVOBS) is an ongoing observational study to assess the clinical and health economic outcomes in MM patients treated with bortezomib in the clinical-practice setting. Here, we compared response and long-term outcomes in relapsed/refractory MM patients who received bortezomib monotherapy or VelDex throughout the treatment period. Methods: Adult patients scheduled to receive bortezomib for relapsed/refractory MM were eligible for inclusion in eVOBS; patients from Belgium, France, Greece, Spain, Sweden, Turkey, and Brazil were included in this analysis. All bortezomib doses and concomitant treatments (except investigational therapies) were permitted; dose adjustments and cycle delays were documented. Patients are being followed for up to 3 years from their last cycle of bortezomib to document long-term outcomes. Due to the non-interventional nature of the study, no predefined response criteria were mandated; response criteria were investigator-defined and were based on European Group for Blood and Marrow Transplantation (EBMT), Southwest Oncology Group (SWOG), or M-protein criteria. Patients who received bortezomib monotherapy or VelDex throughout the treatment period were included in this analysis. Endpoints included response, progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Outcomes were analyzed using Kaplan-Meier methodology; unadjusted analyses and adjusted analyses, accounting for differences in baseline characteristics, were performed. Adjusted analyses were performed using propensity score-based inverse probability weighting (IPW), matched cohorts and multivariate proportional hazards regression. IPW results are shown; similar results were obtained for all three adjusted analyses. Results: A total of 432 patients were included; 106 received bortezomib monotherapy and 326 received VelDex throughout the treatment period. Baseline characteristics were similar between the two groups, with some differences in age, time since diagnosis, and gender: monotherapy patients tended to be older (mean 67.1 vs 62.9 years, p=0.0003) and have a longer disease history (mean 3.1 vs 2.5 years since diagnosis, p=0.049), and the VelDex arm included more male patients (61.7% vs 50.9%, p=0.051). The overall response rate (ORR; at least partial response [PR]; best response) was 72.7% in the VelDex group and 68.4% in the monotherapy group. The complete response (CR) rate was 24.1% and 8.2% in the two groups, respectively. Median follow-up was 11.5 and 8.6 months for the VelDex and monotherapy groups, respectively. As shown by Kaplan-Meier analysis of time to CR, the median time to CR was approximately 3.2 months and approximately 3.6 months for the VelDex and monotherapy groups (unadjusted: HR=3.51, p=0.0071; IPW adjusted: HR=2.42, p=0.0272); at 3 months, approximately 8% and 3% of patients in the VelDex and monotherapy groups had achieved CR, respectively. There was a trend to prolonged PFS with VelDex but the differences were not significant (unadjusted: median PFS was approximately 345 vs 330 days, HR=0.80, p=0.2195; IPW adjusted: median PFS was approximately 345 vs 270 days, HR=0.73; p=0.0758) (Figure). A similar trend was seen in TTP (unadjusted: HR=0.82, p=0.3261; IPW adjusted: HR=0.82; p=0.3393). There was no apparent difference in OS between the two groups (unadjusted: HR=1.15, p=0.5342; IPW adjusted: HR=0.93; p=0.7127) (Figure). Conclusions: The addition of dexamethasone to bortezomib monotherapy appears to increase the CR rate in relapsed/refractory MM patients. Consistent with the higher CR rate, addition of dexamethasone was associated with trends to improved PFS and TTP, but the differences were not significant in both unadjusted and adjusted analyses. Although more data from a larger patient population may be needed to confirm these results, the addition of dexamethasone to bortezomib did not appear to increase OS in these relapsed/refractory patients. Disclosures: Dimopoulos: Millennium: Consultancy; Ortho-Biotech: Consultancy, Honoraria. De Samblanx:Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Hulin:Janssen-Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. De La Rubia:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ganguly:Johnson & Johnson: Employment, Equity Ownership. Diels:Johnson & Johnson: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Dhawan:Johnson & Johnson: Employment, Equity Ownership. Spencer:Janssen-Cilag: Employment. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho-Biotech: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria.

Background Chronic obstructive pulmonary disease (COPD) is a debilitating and progressive disease. The severity of the condition has typically been characterized by a single physiological measurement: forced expiratory volume in 1 second, which has been shown to be prognostic for mortality. Methods To develop a prognostic tool for COPD that is sensitive not only to mortality but also to other important drivers of health status and cost, data were obtained from a pooled analysis of 12 randomized controlled trials and 3 main outcomes were chosen: mortality, hospitalization, and number of exacerbations. Cox models were employed for the time-to-event data (death or hospitalization), and a negative binomial model was used for calculating the count data (exacerbations). From these models, 3 specific indexes were developed on a 100-point scale, and 1 composite index was obtained as a mean of the specific indexes. One-third of the data was reserved for validation purposes. Results All indexes provided good discrimination among tertiles in the training and validation samples. The composite index had a performance very similar to that of the specific index in both the training and validation samples: the overall C statistic was estimated as 0.71 for both mortality and hospitalization. Each 10-point change in the composite index corresponds to an increase of 54% in the hazard ratio of death, 57% in the hazard ratio of hospitalization, and 21% in the incidence rate of exacerbations. Conclusions A composite index for COPD prognosis (the COPD Prognostic Index) has been validated in data not used in its development and is capable of predicting not only mortality, but also hospitalizations and exacerbations. All factors included in the index are straightforward to obtain, which should make the index suitable for use in primary as well as secondary care settings.

Background Although neuroanatomical and cognitive sequelae of low birthweight and preterm birth have been investigated, little is understood as to the likely prevalence of a history of low birthweight or preterm birth, or neuroanatomical correlates of such a history, within the special educational needs population. Our aim was to address these issues in a sample of young people receiving additional learning support. Methods One hundred and thirty-seven participants aged 13–22 years, receiving additional learning support, were recruited via their schools or colleges and underwent structural magnetic resonance imaging (MRI). Obstetric records, available in 98 cases, included birthweight and gestational data in 90 and 95 cases, respectively. Both qualitative and quantitative voxel-based analyses of MRI data were conducted. Results A history of low birthweight and preterm birth was present in 13.3% and 13.7% of cases, respectively. Low birthweight and preterm birth were associated with specific qualitative anomalies, including enlargement of subarachnoid cisterns and thinning of the corpus callosum. Low birthweight was associated with reduced grey matter density (GMD) in the superior temporal gyrus (STG) bilaterally, left inferior temporal gyrus and left insula. Prematurity of birth was associated with reduced GMD in the STG bilaterally, right inferior frontal gyrus and left cerebellar hemisphere. Comparison of subjects with no history of low birthweight or preterm birth with a previously defined control sample of cognitively unimpaired adolescents (n = 72) demonstrated significantly greater scores for several anomalies, including thinning of the corpus callosum, loss of white matter and abnormalities of shape of the lateral ventricles. Conclusion Although a two-fold increased prevalence of a history of low birthweight and preterm birth exists within the special educational needs population, other aetiological factors must be considered for the overwhelming majority of cases. Neuroanatomical findings within this sample include qualitative anomalies of brain structure and grey matter deficits within temporal lobe structures and the cerebellum that persist into adolescence. These findings suggest a neurodevelopmental mechanism for the cognitive difficulties associated with these obstetric risk factors.

Summary Objectives In light of recent results from observational studies showing prolonged survival in subjects taking long-acting β 2 -agonists (LABA) and/or inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD), we investigated their cost-effectiveness (CE). Methods Costs and survival data were collected for a sample of members enrolled in a large Health Maintenance Organization in the United States. An observational study design was used to evaluate cumulative costs and health benefits of LABA, ICS, ICS+LABA, or comparison drugs. Survival was estimated using a parametric regression model. Costs were adjusted for censoring and prognostic factors. CE was evaluated over a time horizon of 36 months and the remaining lifetime of subjects. Results Over 36 months, life expectancy and costs were: 2.4 years (95% confidence interval (CI): 2.3; 2.5) and $28,030 (CI: $23,400; $33,570) for not receiving ICS or LABA; 2.6 years (CI: 2.6; 2.7) and $35,170 (CI: $29,970; $40,620) for ICS alone; 2.6 years (CI: 2.5; 2.7) and $27,380 (CI: $21,780; $32,510) for LABA alone; and, 2.7 years (CI: 2.6; 2.8) and $33,780 (CI: $28,700; $39,440) for subjects treated with ICS+LABA. The lifetime analysis showed similar trends. Conclusions There is an acute need to find effective, life-extending treatments for persons with COPD. ICS, LABA or their combination represent promising treatment options and are currently being tested in randomized trials. If the impact on survival seen in these trials compares to that seen in observational studies, LABA and the combination treatment are likely to be cost-effective in the United States.

Background Little is known about factors that determine health status decline in clinical trials of COPD. Objectives To examine health status changes over 3 years in the TORCH study of salmeterol+fluticasone propionate (SFC) vs. salmeterol alone, fluticasone propionate alone or placebo. Methods St George's Respiratory Questionnaire (SGRQ) was administered at baseline then every 6 months. Measurements and Main Results Data from 4951 patients in 28 countries were available. SFC produced significant improvements over placebo in all three SGRQ domains during the study: (Symptoms -3.6 [95% CI -4.8, -2.4], Activity -2.8 [95% CI -3.9, -1.6], Impacts -3.2 [95% CI -4.3, -2.1]) but the pattern of change over time differed between domains. SGRQ deteriorated faster in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III & IV relative to GOLD stage II (p < 0.001). There was no difference in the relationship between deterioration in SGRQ Total score and forced expiratory volume in one second (FEV1) decline (as % predicted) in men and women. Significantly faster deterioration in Total score relative to FEV1 % predicted was seen in older patients (≥ 65 years) and there was an age-related change in Total score that was independent of change in FEV1. The relationship between deterioration in FEV1 and SGRQ did not differ in different world regions, but patients in Asia-Pacific showed a large improvement in score that was unrelated to FEV1 change. Conclusions In addition to treatment effects, health status changes in clinical trials may be influenced by demographic and disease-related factors. Deterioration in health status appears to be fastest in older persons and those with severe airflow limitation. Trial Registration ClinicalTrials.gov: NCT00268216