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Introduction Early detection of cognitive decline in older adults is a public health priority. Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA), a multisite study, is validating cognition, emotion, motor, and sensory modules of the National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in the aging spectrum from cognitively normal to dementia of the Alzheimer's type (DAT). Methods Participants 65 to 85 years old, in demographic groups racially proportional to the general US population, are recruited in one of three groups to validate the NIHTB: cognitively normal, amnestic mild cognitive impairment (aMCI), or mild DAT. Additional special emphasis cohorts include (1) Blacks in the three clinical groups; (2) Spanish-speakers in the three clinical groups; (3) cognitively normal, population-proportional, over age 85. Discussion Longitudinal study will determine whether NIHTB can predict cognitive decline and is associated with Alzheimer's disease biomarkers. Here, we detail the methods for the ARMADA study.

Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and quantitative assessments were used to evaluate for anxiety in 50 subjects with AS. In-person evaluations assessed behaviors concerning for anxiety and circumstances wherein they occurred. Caregivers completed anxiety and other behavioral rating scales. Caregiver responses were categorized and compared to items from anxiety rating scales. The most common behavioral manifestation of anxiety was "aggression." The most common circumstance was "separation from caregiver/parent." Subjects had elevated scores on anxiety, irritability and hyperactivity scales with lower mean scores among subjects with a maternal deletion. The Pediatric Anxiety Rating Scale best captured behaviors described by caregivers. Existing anxiety scales should be adapted for use in AS.

Introduction Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. Methods A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering CTE criteria. Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records. An expert panel adjudicated TES diagnoses. Results A total of 309 donors were diagnosed with TES; 244 donors had CTE pathology. TES criteria demonstrated sensitivity and specificity of 0.97 and 0.21, respectively. Cognitive (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 1.2–5.1), but not mood/behavior or motor symptoms, were significantly associated with CTE pathology. Having Alzheimer's disease (AD) pathology was significantly associated with reduced TES accuracy (OR = 0.27; 95% CI: 0.12–0.59). Discussion TES criteria provided good evidence to rule out, but limited evidence to rule in, CTE pathology. Requiring cognitive symptoms in revised criteria and using AD biomarkers may improve CTE pathology prediction.

Background Craniosynostosis is one of the most common craniofacial malformations demanding surgical treatment in infancy. Data on overall psychiatric morbidity among children with nonsyndromic craniosynostosis remain limited. This study investigated the risk of psychiatric disorders in nonsyndromic craniosynostosis. Methods The authors reviewed a register-based cohort of all individuals born with nonsyndromic craniosynostosis in Sweden between 1973 to 1986 and 1997 to 2012 (n = 1238). The nonsyndromic craniosynostosis cohort was compared with a matched community cohort (n = 12,380) and with unaffected full siblings (n = 1485). The authors investigated the risk of psychiatric disorders, suicide attempts, and suicides by using Cox regression adjusted for perinatal and somatic factors, season and birth year, sex, parental socioeconomic factors, and parental psychiatric disorders. Results Children with nonsyndromic craniosynostosis had a higher risk of any psychiatric disorder (adjusted Cox-derived hazard ratio, 1.70; 95 percent CI, 1.43 to 2.02), including intellectual disability (adjusted Cox-derived hazard ratio, 4.96; 95 percent CI, 3.20 to 7.70), language disorders (adjusted Cox-derived hazard ratio, 2.36; 95 percent CI, 1.57 to 3.54), neurodevelopmental disorders (adjusted Cox-derived hazard ratio, 1.30; 95 percent CI, 1.01 to 1.69), and other psychiatric disorders (adjusted Cox-derived hazard ratio, 1.43; 95 percent CI, 1.11 to 1.85). Full siblings with nonsyndromic craniosynostosis were more likely, in the crude analyses, to be diagnosed with any psychiatric disorder, including intellectual disability, language disorders, and neurodevelopmental disorders compared with nonaffected siblings. The higher risk for any psychiatric disorder and intellectual disability remained after adjusting for confounders. Conclusions Children with nonsyndromic craniosynostosis demonstrated higher risks of any psychiatric disorder compared with children without nonsyndromic craniosynostosis. This risk cannot fully be explained by familial influences (i.e., genetic or environmental factors). Clinical question/level of evidence Risk, III.

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by difficulty in communication, which includes a high incidence of speech production errors. We hypothesize that these errors are partly due to underlying deficits in motor coordination and control, which are also manifested in degraded fine motor control of facial expressions and purposeful hand movements. In this pilot study, we computed correlations of acoustic, video, and handwriting time-series derived from five children with ASD and five children with neurotypical development during speech and handwriting tasks. These correlations and eigenvalues derived from the correlations act as a proxy for motor coordination across articulatory, laryngeal, and respiratory speech production systems and for fine motor skills. We utilized features derived from these correlations to discriminate between children with and without ASD. Eigenvalues derived from these correlations highlighted differences in complexity of coordination across speech subsystems and during handwriting, and helped discriminate between the two subject groups. These results suggest differences in coupling within speech production and fine motor skill systems in children with ASD. Our long-term goal is to create a platform assessing motor coordination in children with ASD in order to track progress from speech and motor interventions administered by clinicians.

Craniosynostosis is usually diagnosed in early infancy. Treatment almost always involves surgery and care is optimally organized around an interdisciplinary team of specialists at a craniofacial center. This study aimed to investigate Swedish parents' experiences of having a child with craniosynostosis and their perceptions of the initial care process. Semistructured telephone interviews were conducted with 20 parents (10 fathers and 10 mothers) of children with nonsyndromic craniosynostosis who were undergoing surgery at the Uppsala Craniofacial Center. A thematic data analysis revealed 6 themes presented in a timeline following the parents' journey from detection of their child's abnormal skull shape to waiting for surgery: Detection of the abnormal skull shape, thoughts, and feelings before the appointment with the craniofacial team, an appointment with the craniofacial team, searching the Internet and social media, waiting for surgery, and suggestions for improvement. Although meeting with the craniofacial team was considered informative, parents expressed concerns about surgery and their infant's long-term prognosis were evident. Most parents had no previous knowledge about craniosynostosis and craniofacial syndromes and wished for more information already at the time of its detection. The Internet was used both at the time of suspicion that something was wrong with the child and later to learn about risks and consequences, alternative treatments and prognosis.

Background and ObjectivesLate neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested.MethodsThis imaging–pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and β-amyloid (Aβ). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p ≤ 0.05.ResultsThe sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; p = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; p = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; p = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; p = 0.01). There was no association with Aβ. More years of football play was associated with log TLV (unstandardized β 0.04, 95% CI 0.01, 0.06; p = 0.01). Greater log TLV correlated with higher FAQ (unstandardized β 4.94, 95% CI 0.42, 8.57; p = 0.03) and CDS scores (unstandardized β 15.35, 95% CI −0.27, 30.97; p = 0.05).DiscussionWMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging–pathologic correlation studies are needed.Classification of EvidenceThis study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

Chronic obstructive pulmonary disease (COPD) is induced by cigarette smoking and characterized by inflammation of airway tissue. Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n = 8), as well as from ex-smokers with variable degrees of COPD (n = 4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data. However, consensus calls showed little promise of representing true positives due to low mappability of corresponding sequence reads and high overlap with positions harbouring known genetic polymorphisms. A targeted re-sequencing approach suggested that only few mutations would survive stringent verification testing and that our data did not allow the inference of any difference in the mutational load of bronchial brush samples between former smoking COPD cases and controls. High polyclonality in airway brush samples renders medium-depth sequencing insufficient to provide the resolution to detect somatic mutations. Deep sequencing data of airway biopsies are needed to tackle the question.

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was −3.7 in the oxytocin group and −3.5 in the placebo group (least-squares mean difference, −0.2; 95% confidence interval, −1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.)

Objective: To investigate the impact of cleft width and cleft type on the need for secondary surgery and velopharyngeal competence from a longitudinal perspective. Design: Retrospective, longitudinal study. Setting: A single multidisciplinary craniofacial team at a university hospital. Patients: Consecutive patients with unilateral or bilateral cleft lip and palate and cleft palate only (n = 313) born from 1984 to 2002, treated with 2-stage palatal surgery, were reviewed. A total of 213 patients were included. Main Outcome Measures: The impact of initial cleft width and cleft type on secondary surgery. Assessment of hypernasality, audible nasal emission, and glottal articulation from routine follow-ups from 3 to 16 years of age. The assessments were compared with reassessments of 10% of the recordings. Results: Cleft width, but not cleft type, predicted the need for secondary surgery, either due to palatal dehiscence or velopharyngeal insufficiency. The distribution of cleft width between the scale steps on a 4-point scale for hypernasality and audible nasal emission differed significantly at 5 years of age but not at any other age. Presence of glottal articulation differed significantly at 3 and 5 years of age. No differences between cleft types were seen at any age for any speech variable. Conclusions: Cleft width emerged as a predictor of the need for secondary surgery as well as more deviance in speech variables related to velopharyngeal competence during the preschool years. Cleft type was not related to the need for secondary surgery nor speech outcome at any age.

Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females. This work was supported by the European Union, FP7 project # 200506. We acknowledge the helpful discussions with Emanuele Raineri, Barcelona, Spain and with Wilfried Karmaus, Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, Tennessee, USA. CNAG-CRG lab is a member of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001 of the PE I+D+i 2013-2016, funded by ISCIII and FEDER. Work by CB at Leicester and by LZH at Munich was also supported the European Union FP7 project # 270194.

Objective Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose–response relationship between duration of football played and CTE risk and severity. Methods In a convenience sample of 266 deceased American football players from the Veterans Affairs–Boston University–Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias. Results In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19–1.41; p = 3.8 × 10−9) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07–1.22; p = 3.1 × 10−4). Participants with CTE were 1/10th as likely to have played 14.5 years (positive LR = 10.2, 95% CI = 9.8–10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios. Interpretation The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116–131

Background Whether the clinical or pathophysiologic significance of the “treatable trait” high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma. Methods Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U‐BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U‐BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/μL as a cut‐off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values). Results There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U‐BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Conclusion Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different., In a chronic obstructive pulmonary disease (COPD) cohort (EvA, n = 283), 12 genes, whereas in asthma cohort (UBIOPRED, n = 85), 1197 genes in bronchial epithelial brushes were correlated with a blood eosinophil count. The gene CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

Intraosseous meningioma of the chordoid type is a rare clinical entity. Radical surgical removal and subsequent cranioplasty is the treatment of choice. Here, the authors report a severe case involving more than 70% of the calvarial surface area, which was removed and repaired using a prefabricated custom-made, titanium-reinforced, bioceramic implant and bone-cutting guides. Tumor removal and good esthetic outcome were achieved, along with a 17.1% increase of intracranial volume. Bioceramic implants have shown promising initial results and may represent an important new tool in the surgeon’s armamentarium.

Background A distinctive trait of triple negative breast cancer (TNBC) is the acquisition of genome wide highly aberrant copy number states, which is more evident in metastatic settings. The level of copy number alterations can be characterized by quantitative estimates of chromosomal instability, such as allelic imbalanced copy number aberrations, telomeric allelic imbalance (NtAI), homologous recombination deficiency (HRD) score, referred here as genomic scars. Several of these scars are reported as being indicative of BRCAness and potential predictive and/or prognostic biomarkers of chemotherapy response, currently mostly demonstrated in neoadjuvant settings in TNBC. Aims Using several genomic scar measures, we aim to capture chromosomal instability and test their predictive and prognostic value in metastatic or recurrent locally advanced triple negative or BRCA1/2 mutated breast cancer in the TNT trial. Methods Patients recruited to TNT (n=376) had ER-/PR-/Her2- breast cancer or were germline BRCA mutation carriers. Genome-wide copy numbers (CN) were derived from FFPE samples including primary tumours and positive lymph nodes (n=183, docetaxel=93, carboplatin=90; BRCA1 mut=25). Genomic scars were generated using ASCAT (Van loo et al., PNAS 2010) CN profiles. HRD scores were established by Myriad Genetics, Inc. assay (n=272). BRCA1-like classifier was applied as described in Schouten et al., Mol Onc 2015. Shannon diversity index was calculated using ASCAT raw CN profiles. Association of genomic scars with PAM50 subtypes and BRCA1 deficiency status were evaluated using Kruskal-Wallis test; p-values were adjusted for multiple comparisons (Dunn's test). Statistical significance was defined as p Results HRD and NtAI scores were higher in basal like samples compared to non-basal like (median diff. HRD=11.5, p=0.005; NtAI=3, p=0.04). HRD (p=2e-14) and NtAI (p=0.003) scores were also higher in BRCA1 deficient (BRCA1 germline/somatic mutant or BRCA1 methylated) samples compared to non-deficient. Using the BRCA1-like classifier, 42 out of 50 BRCA1 deficient samples and 93 out of 133 BRCA1 non-deficient/undetermined samples were identified as BRCA1-like. The Shannon diversity index, measuring CN heterogeneity, clustered samples into 3 groups. Analysis of ORR showed non-significant trends to preferential response rates with docetaxel in cluster 1 and 3. Membership of cluster 2 predicted higher ORR to carboplatin over docetaxel (interaction p=0.017). PFS indicated a treatment effect in cluster 2, but not in cluster 1 or 3; there was no evidence of interaction between subgroups and treatment (p=0.15). Conclusions Our results suggest that the overall heterogeneity of the copy number landscape is a promising area for seeking predictive/prognostic biomarkers in metastatic TNBC, and combined with other modalities of high-dimensional omics data could provide essential treatment response information. Citation Format: Sipos O, Tovey H, Quist J, Haider S, Nowinski S, Gazinska P, Kernaghan S, Toms C, Timms KM, Lanchbury JS, Linn SC, Pinder SE, Bliss JM, Tutt A, Cheang MC, Grigoriadis A, On behalf of the TNT Trial Management Group and Investigators. Characterization of chromosomal instability in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-07.

Pure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.

Background: Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation and bacterial dysbiosis. The relationship between the airway microbiome and bronchial gene expression in COPD is poorly understood. We aimed to identify differences in the airway microbiome from bronchial brushings in patients with COPD and healthy individuals and to investigate whether any distinguishing bacteria are related to bronchial gene expression. Methods: For this 16S rRNA gene sequencing and host transcriptomic analysis, individuals aged 45–75 years with mild-to-moderate COPD either receiving or not receiving inhaled corticosteroids and healthy individuals in the same age group were recruited as part of the Emphysema versus Airways Disease (EvA) consortium from nine centres in the UK, Germany, Italy, Poland, and Hungary. Individuals underwent clinical characterisation, spirometry, CT scans, and bronchoscopy. From bronchoscopic bronchial brush samples, we obtained the microbial profiles using 16S rRNA gene sequencing and gene expression using the RNA-Seq technique. We analysed bacterial genera relative abundance and the associations between genus abundance and clinical characteristics or between genus abundance and host lung transcriptional signals in patients with COPD versus healthy individuals, and in patients with COPD with versus without inhaled corticosteroids treatment. Findings Between February, 2009, and March, 2012, we obtained brush samples from 574 individuals. We used 546 of 574 samples for analysis, including 207 from healthy individuals and 339 from patients with COPD (192 with inhaled corticosteroids and 147 without). The bacterial genera that most strongly distinguished patients with COPD from healthy individuals were Prevotella (median relative abundance 33·5%, IQR 14·5–49·4, in patients with COPD vs 47·7%, 31·1–60·7, in healthy individuals; p

AimsCraniosynostosis is a congenital condition characterised by premature fusion of one or more cranial sutures. The aim of this study was to analyse ophthalmic function before and after cranial surgery, in children with various types of non-syndromic craniosynostosis.MethodsChildren referred to Uppsala University Hospital for surgery of non-syndromic craniosynostosis were examined preoperatively. Visual acuity was measured with Preferential Looking tests or observation of fixation and following. Strabismus and eye motility were noted. Refraction was measured in cycloplegia and funduscopy was performed. Follow-up examinations were performed 6–12 months postoperatively at the children’s local hospitals.ResultsOne hundred twenty-two children with mean age 6.2 months were examined preoperatively. Refractive values were similar between the different subtypes of craniosynostosis, except for astigmatism anisometropia which was more common in unicoronal craniosynostosis. Strabismus was found in seven children, of which four had unicoronal craniosynostosis.Postoperatively, 113 children were examined, at mean age 15.9 months. The refractive values decreased, except for astigmatism and anisometropia in unicoronal craniosynostosis. Strabismus remained in unicoronal craniosynostosis. Two new cases with strabismus developed in unicoronal craniosynostosis and one in metopic, all operated with fronto-orbital techniques. No child had disc oedema or pale discs preoperatively or postoperatively.ConclusionOphthalmic dysfunctions were not frequent in children with sagittal craniosynostosis and preoperative ophthalmological evaluation may not be imperative. Children with unicoronal craniosynostosis had the highest prevalence of strabismus and anisometropia. Fronto-orbital techniques used to address skull deformity may be related to a higher prevalence of strabismus postoperatively.

Noncontrast Computed Tomography (NCCT) of the brain has been the first-line diagnosis for emergency evaluation of acute stroke, so a rapid and automated detection, localization, and/or segmentation of ischemic lesions is of great importance. We provide the state-of-the-art review of methods for automated detection, localization, and/or segmentation of ischemic lesions on NCCT in human brain scans along with their comparison, evaluation, and classification. Twenty-two methods are (1) reviewed and evaluated; (2) grouped into image processing and analysis-based methods (11 methods), brain atlas-based methods (two methods), intensity template-based methods (1 method), Stroke Imaging Marker-based methods (two methods), and Artificial Intelligence-based methods (six methods); and (3) properties of these groups of methods are characterized. A new method classification scheme is proposed as a 2 × 2 matrix with local versus global processing and analysis, and density versus spatial sampling. Future studies are necessary to develop more efficient methods directed toward deep learning methods as well as combining the global methods with a high sampling both in space and density for the merged radiologic and neurologic data.

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.

Background Recent studies indicate that chronic kidney disease (CKD) is a comorbidity in patients with obstructive sleep apnea (OSA). We hypothesized that the use of the classical muscle-dependent, creatinine-based equation to estimate glomerular filtration rate (GFR) in patients with OSA may be inaccurate due to the extreme body mass index (BMI) of some patients. The aim of this study was to establish the role of cystatin-C-based estimation of GFR for the detection of CKD in patients with OSA and typical comorbidities. Methods Two hundred and forty consecutive patients with newly diagnosed OSA were enrolled into this cross-sectional study. In all patients estimated GFR (eGFR) was calculated with chronic kidney disease-epidemiology collaboration group (CKD-EPI) equations using creatinine and cystatin-C. All patients were examined for comorbidities. Results In obese patients with OSA significant differences between GFR estimations based on creatinine and cystatin were found: eGFR based on muscle-dependent creatinine measurement was significantly higher than the muscle-independent eGFR based on cystatin-C measurement. Conclusions GFR can be routinely screened for using creatinine-based estimations (eGFRcreat). In a selected group of patients with OSA with BMI over 30 kg/m2 the addition of cystatin-C for assessment of eGFR is suggested.

Aneuploidy, defined as the loss and gain of whole and part chromosomes, is a near-ubiquitous feature of cancer genomes, is prognostic, and likely an important determinant of cancer cell biology. In colorectal cancer (CRC), aneuploidy is found in virtually all tumours, including precursor adenomas. However, the temporal evolutionary dynamics that select for aneuploidy remain broadly uncharacterised. Here we perform genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that cross-sectionally represent the distinct stages of tumour evolution, and longitudinally track individual tumours through metastasis and treatment. Precancer lesions (adenomas) exhibited low levels of aneuploidy but high intra-tumour heterogeneity, whereas cancers had high aneuploidy but low heterogeneity, indicating that progression is through a genetic bottleneck that suppresses diversity. Individual CRC glands from the same tumour have similar karyotypes, despite prior evidence of ongoing instability at the cell level. Pseudo-stable aneuploid genomes were observed in metastatic lesions sampled from liver and other organs, after chemo- or targeted therapies, and late recurrences detected many years after the diagnosis of a primary tumour. Modelling indicates that these data are consistent with the action of stabilising selection that ‘traps’ cancer cell genomes on a fitness peak defined by the specific pattern of aneuploidy. These data show that the initial progression of CRC requires the traversal of a rugged fitness landscape and subsequent genomic evolution, including metastatic dissemination and therapeutic resistance, is constrained by stabilising selection.

BACKGROUND AND OBJECTIVES: Families of children with autism spectrum disorder (ASD) often experience challenges navigating multiple systems to access services. Family navigation (FN) is a model to provide information and support to access appropriate services. Few studies have been used to examine FN’s effectiveness for families of children with ASD. This study used mixed methods to (1) characterize FN services received by a sample of families in the Autism Treatment Network; (2) examine change in parent-reported activation, family functioning, and caregiver strain; and (3) explore families’ experiences with FN services. METHODS: Family characteristics and parent outcomes including parent activation, family functioning, and caregiver strain were collected from 260 parents in the Autism Treatment Network. Descriptive statistics and linear mixed models were used for aims 1 and 2. A subsample of 27 families were interviewed about their experiences with FN services to address aim 3. RESULTS: Quantitative results for aims 1 and 2 revealed variability in FN services and improvement in parent activation and caregiver strain. Qualitative results revealed variability in family experiences on the basis of FN implementation differences (ie, how families were introduced to FN, service type, intensity, and timing) and whether they perceived improved skills and access to resources. CONCLUSIONS: Findings suggest FN adaptations occur across different health care delivery systems and may result in highly variable initial outcomes and family experiences. Timing of FN services and case management receipt may contribute to this variability for families of children with ASD.

Introduction: Chronic obstructive pulmonary disease (COPD) and bronchiectasis, chronic inflammation disorders of the bronchial tree through the mechanism of 'spill-over' of inflammatory mediators, may lead to systemic manifestations of illness of the respiratory system and comorbidities. The aim of the study was to evaluate the frequency of coexisting chronic obstructive pulmonary disease and bronchiectasis and influence of bronchiectasis on COPD comorbid diseases. Material and methods: A post-hoc cross-sectional analysis of cohort study of 288 consecutive patients hospitalized due to acute exacerbation of COPD was performed. Results: 177 males (61.5%) and 111 females (38.5%) with mean age = 71.0 8 ± 8.9 yrs, FEV1 % pred. = 34.6 ± 16.8 with COPD diagnosis were studied. In this group, 29 (10.1%) patients presented with bronchiectasis confirmed by HRCT scan. COPD patients with and without bronchiectasis had similar Charlson index results (2.5 vs. 2.1, p = 0.05). COPD patients with bronchiectasis required longer hospitalization during exacerbation. COPD patients with bronchiectasis significantly more often than patients without this comorbidity revealed the features of colonization with P. aeruginosa (OR = 4.17, p = 0.02). Conclusions: Bronchiectasis is a relatively common comorbidity in COPD patients. COPD patients with bronchiectasis are more frequently colonized with P. aruginosa comparing to non-bronchiectasis COPD patients. We did not confirm the influence of bronchiectasis on COPD comorbidities.

OBJECTIVE To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE. METHODS The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset. RESULTS Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p

After craniotomy, the monitoring of the skull healing progression is strongly needed to take a proper medical intervention. The CT scans is however currently used for follow-up after craniotomy res ...

Schwab et al.1 did not find a statistically significant association between position played and career duration and autopsy-confirmed chronic traumatic encephalopathy (CTE) in elite football and ice hockey players. The study's limitations associated with statistical power, measurement error, and sample selection hinder interpretation of the presented data. The authors state that a sample size of about 14 is required “to detect a 50% difference in CTE diagnoses between groups with 80% power.”1 Player position is unlikely to account for a 50% difference in CTE status based on work by Mez et al.,2 which indicates no effect for player position in >250 former football players. Assuming that player position accounts for a much smaller effect in CTE status, such as 10%, a sample size of approximately 400 would be needed. In Mez et al., each additional year of football play accounted for a 30% increase in odds of CTE. Given the sample size and standard deviation reported for career duration in this article, the authors were only 80% powered to detect an effect 2.4 times larger and were only 55% powered to detect the effect presented in Mez et al.

Monitoring of health-related quality of life and symptoms of patients with brain tumors is needed yet not always feasible. This is partially due to lack of brief-yet-precise assessments with minimal administration burden that are easily incorporated into clinics. Dynamic computerized adaptive testing (CAT) or static fixed-length short forms, derived from psychometrically sound item banks, are designed to fill this void.This study evaluated the comparability of scores obtained from CATs and short forms.Patients (ages 7-22 years) were recruited from brain tumor clinics and completed Patient-Reported Outcome Measurement Information System CATs and short forms (Fatigue, Mobility, Upper Extremity, Depressive Symptoms, Anxiety, and Peer Relationships). Pearson correlations, paired t-tests, and Cohen's d were used to evaluate the relationship, significant differences, and the magnitude of the difference between these two scores, respectively.Data from 161 patients with brain tumors were analyzed. Patients completed each CAT within 2 minutes. Scores obtained from CATs and short forms were highly correlated (r = 0.95-0.98). Significantly different CAT vs. short-form scores were found on 4 (of 6) domains yet with negligible effect sizes (|d| 0.09). These relationships varied across patients with different levels of reported symptoms, with the strongest association at the worst or best symptom scores.This study demonstrated the comparability of scores from CATs and short forms. Yet the agreement between these two varied across degrees of symptom severity which was a result of the ceiling effects of static short forms. We recommend CATs to enable individualized assessment for longitudinal monitoring.

Posterior calvarial vault osteodistraction (PCVO) has become increasingly popular in the correction of craniosynostosis. When compared to cranioplasty, PCVO offers a shorter, less invasive operation, greater intracranial volume advancement and a lower rate of relapse. In general, distraction protocols are based primarily on clinical observations rather than systematic research. Faster distraction protocols may reduce complications. However, distraction protocols producing higher forces can increase complications. Thus, we need to understand these forces in order to improve distraction protocols and devices. We developed a force measurement method that can be used on PCVO devices. Here, we present preliminary data about the forces developed during PCVO. We measured the forces in four bicoronal craniosynostosis patients during PCVO. We observed a linear-like trend between the force increase and the distraction distance within distraction sessions. We also observed a step-wise force increase between distraction sessions and found that the distraction force relaxed rapidly shortly after the distraction session. The mean maximum pre distraction force for one distracter was 20.4 N, while the mean maximum end-distraction force for one distracter was 57.6 N. Our data suggests that current treatment protocols might be re-evaluated favouring shorter distraction distances and more frequent distraction sessions. (C) 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Cognitive dysfunction is a major concern for children with brain tumors. A valid, user-friendly screening tool could facilitate prompt referral for comprehensive neuropsychological assessments and therefore early intervention. Applications of the pediatric perceived cognitive function item bank (pedsPCF) such as computerized adaptive testing can potentially serve as such a tool given its brevity and user-friendly nature. This study aimed to evaluate whether pedsPCF was a valid indicator of cerebral compromise using the criterion of structural brain changes indicated by leukoencephalopathy grades.Data from 99 children (mean age = 12.6 years) with brain tumors and their parents were analyzed. Average time since diagnosis was 5.8 years; time since last treatment was 4.3 years. Leukoencephalopathy grade (range 0-4) was based on white matter damage and degree of deep white matter volume loss shown on MRI. Parents of patients completed the pedsPCF. Scores were based on the US general population-based T-score metric (mean = 50; SD = 10). Higher scores reflect better function.Leukoencephalopathy grade distributions were as follows: 36 grade 0, 27 grade 1, 22 grade 2, 13 grade 3, and 1 grade 4. The mean pedsPCF T-score was 48.3 (SD = 8.3; range 30.5-63.7). The pedsPCF scores significantly discriminated patients with different leukoencephalopathy grades, F = 4.14, p = 0.0084. Effect sizes ranged from 0.09 (grade 0 vs. 1) to 1.22 (grade 0 vs. 3/4).This study demonstrates that the pedsPCF is a valid indicator of leukoencephalopathy and provides support for its use as a screening tool for more comprehensive neurocognitive testing.

This study conducted a preliminary examination on cognitive reserve (CR) as a modifier of symptom expression in subjects with autopsy-confirmed chronic traumatic encephalopathy (CTE). The sample included 25 former professional football players neuropathologically diagnosed with CTE stage III or IV. Next of kin interviews ascertained age of cognitive and behavioral/mood symptom onset, and demographic/athletic characteristics. Years of education and occupational attainment defined CR. High occupational achievement predicted later age of cognitive, p = 0.02, and behavioral/mood, p = 0.02, onset. Education was not an individual predictor. These preliminary findings suggest that CR may forestall the clinical manifestation of CTE.

It is unknown if targeted risk reduction counseling in the health care setting, after documented exposure to fentanyl, can affect behavior change to reduce risks and increase utilization of evidence-based overdose prevention strategies.We conducted a retrospective analysis of results (7/2018-6/2019) from questionnaire-facilitated counseling by recovery coaches in the emergency department (ED) and primary care settings following disclosure of a urine toxicology positive for fentanyl.Seventy-five percent of N = 101 respondents were neither aware of nor expecting fentanyl in their substances of use. Fifty-three (70 %) of those initially unaware answered that learning about exposure to and the risks from fentanyl changed their thoughts about reducing or abstaining from use. A greater proportion of patients seen in the ED expressed desire to stop or reduce opioid use as compared to ambulatory clinic patients (91 % vs. 46 %, p0.001). Of those not already engaged in treatment, 18 % and 15 % were interested in medication and behavioural health treatment, respectively, and each of them indicated a change in thought based on the counseling. Forty-five percent of individuals not yet receiving naloxone endorsed interest in receiving it, and 22 % of all respondents were somewhat or very interested in access to safe consumption sites.This study suggests a novel clinical utility in toxicology screens to inform behavior in the setting of illicit fentanyl exposure. In addition to linkages to evidence-based treatment, linkages to harm-mitigating strategies associated with ongoing substance use may be critical to a comprehensive overdose prevention strategy in the clinical setting.

Although substance use disorder (SUD) and autism spectrum disorder (ASD) are highly comorbid with other mental disorders and commonly have onset during childhood,1 little attention has been paid to their overlap. Despite limited data suggesting that up to 4% of patients with ASD also have substance-related problems,2 there are no existing guidelines, protocols, or tailored resources focused on SUD in young people with co-occurring ASD. This is concerning given that the simultaneous presence of these disorders presents unique challenges that complicate clinical care. In particular, many of the symptoms of ASD can interfere with standard SUD treatment. Thus, when treating patients with this comorbidity, practitioners should consider the following: communication difficulties, diminished capacity for motivation and insight, limited social interactions, and obstacles to treatment engagement.

Angelman syndrome (AS) is a neurogenetic disorder associated with impaired expression of the ubiquitin-protein ligase E3A gene on chromosome 15. AS results in intellectual disability with limited expressive language, epilepsy, ataxia, sleep impairment, and problematic behavior which may include anxiety. Buspirone is a serotonin (5-HT)1A receptor partial agonist used in the treatment of anxiety disorders and may, therefore, have a treatment role for patients with AS.We describe three patients who were given open-label buspirone for the treatment of behaviors thought to be related to anxiety.We found significant improvement in symptoms of anxiety with buspirone. Patients tolerated long-term usage of the medication.The findings of this study suggest that buspirone may be effective for the amelioration of behaviors related to anxiety in patients with AS, and well tolerated. Limitations include the open-label nature of these treatments, the small sample size and the absence of a control group.

Background Although both autism spectrum disorder (ASD) and substance use disorder (SUD) are both commonly comorbid with other psychiatric conditions, there is a paucity of research on the overlap of these disorders. The primary aim of the present study was to identify the prevalence of psychiatric comorbidities in young adults with SUD and ASD compared to those with ASD only. Method Multivariate logistic regression controlling for age was used to compare the prevalence of psychiatric disorders in a sample of treatment-seeking adult outpatients with a) ASD without SUD and b) ASD with SUD. Psychiatric and SUD diagnoses were determined by semi-structured interview (SCID for DSM IV). Results The sample included 42 patients with ASD only (mean age ± SD = 26.2 ± 8.9 years) and 21 with ASD and SUD (35.2 ± 12.6). High rates of psychopathology were found in both groups. Comorbid conduct disorder (CD) was significantly more prevalent in the ASD + SUD group (25 %) compared to those without SUD (5%; p Conclusion In both groups, rates of psychopathology were high with CD being significantly more common in young adults with ASD and SUD. These findings highlight the importance of screening for CD in individuals with ASD to mitigate the potential development of comorbid SUD. Further research is needed to determine if CD is a true risk factor for SUD in the ASD population and identify other risk factors.

Many children with autism spectrum disorder (ASD) have notable difficulties in motor, speech and language domains. The connection between motor skills (oral-motor, manual-motor) and speech and language deficits reported in other developmental disorders raises important questions about a potential relationship between motor skills and speech-language deficits in ASD. To this end, we examined data from children with ASD (n = 1781), 2-17 years of age, enrolled in the Autism Speaks-Autism Treatment Network (AS-ATN) registry who completed a multidisciplinary evaluation that included diagnostic, physical, cognitive and behavioral assessments as part of a routine standard of care protocol. After adjusting for age, non-verbal IQ, Attention Deficit Hyperactivity Disorder (ADHD) medication use, and muscle tone, separate multiple linear regression analyses revealed significant positive associations of fine motor skills (FM) with both expressive language (EL) and receptive language (RL) skills in an impaired FM subgroup; in contrast, the impaired gross motor (GM) subgroup showed no association with EL but a significant negative association with RL. Similar analyses between motor skills and interpersonal relationships across the sample found both GM skills and FM skills to be associated with social interactions. These results suggest potential differences in the contributions of fine versus gross motor skills to autistic profiles and may provide another lens with which to view communication differences across the autism spectrum for use in treatment interventions.

PURPOSE Because clinical evaluation of noncontrast computed tomography (CT) has a poor sensitivity in the evaluation of acute ischemic stroke, computer-aided diagnosis may be able to facilitate the performance. Recently, we introduced a computational method for the detection and localization of visible infarcts. Herein, we aimed to evaluate and extend a previous method, the Stroke Imaging Marker (SIM), to localize nonvisible hyperacute ischemia. MATERIALS AND METHODS On the basis of the SIM and its components—the ratio of percentile differences in subranges of Hounsfield Unit (HU) distribution (P-ratio), ratio of voxels count in ranges of brain CT intensity, median HU attenuation value—the infarct localization was performed in 140 early and follow-up scans of 70 patients. In none of the early scans was the infarct visible to a radiologist or an experienced stroke neuroradiologist. The infarcted hemisphere detection rate (HDR) and sensitivity of infarct localization were measured by overlapping the region of detected tissue in the initial scan, with the gold standard set for the fully visible stroke in the follow-up scan. RESULTS The best performance of the algorithm was found for the P-ratio including seven percentile subranges within the range of 35th-75th percentile. The modified SIM provided a 76% ischemic HDR and 54% sensitivity in spatial localization of hyperacute ischemia (68% among properly detected infarct sides). CONCLUSION The improved SIM is a dedicated and potentially useful tool for hyperacute nonvisible brain infarct detection from CT scans and may contribute to reduction of image-to-needle time in patients eligible for revascularization therapy.

Fatal hyperthermia as a result of 3,4-methylenedioxymethamphetamine (MDMA) use involves non-esterified free fatty acids (NEFA) and the activation of mitochondrial uncoupling proteins (UCP). NEFA gain access into skeletal muscle via specific transport proteins, including fatty acid translocase (FAT/CD36). FAT/CD36 expression is known to increase following chronic exercise. Previous studies have demonstrated the essential role of NEFA and UCP3 in MDMA-induced hyperthermia. The aims of the present study were to use a chronic exercise model (swimming for two consecutive hours per day, five days per wk for six wk) to increase FAT/CD36 expression in order to: 1) determine the contribution of FAT/CD36 in MDMA (20 mg/kg, s.c.)-mediated hyperthermia; and 2) examine the effects of the FAT/CD36 inhibitor, SSO (sulfo-N-succinimidyl oleate), on MDMA-induced hyperthermia in chronic exercise and sedentary control rats. MDMA administration resulted in hyperthermia in both sedentary and chronic exercise animals. However, MDMA-induced hyperthermia was significantly potentiated in the chronic exercise animals compared to sedentary animals. Additionally, chronic exercise significantly reduced body weight, increased FAT/CD36 protein expression levels and reduced plasma NEFA levels. The FAT/CD36 inhibitor, SSO (40 mg/kg, ip), significantly attenuated the hyperthermia mediated by MDMA in chronic exercised but not sedentary animals. Plasma NEFA levels were elevated in sedentary and exercised animals treated with SSO prior to MDMA suggesting attenuation of NEFA uptake into skeletal muscle. Chronic exercise did not alter skeletal muscle UCP3 protein expression levels. In conclusion, chronic exercise potentiates MDMA-mediated hyperthermia in a FAT/CD36 dependent fashion.

Aneuploidy, defined as the loss and gain of whole and part chromosomes, is a near-ubiquitous feature of cancer genomes, and has clinical relevance as a prognostic marker and potential therapeutic target. We have previously shown that in colorectal cancer (CRC), aneusomies largely occur upon the transition from benign adenoma to invasive carcinoma (Cross et al., 2018), however the temporal evolutionary dynamics that select for aneuploidy throughout CRC progression remain broadly uncharacterised. We performed multi-region genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that cross-sectionally represent the distinct stages of CRC progression, and longitudinally tracked 22 individual CRC tumours through metastasis and treatment. Genetic diversity measures revealed that although adenomas exhibited low levels of aneuploidy (8.5% genome altered), they harboured high intra-tumour heterogeneity (ITH), whereas cancers had significantly higher aneuploidy (27.2% genome altered) but proportionally lower ITH (p=0.0017), indicating that progression to malignancy is through a genetic bottleneck that suppresses diversity. We generated genome-wide copy number profiles from individual CRC glands, and showed that glands from the same tumour had similar karyotypes, yet displayed ongoing instability at the single cell level. Remarkably, we found that aneuploid genomes were broadly stable in metastatic lesions, even after chemo- or targeted therapies, and in recurrences detected many years after the primary diagnosis. Computational modelling of the dynamics of aneusomy accrual during CRC progression to metastasis was consistent with stabilising selection acting to ‘trap’ cancer cell genomes on a fitness peak defined by the optimal patterns of aneuploidy. These data show that although a genetic bottleneck underlies the initial progression from adenoma to CRC, further evolution of CRC is constrained largely by stabilising selection, even through metastatic dissemination and therapeutic resistance. References Cross, W., Kovac, M., Mustonen, V., Temko, D., Davis, H., Baker, A.-M., … Tomlinson, I. P. M. (2018). The evolutionary landscape of colorectal tumorigenesis. Nature Ecology & Evolution, 2(10), 1661–1672. https://doi.org/10.1038/s41559-018-0642-z Citation Format: Salpie Nowinski, William Cross, Maximilian Mossner, George Cresswell, Abhirup Banerjee, Marc Williams, Laura Gay, Ann-Marie Baker, Binxgin Lu, Christopher Kimberley, Hayley Davis, Nik Matthews, Miangela M. Lacle, Ian P.M. Tomlinson, Marnix Jansen, Alan Watson, Chris Barnes, Nicholas A. Wright, John Bridgewater, Manuel Rodriguez-Justo, Hemant Kocher, Simon J. Leedham, Andrea Sottoriva, Trevor A. Graham. Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PR06.

Background Early detection of cognitive decline in older individuals can be accomplished with brief, computerized measures in diverse settings. The goal of the ARMADA study is to validate the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in the neurological aging spectrum from cognitively normal to dementia, and to extend the age range to allow for longitudinal assessment of the oldest individuals. Here, we present baseline data from general population individuals over 85 years of age without cognitive impairment compared with those 65 to 85. Method ARMADA is a multi-site study recruiting participants from established research cohorts. Participants included cognitively average-for-age individuals between the ages of 65–85 (n = 82) and another group 86 and older (n = 105). Baseline characteristics and preliminary data are presented for the Cognition, Emotion, Motor and Sensation modules of the NIHTB. Results Analysis of preliminary baseline data revealed that mean uncorrected standard scores of most cognitive, motor, and sensation measures differed among the groups in the expected direction, such that individuals 65–85 had better performance than individuals 86 and older. Conversely, group scores were similar on most emotion measures. Conclusions This analysis of preliminary baseline data from ARMADA provides initial evidence for the utility of the NIHTB in individuals over age 85 without cognitive impairment, who, as a group, scored lower than those from age 65–85. These results demonstrate the importance of establishing cohort-specific norms relevant to the oldest age group. Longitudinal follow-ups over two years will track cognitive, motor, emotion, and sensory functioning in this group.

Clinicians and educators are increasingly using technology within the context of existing therapies and teaching methodologies. The growing use of mobile clinical tools is particularly exciting for individuals with autism spectrum disorder (ASD), as technologically based interventions have been shown to be both efficacious (to target academics, adaptive behavior, disruptive behavior, etc.) and accepted in this population (Odom et al., 2015). In addition, these tools have the potential to address two significant impediments in ASD intervention, the anxiety and/or skill deficits often associated with face-to-face interactions and skill generalization outside of the therapy office (Wieckowski & White, 2017). In other words, the use of technology may serve as an important preliminary or prerequisite step for face-to-face therapeutic progress. The purpose of this paper is to present a new, interactive clinical app that explicitly utilizes an individual's restricted interests to teach skills and improve communication. The paper will briefly review the ways in which individuals with ASD may be good candidates for technological-based interventions, explore the current role of technology in existing evidence-based therapies, and discuss the use of a new technology, Sidekicks!, that has been developed for this population. A case example will then illustrate the use of Sidekicks! and its anticipated functionality across several public service settings, including hospitals, outpatient clinics, and school systems, thereby coordinating the intervention efforts of various professionals involved in the treatment of children with ASD. Finally, limitations of the app (and of technology more generally) and the need for future research will be discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615. The minor allele frequency (MAF = 0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF = 0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile = 0.42, 95% confidence interval [CI] 0.22–0.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.29–0.98, p = 0.043), and increased synaptic protein density (β = 0.306, 95% CI 0.065–0.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.16–0.99, p = 0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.

In the BDAS project one of the goals is to provide a solution to the monitoring bone healing issue complementing current techniques. Data have been collected in clinical trials from infants treated for Craniosynostosis by a craniotomy surgery. The data are collected with a biomedical sensor based in microwave technology. This sensor could be able to sense changes in the composition of the different tissues in the upperhemisphere of the head by noticing a difference in the propagation of the microwaves, as the bone injury from the craniotomy heals over time. In this thesis, we analyse the clinical data in BDAS project incorporating new approaches with respect to previous analysis methods. These new approaches could give new insight into the proposed solution, but more analysis need to be done.

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p 8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5–25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

This chapter, transcribed from a panel discussion at the Boston University Alzheimer’s Disease Center conference on chronic traumatic encephalopathy (CTE), begins with the role of the Concussion Legacy Foundation (ConcussionFoundation.org). The panel discussion with one former boxer and two former NFL players ensues. Issues discussed include these athletes’ concerns for the possible development of CTE in themselves and in others currently engaged in boxing or football. The athletes were also asked about whether they would allow their children to follow in their footsteps in boxing or football. Lastly, questions were taken from the conference participants.