Search

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 In the TNT trial of triple negative breast cancer (NCT00532727), germline BRCA1/2 mutations were present in 28% of carboplatin responders. We assessed quantitative measures of structural chromosomal instability (CIN) to identify a wider patient subgroup within TNT with preferential benefit from carboplatin over docetaxel. Patients and methods Copy number aberrations (CNAs) were established from 135 formalin-fixed paraffin-embedded primary carcinomas using Illumina OmniExpress SNP-arrays. Seven published [allelic imbalanced CNA (AiCNA); allelic balanced CNA (AbCNA); copy number neutral loss of heterozygosity (CnLOH); number of telomeric allelic imbalances (NtAI); BRCA1-like status; percentage of genome altered (PGA); homologous recombination deficiency (HRD) scores] and two novel [Shannon diversity index (SI); high-level amplifications (HLAMP)] CIN-measurements were derived. HLAMP was defined based on the presence of at least one of the top 5% amplified cytobands located on 1q, 8q and 10p. Continuous CIN-measurements were divided into tertiles. All nine CIN-measurements were used to analyse objective response rate (ORR) and progression-free survival (PFS). Results Patients with tumours without HLAMP had a numerically higher ORR and significantly longer PFS in the carboplatin (C) than in the docetaxel (D) arm [56% (C) versus 29% (D), PHLAMP,quiet = 0.085; PFS 6.1 months (C) versus 4.1 months (D), Pinteraction/HLAMP = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), PNtAI,intermediate = 0.03; 62% (C) versus 33% (D), PAiCNA,intermediate = 0.076]. Patients with high AiCNA and PGA had shorter PFS in the carboplatin arm [3.4 months (high) versus 5.7 months (low/intermediate); and 3.8 months (high) versus 5.6 months (low/intermediate), respectively; Pinteraction/AiCNA = 0.027, Padj.interaction/AiCNA = 0.125 and Pinteraction/PGA = 0.053, Padj.interaction/PGA = 0.176], whilst no difference was observed in the docetaxel arm. Conclusions Patients with tumours lacking HLAMP and demonstrating intermediate CIN-measurements formed a subgroup benefitting from carboplatin relative to docetaxel treatment within the TNT trial. This suggests a complex and paradoxical relationship between the extent of genomic instability in primary tumours and treatment response in the metastatic setting., Highlights • Patients with intermediate levels of allelic imbalanced CNAs show a better response rate to carboplatin in TNT. • The lack of amplifications on 1q, 8q and 10p is associated with a superior carboplatin response in TNT. • The relation between chromosomal instability in primary tumours and carboplatin response in advanced settings is non-linear.

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.

Stroke is a leading cause of death and a major cause of permanent disability. Its management is demanding because of variety of protocols, imaging modalities, pulse sequences, hemodynamic maps, criteria for treatment, and time constraints to promptly evaluate and treat. To cope with some of these issues, we propose novel, patented solutions in stroke management by employing multiple brain atlases for diagnosis, treatment, and prediction. Numerous and diverse CT and MRI scans are used: ARIC cohort, ischemic and hemorrhagic stroke CT cases, MRI cases with multiple pulse sequences, and 128 stroke CT patients, each with 170 variables and one year follow-up. The method employs brain atlases of anatomy, blood supply territories, and probabilistic stroke atlas. It rapidly maps an atlas to scan and provides atlas-assisted scan processing. Atlas-to-scan mapping is application-dependent and handles three types of regions of interest (ROIs): atlas-defined ROIs, atlas-quantified ROIs, and ROIs creating an atlas. An ROI is defined by atlas-guided anatomy or scan-derived pathology. The atlas defines ROI or quantifies it. A brain atlas potential has been illustrated in four atlas-assisted applications for stroke occurrence prediction and screening, rapid and automatic stroke diagnosis in emergency room, quantitative decision support in thrombolysis in ischemic stroke, and stroke outcome prediction and treatment assessment. The use of brain atlases in stroke has many potential advantages, including rapid processing, automated and robust handling, wide range of applications, and quantitative assessment. Further work is needed to enhance the developed prototypes, clinically validate proposed solutions, and introduce them to clinical practice.

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: Biologic augmentation via extracellular matrix (ECM) scaffolds has been utilized to address rotator cuff tears with poor-quality tissue. Purpose: To evaluate the cellular changes in graft explants taken from patients treated with porcine dermal grafts for rotator cuff tears. Study Design: Case series; Level of evidence, 4 Methods: Four graft biopsy specimens were obtained from patients treated with porcine dermal grafts in an interposition technique for rotator cuff tears and compared with a nonimplanted graft and a normal rotator cuff specimen. Biopsy of the graft site was performed at 18 days, 3 months, 7 months, and 10.5 months after implantation. Hematoxylin and eosin staining was used to evaluate for cellular and vascular changes. Picrosirius red (PSR) stain with 90° polarized light was performed to evaluate collagen fibril size and orientation. All biopsy specimens were analyzed by a pathologist. Results: There was evidence of progressive remodeling of the porcine dermal grafts. The most mature grafts demonstrated vessel infiltration and extensive remodeling without evidence of inflammation, foreign body reaction, or tissue rejection. PSR demonstrated increased organization of collagen domains, resembling normal tendon by 10.5 months postoperatively. Conclusion: This series suggests that ECM grafts may serve as an effective scaffold for host cell infiltration, collagen reorganization, and vascularization as a result of histologic changes demonstrated with retrieval of specimens from patients with rotator cuff tears that were augmented with porcine dermal grafts.

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.)

Background Various surgical methods are used for early treatment of nonsyndromic sagittal craniosynostosis. The craniofacial centers in Uppsala and Helsinki fundamentally both use the H-Craniectomy: Renier's technique. However, the Helsinki group systematically adds coronal suturectomies to prevent secondary coronal synostosis and posterior barrel staves to address posterior bulleting. The effects of these additions in early treatment of sagittal craniosynostosis are currently unknown. Methods Thirty-six patients from Uppsala and 27 patients from Helsinki were included in the study. Clinical data and computed tomography scans were retrieved for all patients. Results The Helsinki patients had a smaller preoperative Cranial index (CI) (65 vs 72) and a smaller preoperative width (10.1 vs 11.2). There was no difference in postoperative CI, corresponding to a difference in change in CI. Regression analysis indicated that the larger change in CI in the Helsinki group was mainly due to a lower preoperative CI allowing for a larger normalization. The Helsinki patients had less growth in length (1.5 vs 2.1 cm) and more growth in width (2.3 vs 1.9 cm). There were no differences in head circumference or surgical complications. Secondary coronal synostosis was present in 43% of the Uppsala group at 3 years of age, while calvarial defects located at sites of previous coronal suturectomies and posterior barrel staving were seen in the Helsinki group 1 year postoperatively. Conclusions Lower preoperative CI appears to be the main factor in determining the amount of normalization in CI. Prophylactic coronal suturectomies do not seem to benefit preservation of coronal growth function since the modification correlates to less sagittal growth and more growth in width.

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.

Genomic instability is a key feature of carcinogenesis, giving rise to tumour promoting aberrations. The inherent unpredictability of these processes leads to a high degree of intratumour heterogeneity, previously shown to be advantageous for cancer progression in a series of cancer types. We sought to explore the role of genomic instability and intratumour heterogeneity in the progression of ductal carcinoma in situ (DCIS) to invasive disease, in a cohort of 49 women with pure DCIS that developed subsequent ipsilateral invasive disease and 90 women with pure DCIS with no evidence of recurrence with a median follow up of 5.4 years. All samples were identified from within the Sloane project, a prospective national cohort study of DCIS within the UK National Health Service Breast Screening Programme. DNA extracted from bulk tissue samples was processed on the HumanCytoSNP array, and allele-specific copy number aberration (CNA) data was obtained from ASCAT. We measured genomic instability using Scores Of Chromosomal Instability Scarring (SCINS), as well as by calculating the Shannon diversity index for the different copy number states occurring in the tumour genome. We also attempted to deconvolute the clonal structure of the tumours by applying the Shannon diversity index on the raw copy number estimates provided by ASCAT. Non-integer copy number states were interpreted as indicative of the presence of subclonal CNAs. As a positive control, we compared ER+ and ER- DCIS in a larger cohort of 173 DCIS samples (129 ER+ and 44 ER-), using the same methods. We expect ER- tumours to be more genomically unstable, and consequentially more clonally diverse. Measured using SCINS, both copy-neutral loss of heterozygosity (≥ 4 Mbp) and allelic-imbalanced CNAs (≥ 8 Mbp) were shown to be higher in ER- tumours (Fisher’s exact test, p = 0.014 and p = 0.034, respectively). Overall genomic instability was also shown to be higher in ER- tumours using the Shannon diversity index (Fisher’s exact test, p = 0.0085). Our attempt at clonal structure deconvolution also indicates increased heterogeneity in ER- tumours (Fisher’s exact test, p = 0.027). However, no significant difference was identified in the genomic instability or heterogeneity of DCIS that developed subsequent invasive disease compared to that of indolent DCIS, using any of the aforementioned measures. We were therefore unable to identify evidence of a direct link between DCIS heterogeneity and progression to invasive cancer. Our methods did, however, demonstrate that DCIS in general is highly genomically diverse, with ER- tumours exhibiting increased diversity compared to ER+ ones. We aim to validate these findings using spatial sampling data from our cohort, as well as integrating mutation data to allow the use of established clonal heterogeneity deconvolution pipelines. Citation Format: Anargyros Megalios, Vandna Shah, Rana Shami, Salpie Nowinski, Jelmar Quist, Mathini Sridharan, Carolina Salinas de Souza, Karen Clements, Anita Grigoriadis, Sarah Pinder, Alastair Thompson, Elinor Sawyer. Heterogeneity of DCIS does not appear to be a biomarker for development of subsequent invasive cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-05.

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.

The Social Emotional Behavioral (SEB) Team of the National Children's Study (NCS) was tasked with making recommendations for assessment of important aspects of social-emotional health and function in children. This paper describes the constructs recommended for assessment along with the rationale for their assessment. These constructs, representing aspects of Social Relationships, Social Capital, Temperament, Negative Affect, Externalizing Behavior, Social Competence, Self-efficacy, Self-image, Psychological well-being, Ethnic/racial Socialization, Perceived Discrimination, Sexual Orientation, Religiosity, and Perceived Stress and Resilience were identified as being critical to the understanding of children's health and development from birth to age 21.

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.

Secondary Coronal Synostosis (SCS) in patients operated for non-syndromic Sagittal Craniosynostosis is a postoperative phenomenon with unclear implications. The aim of this study was to investigate whether SCS is a negative or a benign occurrence in the postoperative course. The authors hypothesized that SCS is related to reduced cranial growth and intracranial hypertension. Thirty-one patients operated for SC at an early age with the H-craniectomy technique were included in the study. Associations between SCS and cranial shape, growth, and signs of intracranial hypertension were analyzed. Intracranial volume distribution was assessed by measuring partial intracranial volumes defined by skull base landmarks. A total of 12/31 patients developed SCS during the postoperative course. The presence of SCS was associated with a higher prevalence of gyral impressions and a larger normalization of Cranial Index due to less growth in the anteroposterior plane. The SCS group had a smaller postoperative intracranial volume due to less posterior intracranial volume as well as less growth in head circumference. Whether this is a growth restriction caused by the SCS or a secondary effect of less primary brain growth remains to be determined. However, the correlation between SCS, less cranial growth and gyral impressions does imply that SCS should be taken into consideration during clinical follow-up as a potentially adverse event.

Objective We evaluated the usefulness of a three-dimensional (3D) interactive atlas to illustrate and teach surgical skull base anatomy in a clinical setting. Study Design A highly detailed atlas of the adult human skull base was created from multiple high-resolution magnetic resonance imaging (MRI) and computed tomography (CT) scans of a healthy Caucasian male. It includes the parcellated and labeled bony skull base, intra- and extracranial vasculature, cranial nerves, cerebrum, cerebellum, and brainstem. We are reporting retrospectively on our experiences with employing the atlas for the simulation and teaching of neurosurgical approaches and concepts in a clinical setting. Setting The study was conducted at the University Hospital Mainz, Germany, and Hirslanden Hospital, Zürich, Switzerland. Participants Medical students and neurosurgical residents participated in this study. Results Handling the layered graphical user interface of the atlas requires some training; however, navigating the detailed 3D content from intraoperative perspectives led to quick comprehension of anatomical relationships that are otherwise difficult to perceive. Students and residents appreciated the collaborative learning effect when working with the atlas on large projected screens and markedly improved their anatomical knowledge after interacting with the software. Conclusion The skull base atlas provides an effective way to study essential surgical anatomy and to teach operative strategies in this complex region. Interactive 3D computer graphical environments are highly suitable for conveying complex anatomy and to train and review surgical concepts. They remain underutilized in clinical practice.

Cells harbor two systems for fatty acid synthesis, one in the cytoplasm (catalyzed by fatty acid synthase, FASN) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, especially in higher eukaryotes, with the major product(s), metabolic roles, and cellular function(s) being essentially unknown. Here we show that hypomorphic mtFAS mutant mouse skeletal myoblast cell lines display a severe loss of electron transport chain (ETC) complexes and exhibit compensatory metabolic activities including reductive carboxylation. This effect on ETC complexes appears to be independent of protein lipoylation, the best characterized function of mtFAS, as mutants lacking lipoylation have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. Together, these data suggest that ETC activity in mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid synthesis with the oxidation of carbon fuels., eLife digest In human, plant and other eukaryotic cells, fats are an important source of energy and also play many other roles including waterproofing, thermal insulation and energy storage. Eukaryotic cells have two systems that make the building blocks of fats (known as fatty acids) and one of these systems, called the mtFAS pathway, operates in small compartments known as mitochondria. This pathway only has one known product, a small fat molecule called lipoic acid, which mitochondria attach to several enzymes to allow them to work properly. The main role of mitochondria is to break down fats and other molecules to release chemical energy that powers many processes in cells. They achieve this using large groups of proteins known as ETC complexes. To build these complexes, families of proteins known as ETC assembly factors carefully coordinate the assembly of many proteins and small molecules into specific structures. However, it remains unclear precisely how this process works. Here, Nowinski et al. used a gene editing technique to mutate the genes encoding three enzymes in the mtFAS pathway in mammalian cells. The experiments found that the mutant cells had fewer ETC complexes and seemed to be less able to break down fats and other molecules than ‘normal’ cells. Furthermore, a family of ETC assembly factors were less stable in the mutant cells. These findings suggest that the mtFAS pathway controls how mitochondria assemble ETC complexes. Further experiments indicated that lipoic acid is not involved in the assembly of ETC complexes and that the mtFAS pathway produces another, as yet unidentified, product that regulates this process, instead. MEPAN syndrome is a rare neurological disorder that leads to progressive loss of control of movement, slurred speech and impaired vision in children. Patients with this syndrome have genetic mutations affecting components of the mtFAS pathway, therefore, a better understanding of how the pathway works may help researchers develop new treatments in the future. More broadly, these findings will have important ramifications for many other situations in which the activity of ETC complexes in mitochondria is modified.

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