Psychiatric disorders are associated with accelerated aging and enhanced risk for neurodegenerative disorders. Brain aging is associated with molecular, cellular and structural changes that are robust on the group-level, yet show substantial inter-individual variability. Here we assessed deviations in gene expression from normal age-dependent trajectories, and tested their validity as predictors of risk for major mental illnesses and neurodegenerative disorders. We performed large-scale gene expression and genotype analyses in postmortem samples of two frontal cortical brain regions from 214 control subjects aged 20–90 years. Individual estimates of “molecular age” were derived from age-dependent genes, identified by robust regression analysis. Deviation from chronological age was defined as “delta age”. Genetic variants associated with deviations from normal gene expression patterns were identified by expression quantitative trait loci (cis-eQTL) of age-dependent genes or genome-wide association study (GWAS) on delta age, combined into distinct polygenic risk scores (PRS cis-eQTL and PRS GWAS ), and tested for predicting brain disorders or pathology in independent postmortem expression datasets and clinical cohorts. In these validation datasets, molecular ages, defined by 68 and 76 age-related genes for two brain regions respectively, were positively correlated with chronological ages (r=0.88/0.91), elevated in bipolar disorder (BP) and schizophrenia (SCZ), and unchanged in major depressive disorder (MDD). Exploratory analyses in independent clinical datasets show that PRSs were associated with SCZ and MDD diagnostics, and with cognition in SCZ and pathology in Alzheimer’s disease (AD). These results suggest that older molecular brain aging is a common feature of severe mental illnesses and neurodegeneration.
Oligometastasis in metastatic HPV-positive oropharyngeal SCC portends a better prognosis than polymetastasis.
Objectives: 1) Characterize the spectrum of airway anomalies in patients with craniosynostosis, and 2) identify clinical characteristics of these patients that may be associated with the development of airway anomalies.Methods: This study is a retrospective case series assessing the type and frequency of airway anomalies in all patients with craniosynostosis seen at a tertiary-care children's hospital between 2000 and 2016. Cohort analyses were then performed to identify differences in airway anomalies dependent on syndromic associations, multisutural fusion, and location of suture fusion. Clinical characteristics examined included demographics and additional neurologic and craniofacial abnormalities.Results: Four hundred and ninety-six patients with craniosynostosis (83.5% white, 64.5% male; 33.9% sagittal, 28.8% metopic, 11.5% coronal, 1.2% lambdoid, and 24.6% multisutural) were included. Notable airway anomalies included the following: 13.3% adenotonsillar hypertrophy, 8.9% laryngomalacia, 7.3% tracheomalacia, 7.1% subglottic stenosis, 4.0% bronchomalacia, 3.8% laryngeal cleft, and 1.2% vocal fold paresis. Multisutural craniosynostosis patients (n = 122) were more likely to have obstructive sleep apnea (P = 0.005), adenotonsillar hypertrophy (P = 0.014), tracheomalacia (P = 0.011), subglottic stenosis (P < 0.001), and epiglottic/base of tongue collapse (P = 0.003) and require tracheostomy (P = 0.001) and mechanical ventilation (P = 0.017) compared with single suture craniosynostosis. Syndromic craniosynostosis patients (n = 33) were more likely to have obstructive sleep apnea (P < 0.001), laryngomalacia (P = 0.047), and subglottic stenosis (P = 0.009) compared with nonsyndromic patients.Conclusion: Airway anomalies are prevalent in patients with craniosynostosis; patients with multisutural or syndromic types have an increased risk of developing certain abnormalities. There should be a lower threshold for referral for airway evaluation in these populations.
Objective: To perform a systematic review with meta-analysis to investigate the utility of post-treatment PET/CT specifically in HPV-associated oropharyngeal squamous cell carcinoma following curative intent treatment. Methods: Random-effects meta-analysis was used to pool data from 7 observational studies (2013-2019) obtained from a database search of PubMed, Web of Science, and EMBASE using an a priori protocol with dual independent evaluation for inclusion, risk of bias assessment for acceptable methodology, and extraction of data for analysis. PET/CT results, treatment failure, imaging and interventions subsequent to PET/CT findings, and efficacy of salvage therapy were extracted. Results: Of the 907 post-treatment scans, PET/CT results were largely negative (76.2%; 95% CI, 63.4-85.6) and least often positive (11.3%; 95% CI, 8.8-14.4). PET/CT results were equivocal for 22.5% (95% CI, 12.5-36.9) and equivocal/positive for 34.2% of patients (95% CI, 25.1-44.5). Patients with an initial positive scan had the highest treatment failure rates (43.1%; 95% CI, 21.4-67.7) and those with an initial negative scan had the lowest rates (7.4%; 95% CI, 5.7-9.7). The equivocal and equivocal/positive scans had intermediate prevalence of 16.5% (95% CI, 9.4-27.6) and 16.7% (95% CI, 9.1-28.7), respectively. Conclusion: The low treatment failure rate following a negative PET/CT scan is reassuring, but the data are consistent with treatment failure rates up to 9.7% suggesting follow-up of these patients is prudent. Additionally, the low positive predictive value for treatment failure observed alludes to use of post-treatment PET/CT in HPV-associated disease frequently leading to unnecessary subsequent imaging and intervention.
Study of the neurodevelopmental molecular mechanisms of schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously used cell lines with neural progenitor properties (CNON) derived from superior or middle turbinates of patients with schizophrenia and control groups to study gene expression specific to schizophrenia. In this study, we compared single cell-RNA seq data from two CNON cell lines, one derived from an individual with schizophrenia (SCZ) and the other from a control group, with two biopsy samples from the middle turbinate (MT), also from an individual with SCZ and a control. In addition, we compared our data with previously published data from olfactory neuroepithelium (1). Our data demonstrated that CNON originated from a single cell type which is present both in middle turbinate and olfactory neuroepithelium. CNON express multiple markers of mesenchymal cells. In order to define relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data of embryonic brain (2) and found that the expression profile of CNON very closely matched one of the cell types in the embryonic brain. Finally, we evaluated differences between SCZ and control samples to assess usability and potential benefits of using single cell RNA-seq of CNON to study etiology of schizophrenia.
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