Neurocognitive Risk in Children With Cochlear Implants

IMPORTANCE Children who receive a cochlear implant (CI) for early severe to profound sensorineural hearing loss may achieve age-appropriate spoken language skills not possible before implantation. Despite these advances, reduced access to auditory experience may have downstream effects on fundamental neurocognitive processes for some children with CIs. OBJECTIVE To determine the relative risk (RR) of clinically significant executive functioning deficits in children with CIs compared with children with normal hearing (NH). DESIGN, SETTING, AND PARTICIPANTS In this prospective, cross-sectional study, 73 children at a hospital-based clinic who received their CIs before 7 years of age and 78 children with NH, with average to above average mean nonverbal IQ scores, were recruited in 2 age groups: preschool age (age range, 3–5 years) and school age (age range, 7–17 years). No children presented with other developmental, cognitive, or neurologic diagnoses. INTERVENTIONS Parent-reported checklist measures of executive functioning were completed during psychological testing sessions. MAIN OUTCOMES AND MEASURES Estimates of the RR of clinically significant deficits in executive functioning (≥ 1 SDs above the mean) for children with CIs compared with children with NH were obtained based on 2 parent-reported child behavior checklists of everyday problems with executive functioning. RESULTS In most domains of executive functioning, children with CIs were at 2 to 5 times greater risk of clinically significant deficits compared with children with NH. The RRs for preschoolers and school-aged children, respectively, were greatest in the areas of comprehension and conceptual learning (RR [95% CI], 3.56 [1.71–7.43] and 6.25 [2.64–14.77]), factual memory ( 4.88 [1.58–15.07] and 5.47 [2.03–14.77]), attention (3.38 [1.03–11.04] and 3.13 [1.56–6.26]), sequential processing (11.25 [1.55–81.54] and 2.44 [1.24–4.76]), working memory (4.13 [1.30–13.06] and 3.64 [1.61–8.25] for one checklist and 1.77 [0.82–3.83] and 2.78 [1.18–6.51] for another checklist), and novel problem-solving (3.93 [1.50–10.34] and 3.13 [1.46–6.67]). No difference between the CI and NH samples was found for visual-spatial organization (2.63 [0.76–9.03] and 1.04 [0.45–2.40] on one checklist and 2.86 [0.98–8.39] for school-aged children on the other checklist). CONCLUSIONS AND RELEVANCE A large proportion of children with CIs are at risk for clinically significant deficits across multiple domains of executive functioning, a rate averaging 2 to 5 times that of children with NH for most domains. Screening for risk of executive functioning deficits should be a routine part of the clinical evaluation of all children with deafness and CIs

Executive Functioning Skills in Preschool-Age Children With Cochlear Implants

Purpose The purpose of this study was to determine whether deficits in executive functioning (EF) in children with cochlear implants (CIs) emerge as early as the preschool years. Method Two groups of children ages 3 to 6 years participated in this cross-sectional study: 24 preschoolers who had CIs prior to 36 months of age and 21 preschoolers with normal hearing (NH). All were tested on normed measures of working memory, inhibition-concentration, and organization-integration. Parents completed a normed rating scale of problem behaviors related to EF. Comparisons of EF skills of children with CIs were made to peers with NH and to published nationally representative norms. Results Preschoolers with CIs showed significantly poorer performance on inhibition-concentration and working memory compared with peers with NH and with national norms. No group differences were found in visual memory or organization-integration. When data were controlled for language, differences in performance measures of EF remained, whereas differences in parent-reported problems with EF were no longer significant. Hearing history was generally unrelated to EF. Conclusions This is the first study to demonstrate that EF deficits found in older children with CIs begin to emerge as early as preschool years. The ability to detect these deficits early has important implications for early intervention and habilitation after cochlear implantation

Blood Omega-3 Fatty Acids Are Inversely Associated With Albumin-Creatinine Ratio in Young and Healthy Adults (The Omega-Kid Study).

Background: Omega-3 fatty acids are associated with a lower risk of cardiovascular disease (CVD) and with beneficial effects on CV risk factors. The albumin-creatinine ratio (ACR) is a risk factor for CVD, all-cause mortality and accelerated glomerular filtration rate (GFR) decline in the general population. We aimed to investigate the association between n-3 PUFAS and ACR in heathy individuals with preserved GFR. Design and Methods: The present cross-sectional analysis is part of the GAPP study, a population-based cohort of healthy adults aged 25-41 years. Individuals with known CVD, diabetes, or a BMI >35 kg/m2 were excluded. eGFR was calculated according to the combined Creatinine/Cystatin C CKD-EPI formula. ACR was obtained from a fasting morning urine sample. The Omega-3 Index (relative amount of EPA and DHA of total fatty acids in %) was obtained from whole blood aliquots. Results: Overall, 2001 participants (median age 37 years IQR 31; 40, 53% female) were included in this analysis. Median Omega-3 Index was 4.59 (IQR 4.06; 5.25) and median eGFR 111 ml/min/1.73 m2 (IQR 103; 118). Median ACR was 0.14 mg/mmol (IQR 0; 0.43). We found a significant inverse association of the Omega-3 Index with ACR (ratio 0.84, 95%CI 0.73-0.96; p = 0.011) which remained after comprehensive adjustment (ratio 0.86, 95%CI 0.74-1.00; p = 0.048). No association of the Omega-3 Index with eGFR was found. The adjusted difference in eGFR per 1-unit increase in Omega3-Index was -0.21 (95%CI -0.76; 0.35; p = 0.47). Conclusions: A higher Omega-3 Index was significantly associated with lower ACR in this young and healthy population with preserved eGFR. Omega-3 fatty acids may exhibit cardio- and nephroprotective effects in healthy individuals through modulation of ACR

S-nitrosocysteamine-functionalised porous graphene oxide nanosheets as nitric oxide delivery vehicles for cardiovascular applications

Nitric oxide (NO) is a key signalling molecule released by vascular endothelial cells that is essential for vascular health. Low NO bioactivity is associated with cardiovascular diseases, such as hypertension, atherosclerosis, and heart failure and NO donors are a mainstay of drug treatment. However, many NO donors are associated with the development of tolerance and adverse effects, so new formulations for controlled and targeted release of NO would be advantageous. Herein, we describe the design and characterisation of a novel NO delivery system via the reaction of acidified sodium nitrite with thiol groups that had been introduced by cysteamine conjugation to porous graphene oxide nanosheets, thereby generating S-nitrosated nanosheets. An NO electrode, ozone-based chemiluminescence and electron paramagnetic resonance spectroscopy were used to measure NO released from various graphene formulations, which was sustained at >5 × 10  mol cm min for at least 3 h, compared with healthy endothelium (cf. 0.5-4 × 10  mol cm min ). Single cell Raman micro-spectroscopy showed that vascular endothelial and smooth muscle cells (SMCs) took up graphene nanostructures, with intracellular NO release detected via a fluorescent NO-specific probe. Functionalised graphene had a dose-dependent effect to promote proliferation in endothelial cells and to inhibit growth in SMCs, which was associated with cGMP release indicating intracellular activation of canonical NO signalling. Chemiluminescence detected negligible production of toxic N-nitrosamines. Our findings demonstrate the utility of porous graphene oxide as a NO delivery vehicle to release physiologically relevant amounts of NO in vitro, thereby highlighting the potential of these formulations as a strategy for the treatment of cardiovascular diseases

Mitosis Phase Enrichment with Identification of Mitotic Centromere-Associated Kinesin As a Therapeutic Target in Castration-Resistant Prostate Cancer

The recently described transcriptomic switch to a mitosis program in castration-resistant prostate cancer (CRPC) suggests that mitotic proteins may be rationally targeted at this lethal stage of the disease. In this study, we showed upregulation of the mitosis-phase at the protein level in our cohort of 51 clinical CRPC cases and found centrosomal aberrations to also occur preferentially in CRPC compared with untreated, high Gleason–grade hormone-sensitive prostate cancer (P<0.0001). Expression profiling of chemotherapy-resistant CRPC samples (n = 25) was performed, and the results were compared with data from primary chemotherapy-naïve CRPC (n = 10) and hormone-sensitive prostate cancer cases (n = 108). Our results showed enrichment of mitosis-phase genes and pathways, with progression to both castration-resistant and chemotherapy-resistant disease. The mitotic centromere-associated kinesin (MCAK) was identified as a novel mitosis-phase target in prostate cancer that was overexpressed in multiple CRPC gene-expression datasets. We found concordant gene expression of MCAK between our parent and murine CRPC xenograft pairs and increased MCAK protein expression with clinical progression of prostate cancer to a castration-resistant disease stage. Knockdown of MCAK arrested the growth of prostate cancer cells suggesting its utility as a potential therapeutic target

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment