N95 vs Half-face Respirator Wear in Surgical Trainees: Physiologic and Psychological Effects of Prolonged Use

Objectives: As specialists of the upper airway, otolaryngologists are at high risk for COVID-19 transmission. N95 and half-face respirator (HFR) masks are commonly worn, each with advantages in functionality and comfort. In this study, physiologic and psychological parameters of prolonged N95 vs HFR wear were compared. Study Design: Prospective crossover cohort study. Setting: Single academic tertiary care hospital. Methods: A prospective crossover cohort study was performed. Healthy otolaryngology trainees and medical students (N = 23) participated and wore N95 and HFR masks continuously for 3 hours each on separate days. Various measures were analyzed: vitals, spirometry variables, scores on the State-Trait Anxiety Inventory and HIT-6 (Headache Impact Test–6), distress, and “difficulty being understood.” Results: The average age was 26.3 years (SD, 3.42). There were no significant differences in vital signs and spirometry variables between N95 and HFR wear. N95 wear was associated with decreases in oxygen saturation of approximately 1.09% more than with HFRs (95% CI, 0.105-2.077). State-Trait Anxiety Inventory scores increased more with HFR wear when compared with mean changes with N95 wear (95% CI, 1.350-8.741). There were no significant differences in HIT-6 scores or distress levels between masks. The proportions of participants reporting difficulty being understood was significantly higher with HFRs. Conclusions: Oxygen saturation decreases with prolonged N95 wear, but anxiety and difficulty being understood are greater with HFR wear. Although HFRs have less resistance to gas exchange, N95 respirators may produce less anxiety and distress in clinical situations. Further studies are warranted to evaluate the clinical significance of these differences. Level of Evidence: 2

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<p><b>Pod-IVR Pharmacokinetics in macaques</b> (A) <i>In vivo</i> release of TDF and FTC from each pod-IVR (N = 6/time point) over the course of the efficacy study determined by residual drug measurements from the pod-IVRs that were in place for 19 weeks with IVRs exchanged for new devices every 2 weeks. The top and bottom of the boxes show the 75th and 25th percentiles, respectively, and the line in the middle of the box is the median value. The dotted lines show the mean (N = 6) <i>in vivo</i> release from identical pod-IVRs obtained during the PK study preceding this efficacy study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157061#pone.0157061.ref026" target="_blank">26</a>]. (B) <i>In vivo</i> release profile for individual macaques (T1-T6) shows variability between animals. (C) TDF, TFV, TDF+TFV, and FTC levels in vaginal fluids collected at each ring exchange. Vaginal fluids were collected with Weck-Cel sponges proximal and distal to the pod-IVR placement. The dotted horizontal lines correspond to the medians from our previous PK study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157061#pone.0157061.ref026" target="_blank">26</a>]. Left panels-proximal; Right panels-distal; Dots-median.</p

Molecular regulation of auditory hair cell death and approaches to protect sensory receptor cells and/or stimulate repair following acoustic trauma

International audienceLoss of auditory sensory hair cells (HCs) is the most common cause of hearing loss. This review addresses the signaling pathways that are involved in the programmed and necrotic cell death of auditory HCs that occur in response to ototoxic and traumatic stressor events. The roles of inflammatory processes, oxidative stress, mitochondrial damage, cell death receptors, members of the mitogen-activated protein kinase (MAPK) signal pathway and pro- and anti-cell death members of the Bcl-2 family are explored. The molecular interaction of these signal pathways that initiates the loss of auditory HCs following acoustic trauma is covered and possible therapeutic interventions that may protect these sensory HCs from loss via apoptotic or non-apoptotic cell death are explored

Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells

Neurofibromatosis type 2 (NF2) is a genetic syndrome that predisposes individuals to multiple benign tumors of the central and peripheral nervous systems, including vestibular schwannomas. Currently, there are no FDA approved drug therapies for NF2. Loss of function of merlin encoded by the NF2 tumor suppressor gene leads to activation of multiple mitogenic signaling cascades, including platelet-derived growth factor receptor (PDGFR) and SRC in Schwann cells. The goal of this study was to determine whether ponatinib, an FDA-approved ABL/SRC inhibitor, reduced proliferation and/or survival of merlin-deficient human Schwann cells (HSC). Merlin-deficient HSC had higher levels of phosphorylated PDGFRα/β, and SRC than merlin-expressing HSC. A similar phosphorylation pattern was observed in phospho-protein arrays of human vestibular schwannoma samples compared to normal HSC. Ponatinib reduced merlin-deficient HSC viability in a dose-dependent manner by decreasing phosphorylation of PDGFRα/β, AKT, p70S6K, MEK1/2, ERK1/2 and STAT3. These changes were associated with decreased cyclin D1 and increased p27Kip1levels, leading to a G1 cell-cycle arrest as assessed by Western blotting and flow cytometry. Ponatinib did not modulate ABL, SRC, focal adhesion kinase (FAK), or paxillin phosphorylation levels. These results suggest that ponatinib is a potential therapeutic agent for NF2-associated schwannomas and warrants further in vivo investigation

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

Luminous Infrared Galaxies with the Submillimeter Array: II. Comparing the CO(3-2) Sizes and Luminosities of Local and High-Redshift Luminous Infrared Galaxies

We present a detailed comparison of the CO(3-2) emitting molecular gas between a local sample of luminous infrared galaxies (U/LIRGs) and a high redshift sample that comprises submm selected galaxies (SMGs), quasars, and Lyman Break Galaxies (LBGs). The U/LIRG sample consists of our recent CO(3-2) survey using the Submillimeter Array while the CO(3-2) data for the high redshift population are obtained from the literature. We find that the L(CO(3-2)) and L(FIR) relation is correlated over five orders of magnitude, which suggests that the molecular gas traced in CO(3-2) emission is a robust tracer of dusty star formation activity. The near unity slope of 0.93 +/- 0.03 obtained from a fit to this relation suggests that the star formation efficiency is constant to within a factor of two across different types of galaxies residing in vastly different epochs. The CO(3-2) size measurements suggest that the molecular gas disks in local U/LIRGs (0.3 - 3.1 kpc) are much more compact than the SMGs (3 - 16 kpc), and that the size scales of SMGs are comparable to the nuclear separation (5 - 40 kpc) of the widely separated nuclei of U/LIRGs in our sample. We argue from these results that the SMGs studied here are predominantly intermediate stage mergers, and that the wider line-widths arise from the violent merger of two massive gas-rich galaxies taking place deep in a massive halo potential.Comment: 16 pages, 5 figures, ApJ Accepte

Epilepsy in Dcx Knockout Mice Associated with Discrete Lamination Defects and Enhanced Excitability in the Hippocampus

Patients with Doublecortin (DCX) mutations have severe cortical malformations associated with mental retardation and epilepsy. Dcx knockout (KO) mice show no major isocortical abnormalities, but have discrete hippocampal defects. We questioned the functional consequences of these defects and report here that Dcx KO mice are hyperactive and exhibit spontaneous convulsive seizures. Changes in neuropeptide Y and calbindin expression, consistent with seizure occurrence, were detected in a large proportion of KO animals, and convulsants, including kainate and pentylenetetrazole, also induced seizures more readily in KO mice. We show that the dysplastic CA3 region in KO hippocampal slices generates sharp wave-like activities and possesses a lower threshold for epileptiform events. Video-EEG monitoring also demonstrated that spontaneous seizures were initiated in the hippocampus. Similarly, seizures in human patients mutated for DCX can show a primary involvement of the temporal lobe. In conclusion, seizures in Dcx KO mice are likely to be due to abnormal synaptic transmission involving heterotopic cells in the hippocampus and these mice may therefore provide a useful model to further study how lamination defects underlie the genesis of epileptiform activities