Prognostic factors for outcomes of idiopathic sudden sensorineural hearing loss: protocol for the SeaSHeL national prospective cohort study

INTRODUCTION: The mainstay of treatment for idiopathic sudden sensorineural hearing loss (SSNHL) includes oral steroids, intratympanic steroid injections or a combination of both. The National Institute for Health and Care Excellence, in their recent hearing loss guidelines, highlighted the paucity of evidence assessing the comparative effectiveness of these treatments; and the National Institute for Health Research (NIHR) Health Technology Assessment Programme has since released a commissioned call for a trial to identify the most effective route of administration of steroids as a first-line treatment for idiopathic SSNHL. For such trials to be run effectively, reliable information is needed on patients with SSNHL: where they present, numbers, demographics, treatment pathways, as well as outcomes. This study will collect these data in a nationwide cohort study of patients presenting with SSNHL across 97 National Health Service (NHS) trusts. The study will be delivered through ear, nose and throat (ENT) trainee networks, the NIHR Clinical Research Network (CRN) Audiology Champions and the NIHR CRN. Importantly, this study will also provide a dataset to develop a prognostic model to predict recovery for patients with idiopathic SSNHL. The study objectives are to: (1) map the patient pathway and identify the characteristics of adult patients presenting to NHS ENT and hearing services with SSNHL, (2) develop a prognostic model to predict recovery for patients with idiopathic SSNHL and (3) establish the impact of idiopathic SSNHL on patients' quality of life (QoL). METHODS AND ANALYSIS: Study design: national multicentre prospective cohort study across 97 NHS trusts. INCLUSION CRITERIA: adult patients presenting to NHS ENT and hearing services with SSNHL. OUTCOMES: change in auditory function; change in QoL score. ANALYSIS: multivariable prognostic model, using prespecified candidate predictors. Mean change in QoL scores will be calculated from initial presentation to follow-up. ETHICS AND DISSEMINATION: Health Research Authority and NHS Research Ethics Committee approved the study. Publication will be on behalf of study sites and collaborators. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04108598)

Age-Related Differences in Susceptibility to Carcinogenesis: A Quantitative Analysis of Empirical Animal Bioassay Data

In revising cancer risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) analyzed animal cancer bioassay data over different periods of life. In this article, we report an improved analysis of these data (supplemented with some chemical carcinogenesis observations not included in the U.S. EPA’s original analysis) and animal bioassay studies of ionizing radiation. We use likelihood methods to avoid excluding cases where no tumors were observed in specific groups. We express dosage for animals of different weights on a metabolically consistent basis (concentration in air or food, or per unit body weight to the three-quarters power). Finally, we use a system of dummy variables to represent exposures during fetal, preweaning, and weaning–60-day postnatal periods, yielding separate estimates of relative sensitivity per day of dosing in these intervals. Central estimate results indicate a 5- to 60-fold increased carcinogenic sensitivity in the birth–weaning period per dose ÷ (body weight(0.75)-day) for mutagenic carcinogens and a somewhat smaller increase—centered about 5-fold—for radiation carcinogenesis per gray. Effects were greater in males than in females. We found a similar increased sensitivity in the fetal period for direct-acting nitrosoureas, but no such increased fetal sensitivity was detected for carcinogens requiring metabolic activation. For the birth–weaning period, we found an increased sensitivity for direct administration to the pups similar to that found for indirect exposure via lactation. Radiation experiments indicated that carcinogenic sensitivity is not constant through the “adult” period, but the dosage delivered in 12- to 21-month-old animals appears a few-fold less effective than the comparable dosage delivered in young adults (90–105 days of age)

Silicon Mie Resonators for Highly Directional Light Emission from monolayer MoS2

Controlling light emission from quantum emitters has important applications ranging from solid-state lighting and displays to nanoscale single-photon sources. Optical antennas have emerged as promising tools to achieve such control right at the location of the emitter, without the need for bulky, external optics. Semiconductor nanoantennas are particularly practical for this purpose because simple geometries, such as wires and spheres, support multiple, degenerate optical resonances. Here, we start by modifying Mie scattering theory developed for plane wave illumination to describe scattering of dipole emission. We then use this theory and experiments to demonstrate several pathways to achieve control over the directionality, polarization state, and spectral emission that rely on a coherent coupling of an emitting dipole to optical resonances of a Si nanowire. A forward-to-backward ratio of 20 was demonstrated for the electric dipole emission at 680 nm from a monolayer MoS2 by optically coupling it to a Si nanowire

Outline of a Genome Navigation System Based on the Properties of GA-Sequences and Their Flanks

Introducing a new method to visualize large stretches of genomic DNA (see Appendix S1) the article reports that most GA-sequences [1] shared chains of tetra-GA-motifs and contained upstream poly(A)-segments. Although not integral parts of them, Alu-elements were found immediately upstream of all human and chimpanzee GA-sequences with an upstream poly(A)-segment. The article hypothesizes that genome navigation uses these properties of GA-sequences in the following way. (1) Poly(A) binding proteins interact with the upstream poly(A)-segments and arrange adjacent GA-sequences side-by-side (‘GA-ribbon’), while folding the intervening DNA sequences between them into loops (‘associated DNA-loops’). (2) Genome navigation uses the GA-ribbon as a search path for specific target genes that is up to 730-fold shorter than the full-length chromosome. (3) As to the specificity of the search, each molecule of a target protein is assumed to catalyze the formation of specific oligomers from a set of transcription factors that recognize tetra-GA-motifs. Their specific combinations of tetra-GA motifs are assumed to be present in the particular GA-sequence whose associated loop contains the gene for the target protein. As long as the target protein is abundant in the cell it produces sufficient numbers of such oligomers which bind to their specific GA-sequences and, thereby, inhibit locally the transcription of the target protein in the associated loop. However, if the amount of target protein drops below a certain threshold, the resultant reduction of specific oligomers leaves the corresponding GA-sequence ‘denuded’. In response, the associated DNA-loop releases its nucleosomes and allows transcription of the target protein to proceed. (4) The Alu-transcripts may help control the general background of protein synthesis proportional to the number of transcriptionally active associated loops, especially in stressed cells. (5) The model offers a new mechanism of co-regulation of protein synthesis based on the shared segments of different GA-sequences

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined "fuzziness", often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs. © 2013 Song et al

Consumer satisfaction with primary care provider choice and associated trust

BACKGROUND: Development of managed care, characterized by limited provider choice, is believed to undermine trust. Provider choice has been identified as strongly associated with physician trust. Stakeholders in a competitive healthcare market have competing agendas related to choice. The purpose of this study is to analyze variables associated with consumer's satisfaction that they have enough choice when selecting their primary care provider (PCP), and to analyze the importance of these variables on provider trust. METHODS: A 1999 randomized national cross-sectional telephone survey conducted of United States residential households, who had a telephone, had seen a medical professional at least twice in the past two years, and aged ≥ 20 years was selected for secondary data analyses. Among 1,117 households interviewed, 564 were selected as the final sample. Subjects responded to a core set of questions related to provider trust, and a subset of questions related to trust in the insurer. A previously developed conceptual framework was adopted. Linear and logistic regressions were performed based on this framework. RESULTS: Results affirmed 'satisfaction with amount of PCP choice' was significantly (p < .001) associated with provider trust. 'PCP's care being extremely effective' was strongly associated with 'satisfaction with amount of PCP choice' and 'provider trust'. Having sought a second opinion(s) was associated with lower trust. 'Spoke to the PCP outside the medical office,' 'satisfaction with the insurer' and 'insurer charges less if PCP within network' were all variables associated with 'satisfaction with amount of PCP choice' (all p < .05). CONCLUSION: This study confirmed the association of 'satisfaction with amount of PCP choice' with provider trust. Results affirmed 'enough PCP choice' was a strong predictor of provider trust. 'Second opinion on PCP' may indicate distrust in the provider. Data such as 'trust in providers in general' and 'the role of provider performance information' in choice, though import in PCP choice, were not available for analysis and should be explored in future studies. Results have implications for rethinking the relationships among consumer choice, consumer behaviors in making trade-offs in PCP choice, and the role of healthcare experiences in 'satisfaction with amount of PCP choice' or 'provider trust.

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

Tonsillar ectopia in idiopathic scoliosis: does it play a role in the pathogenesis and prognosis or is it only an incidental finding?

ABSTRACT: BACKGROUND: There is an ongoing controversy about the significance of tonsillar ectopia among patients with idiopathic scoliosis (IS). AIM: To find out if tonsillar ectopia occurs more frequently among patients with IS and if it plays any etiological or prognostic role in IS. STUDY DESIGN: Retrospective study. METHODS: Retrospective analysis of 155 consecutive spine MRIs (79 patients with IS and 76 controls; aged 7-25 years; 55% were female) with regard to the position of the cerebellar tonsils in relation to foramen magnum and the sagittal diameter of foramen magnum. All images were evaluated independently by two neuroradiologists. Interobserver and intraobserver reliability analysis was performed by calculation of kappa-value, intraclass correlation coefficient, and systematic and random errors. The occurrence of tonsillar ectopia among patients with IS and controls was estimated and the association of tonsillar ectopia with different predictors has been tested. Statistical significance was set to P </= 0.05. RESULTS: The interobserver and intraobserver agreement with regard to the occurrence of tonsillar ectopia was almost perfect (kappa 0.84 and 0.89, respectively). Tonsillar ectopia was found in 37% of patients with IS compared with 13% among controls (p < 0.001 and odds ratio of 3.8, 95% CI 1.7-8.5). The occurrence of tonsillar ectopia was not associated with the severity of scoliotic deformity (p = 0.85), or rapid progression of scoliosis (p = 0.76). Neurological deficit occurs twice as frequently in patients with tonsillar ectopia as in those with no tonsillar ectopia. Two of five patients with tonsillar ectopia showed improvement of their neurological deficit after the surgical correction of scoliosis. CONCLUSION: As tonsillar ectopia is significantly more frequent among patients with IS and may exhibit some prognostic utility in patients with neurological deficit, we forward the hypothesis that tonsillar ectopia may play a role in the development of the deformity in some patients with IS. However, occurrence of tonsillar ectopia among 13% of controls precludes stating a definitive role of tonsillar ectopia in the pathogenesis of IS. Some patients with IS, tonsillar ectopia and neurological deficit showed neurological improvement following the surgical correction of scoliosis

Fuzzy-logic controlled genetic algorithm for the rail-freight crew-scheduling problem

AbstractThis article presents a fuzzy-logic controlled genetic algorithm designed for the solution of the crew-scheduling problem in the rail-freight industry. This problem refers to the assignment of train drivers to a number of train trips in accordance with complex industrial and governmental regulations. In practice, it is a challenging task due to the massive quantity of train trips, large geographical span and significant number of restrictions. While genetic algorithms are capable of handling large data sets, they are prone to stalled evolution and premature convergence on a local optimum, thereby obstructing further search. In order to tackle these problems, the proposed genetic algorithm contains an embedded fuzzy-logic controller that adjusts the mutation and crossover probabilities in accordance with the genetic algorithm’s performance. The computational results demonstrate a 10% reduction in the cost of the schedule generated by this hybrid technique when compared with a genetic algorithm with fixed crossover and mutation rates

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders