The role of the clinically obtained acoustic reflex as a research tool for sub-clinical hearing pathologies

The acoustic reflex (AR) shows promise as an objective test for the presence of cochlear synaptopathy in rodents. The AR has also been shown to be reduced in humans with tinnitus compared to those without. The aim of the present study was twofold: (a) to determine if AR strength (quantified as both threshold and growth) varied with lifetime noise exposure, and thus provided an estimate of the degree of synaptopathy and (b) to identify which factors should be considered when using the AR as a quantitative measure rather than just present/absent responses. AR thresholds and growth functions were measured using ipsilateral and contralateral, broadband and tonal elicitors in adults with normal hearing and varying levels of lifetime noise exposure. Only the clinical standard 226 Hz probe tone was used. AR threshold and growth were not related to lifetime noise exposure, suggesting that routine clinical AR measures are not a sensitive measure when investigating the effects of noise exposure in audiometrically normal listeners. Our secondary, exploratory analyses revealed that AR threshold and growth were significantly related to middle-ear compliance. Listeners with higher middle-ear compliance (though still in the clinically normal range) showed lower AR thresholds and steeper AR growth functions. Furthermore, there was a difference in middle-ear compliance between the sexes, with males showing higher middle-ear compliance values than females. Therefore, it may be necessary to factor middle-ear compliance values into any analysis that uses the AR as an estimate of auditory function

Intestinal barrier tightening by a cell-penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis.

Patients afflicted with ulcerative colitis (UC) are at increased risk of colorectal cancer. While its causes are not fully understood, UC is associated with defects in colonic epithelial barriers that sustain inflammation of the colon mucosa caused by recruitment of lymphocytes and neutrophils into the lamina propria. Based on genetic evidence that attenuation of the bridging integrator 1 (Bin1) gene can limit UC pathogenicity in animals, we have explored Bin1 targeting as a therapeutic option. Early feasibility studies in the dextran sodium sulfate mouse model of experimental colitis showed that administration of a cell-penetrating Bin1 monoclonal antibody (Bin1 mAb 99D) could prevent lesion formation in the colon mucosa in part by preventing rupture of lymphoid follicles. In vivo administration of Bin1 mAb altered tight junction protein expression and cecal barrier function. Strikingly, electrophysiology studies in organ cultures showed that Bin1 mAb could elevate resistance and lowe

Investigating the Role of Brain Natriuretic Peptide (BNP) and N-Terminal-proBNP in Thrombosis and Acute Ischemic Stroke Etiology

Acute ischemic stroke; Brain natriuretic peptide; ThrombusIctus isquèmic agut; Pèptid natriurètic cerebral; TrombeIctus isquémico agudo; Péptido natriurético cerebral; TromboThe need for biomarkers for acute ischemic stroke (AIS) to understand the mechanisms implicated in pathological clot formation is critical. The levels of the brain natriuretic peptides known as brain natriuretic peptide (BNP) and NT-proBNP have been shown to be increased in patients suffering from heart failure and other heart conditions. We measured their expression in AIS clots of cardioembolic (CE) and large artery atherosclerosis (LAA) etiology, evaluating their location inside the clots, aiming to uncover their possible role in thrombosis. We analyzed 80 thrombi from 80 AIS patients in the RESTORE registry of AIS clots, 40 of which were of CE and 40 of LAA etiology. The localization of BNP and NT-BNP, quantified using immunohistochemistry and immunofluorescence, in AIS-associated white blood cell subtypes was also investigated. We found a statistically significant positive correlation between BNP and NT-proBNP expression levels (Spearman’s rho = 0.668 p < 0.0001 *). We did not observe any statistically significant difference between LAA and CE clots in BNP expression (0.66 [0.13–3.54]% vs. 0.53 [0.14–3.07]%, p = 0.923) or in NT-proBNP expression (0.29 [0.11–0.58]% vs. 0.18 [0.05–0.51]%, p = 0.119), although there was a trend of higher NT-proBNP expression in the LAA clots. It was noticeable that BNP was distributed throughout the thrombus and especially within platelet-rich regions. However, NT-proBNP colocalized with neutrophils, macrophages, and T-lymphocytes, suggesting its association with the thrombo-inflammatory process.This publication has emanated from research conducted with the financial support of Science Foundation Ireland (SFI) and is co-funded by the European Regional Development Fund under Grant Number 13/RC/2073_2. Furthermore, it was supported by the industrial partner Cerenovus

"I worry about money every day": The financial stress of second-level initial teacher education in Ireland

In Ireland, the past ten years have seen the emergence of new policies and practices in initial teacher education (ITE) in response to national priorities and the professed aim of progressing standards. A key mechanism of this process was to universally extend the duration of postgraduate ITE programs from twelve to twenty-four months to broaden student teachers' professional development. While this has been a positive move in many aspects, it has also been rendered problematic due to the inability of policymakers to reconstruct financial mechanisms to support student teacher enrolment, retention and progression. This paper examines second-level student teachers' experiences (N = 391) regarding the costs, both financial and emotional, of becoming a teacher in Ireland. The results show that while enrolled on their ITE course, there is a mean deficit of €151 per week in student teacher spending. Over 40% of student teachers rely on their family and/or partner to fund their participation. The qualitative data reveals that this has a huge impact on their personal and family finances and leads to high levels of financial stress. Suggestions on how this financial pressure could be alleviated include paid teaching while on school placement and lowering the cost of the course

Estimating the impact of alternative programmatic cotrimoxazole strategies on mortality among children born to mothers with HIV: A modelling study

BACKGROUND: World Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed. METHODS AND FINDINGS: Using a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV. Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d'Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis. CONCLUSIONS: Changing current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings

Structural and functional properties of subsidiary atrial pacemakers in a goat model of sinus node disease

Background: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases.Methods: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through an ablation catheter and surface electrocardiogram (ECG). Structural characterization of the goat SAN and SAP was assessed by histology and immunofluorescence techniques.Results: When the SAN was ablated, SAPs featured a shortened atrioventricular conduction, consistent with the location in proximity of atrioventricular junction. SAP recovery time showed significant prolongation compared to the SAN recovery time, followed by a decrease over a follow-up of 4 weeks. Like the SAN tissue, the SAP expressed the main isoform of pacemaker hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Na+/Ca2+ exchanger 1 (NCX1) and no high conductance connexin 43 (Cx43). Structural characterization of the right atrium (RA) revealed that the SAN was located at the earliest activation [i.e., at the junction of the superior vena cava (SVC) with the RA] and was surrounded by the paranodal-like tissue, extending down to the inferior vena cava (IVC). Emerged SAPs were localized close to the IVC and within the thick band of the atrial muscle known as the crista terminalis (CT).Conclusions: SAN ablation resulted in the generation of chronic SAP activity in 60% of treated animals. SAP displayed development over time and was located within the previously discovered PNA in humans, suggesting its role as dominant pacemaker in SND. Therefore, SAP in goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning pacemaker

Marginal structural models for repeated measures where intercept and slope are correlated: An application exploring the benefit of nutritional supplements on weight gain in HIV-infected children initiating antiretroviral therapy

BackgroundThe impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear.MethodsIn the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications.ResultsIn simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction.DiscussionThis study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures