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Objectives:This study examined the subjective psychological and social effects of highly asymmetric hearing loss (single-sided deafness [SSD]) in adults.Design:Three group interviews were conducted using the critical incident technique and analysed using an inductive thematic analysis.Study sample:Eight adults with a clinical diagnosis of a moderately severe hearing loss or greater in one ear and normal or near-normal hearing in the other ear.Results:A range of functional hearing difficulties associated with SSD including impaired speech in background noise and reduced spatial awareness were reported to affect social and psychological well-being. Social consequences of SSD resulted from activity limitations and participation restrictions including withdrawal from and within situations. Participants reported psychological effects including worrying about losing the hearing in their other ear, embarrassment related to the social stigma attached to hearing loss and reduced confidence and belief in their abilities to participate.Conclusions: Single-sided deafness can be associated with many negative consequences. Counselling may help overcome the psychological consequences of hearing loss regardless of whether technological support such as a hearing aid is prescribed. The audiological management of these individuals should support the development of listening strategies and set appropriate expectations for participation in everyday listening situations. [ABSTRACT FROM AUTHOR]

We report a preregistered analysis to test whether children meeting diagnostic criteria for language disorder (LD) have higher self-reported and/or parent-reported mental health symptoms during the transition from primary to secondary education. Data are from a UK-based longitudinal cohort study, The Surrey Communication and Language in Education Study (SCALES). SCALES oversampled children at risk of LD at school entry. Language was measured using a battery of standardised assessments in Year 1 (age 5–6 years, n = 529), and mental health symptoms were measured using self and parent report in Year 6 (age 10–11 years, n = 384) and Year 8 (age 12–13 years, n = 246). Social experiences were also measured using self-report measures in Year 6. Mental health symptoms were stable during the transition from primary to secondary school. Symptom rates did not differ between children with and without LD based on self-report, but children with LD had higher parent-reported mental health symptoms than their peers with typical language. Similarly, early language was negatively associated with parent-reported but not self-reported mental health symptoms. Early language was associated with fewer child-reported positive social experiences in Year 6, but social experiences did not mediate the association between language and mental health. We found poor agreement between parent and self-reported child mental health symptoms across language groups. Future studies should aim to determine sources of disagreement between parent and child report, particularly for children with communication difficulties who may struggle to accurately self-report mental health symptoms. [ABSTRACT FROM AUTHOR]

Objective: Unilateral deafness and highly asymmetric hearing loss can impair listening abilities in everyday situations, create substantial audiological handicap, and reduce overall quality of life. Preliminary evidence suggests that cochlear implantation may be effective in reversing some of these detrimental effects. Patient-level data from existing studies were re-analysed to explore potential factors that may be predictive of improved speech perception scores following implantation.Methods: Logistic regression modelling examined whether improved speech perception following implantation under various listening conditions was related to the duration of deafness of the severe-to-profoundly deaf ear and/or the level of hearing in the better ear.Results: Patients with a shorter duration of deafness were more likely to improve in listening conditions that created a less favourable SNR at the implanted ear than the non-implanted ear. Those with more residual hearing in the better ear were more likely to improve in the listening condition that created a less favourable SNR at that ear.Discussion: The analysis suggests that characteristics of both ears may be relevant when seeking to identify those candidates who are likely to obtain benefit to speech perception following cochlear implantation. [ABSTRACT FROM AUTHOR]

Unilateral severe-to-profound hearing loss, or single-sided deafness (SSD), impairs listening abilities supported by the use of two ears, including speech perception in background noise and sound localisation. Hearing-assistive devices can aid listening by re-routing sounds from the impaired to the non-impaired ear or by restoring input to the impaired ear. A systematic review of the literature examined the impact of hearing-assistive devices on the health-related quality of life (HRQoL) of adults with SSD as measured using generic and disease-specific instruments. A majority of studies used observational designs, and the quality of the evidence was low to moderate. Only two studies used generic instruments. A mixed-effect meta-analysis of disease-specific measures suggested that hearing-assistive devices have a small-to-medium impact on HRQoL. The Speech, Spatial and Qualities of Hearing Scale and the Health Utilities Index Mark 3 (HUI3) were identified as instruments that are sensitive to device-related changes in disease-specific and generic HRQoL, respectively. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Unilateral severe-to-profound hearing loss, or single-sided deafness (SSD), impairs listening abilities supported by the use of two ears, including speech perception in background noise and sound localisation. Hearing-assistive devices can aid listening by re-routing sounds from the impaired to the non-impaired ear or by restoring input to the impaired ear. A systematic review of the literature examined the impact of hearing-assistive devices on the health-related quality of life (HRQoL) of adults with SSD as measured using generic and disease-specific instruments. A majority of studies used observational designs, and the quality of the evidence was low to moderate. Only two studies used generic instruments. A mixed-effect meta-analysis of disease-specific measures suggested that hearing-assistive devices have a small-to-medium impact on HRQoL. The Speech, Spatial and Qualities of Hearing Scale and the Health Utilities Index Mark 3 (HUI3) were identified as instruments that are sensitive to device-related changes in disease-specific and generic HRQoL, respectively. [ABSTRACT FROM AUTHOR]

The article discusses the history of women's protection clauses in constitutions worldwide and their role in the promotion of social change and equality. It explores the basic categories of these clauses including equal treatment for both gender, political guarantees for women and economic freedom. It examines the differences between the historical and legal backgrounds of Canadian Charter of Rights and Freedoms and Colombian Constitution, along with the lessons that could be learned on them.

Abstract: The investigation of drug delivery and metabolism requires the analysis of molecules in complicated biological matrices such as human serum. In NMR-based metabonomic analysis, T 2 relaxation editing with a CPMG filter is commonly used to suppress background signals from proteins and other endogenous components. Radio frequency pulse imperfections and incomplete irradiation across the spectral bandwidth can cause phase and baseline distortions in CPMG spectra. These distortions are exacerbated by water suppression techniques. Baseline correction methods included in commercially available data processing software packages may be incapable of producing artifact-free spectra. To increase the analytical precision of metabolic profiling, one NMR spectroscopist may be responsible for manually phasing and baseline correcting hundreds of spectra individually to remove operator-dependent variations, significantly reducing throughput. For metabonomic analysis of human serum, it was observed that the application of a pulsed field gradient filter produced 1H NMR spectra well suited to automatic phasing routines. Superior baseline characteristics, an increased tolerance to radio frequency pulse imperfections, and improved water suppression were achieved. A concomitant reduction in signal intensity compared with the CPMG method was easily recovered by increasing the number of scans. Principal component analysis (PCA) of spectra, acquired under a variety of experimental conditions, revealed the improved reproducibility and robustness of 1H NMR pulsed field gradient-filtered metabonomic analyses of serum compared to the CPMG method. [Copyright &y& Elsevier]

The utility of high-resolution magic-angle spinning (HR-MAS) NMR for studying drug delivery in whole tissues was explored by dosing female Sprague-Dawley rats with topical or injectable benzoic acid (BA). In principle, HR- MAS NMR permits the detection of both intra- and extracellular compounds. This is an advantage over the previous detection of topically applied BA using microdialysis coupled to HPLC/UV as microdialysis samples only the extracellular space. Skin and muscle samples were analyzed by 1H HR-MAS NMR, and BA levels were determined using an external standard solution added to the sample rotor. One to two percent of the BA topical dose was detected in the muscle, showing that BA penetrated through the dermal and subcutaneous layers. Since BA was not detected in the muscle in the microdialysis studies, the NMR spectra revealed the intracellular localization of BA. The amount of BA detected in muscle after subcutaneous injection correlated with the distance from the dosing site. Overall, the results suggest that HR- MAS NMR can distinguish differences in the local concentration of BA varying with tissue type, dosage method, and tissue proximity to the dosing site. The results illustrate the potential of this technique for quantitative analysis of drug delivery and distribution and the challenges to be addressed as the method is refined. [ABSTRACT FROM AUTHOR]

It is important to characterize drug-albumin binding during drug discovery and lead optimization as strong binding may reduce bioavailability and/or increase the drug's in vivo half-life. Despite knowing about the location of human serum albumin (HSA) drug binding sites and the residues important for binding, less is understood about the binding dynamics between exogenous drugs and endogenous fatty acids. In contrast to highly specific antibody-antigen interactions, the conformational flexibility of albumin allows the protein to adopt multiple conformations of approximately equal energy in order to accommodate a variety of ligands. Nuclear magnetic resonance (NMR) diffusion measurements are a simple way to quantitatively describe ligand-protein interactions without prior knowledge of the number of binding sites or the binding stoichiometry. This method can also provide information about ligand orientation at the binding site dye to buildup of exchange-transferred NOE (trNOE) on the diffusion time scale of the experiment. The results of NMR diffusion and NOE experiments reveal multiple binding interactions of HSA with dansylglycine, a drug site II probe, and caprylate, a medium-chain fatty acid that also has primary affinity for HSA's drug site II. Interligand NOE (ilNOE) detected in the diffusion analysis of a protein solution containing both ligands provides insight into the conformations adopted by these ligands while bound in common HSA binding pockets. The results demonstrate the ability of NMR diffusion experiments to identify ternary complex formation and show the potential of this method for characterizing other biologically important ternary structures, such as enzyme-cofactor-inhibitor complexes. [ABSTRACT FROM AUTHOR]

We recently attempted to generate an affinity chromatography adsorbent to purify cytochrome P450 4A1 by coupling 11-(1'-imidazolyl)-3,6,9-trioxaundecanoic acid to Toyopearl AF-Amino 650 M resin. Variations in ligand density for several resin batches were quantified by high-resolution magic-angle spinning (HR-MAS) NMR spectroscopy using a novel resin internal standard. The uniquely designed ImQ internal resin standard yields its signature resonance in a transparent region of the analyte spectrum making suppression of the polymer background unnecessary. This method enabled us to target a reasonable ligand density for enzyme purification and provides an advantageous alternative to quantitation against soluble standards or protonated solvent. [ABSTRACT FROM AUTHOR]

Examines the impact of transferred nuclear Overhauser (trNOE) on nuclear magnetic resonance diffusion measurements of ligand-protein binding. Impact of trNOE on the observed signal decay; Influence of trNOE on the measured signals of binding ligands; Use of trNOE to gain insight into ligand-protein interactions.

Many diffusion-ordered spectroscopy (DOSY) NMR techniques have recently been developed to aid in the deconvolution of complex mixtures. Spectroscopic separation based on chemical and physical properties facilitates the identification of mixture components while eliminating time-consuming separation steps and preserving the chemical environment. One way to improve resolution in such experiments is to spread the spectroscopic information into two dimensions. The 2D-J-DOSY experiment has been designed to resolve mixture components in terms of a chemical shift and proton coupling constant as well as distinguishing them on the basis of translational diffusion. Acquiring a series of spectra as a function of gradient amplitude permits the determination of diffusion coefficients for components that cannot be resolved in the one-dimensional (1D) 1H NMR spectrum. Comparison of the resulting values with those obtained through the traditional 1D diffusion experiment for a mixture of sugars validates The 2D-J-DOSY technique. [Copyright &y& Elsevier]

Following hematopoietic stem cell transplant (HSCT) for non-malignant diseases (NMD), mixed donor chimerism is a common occurrence in reduced toxicity myeloablative (RTM) and reduced intensity conditioning (RIC) conditioning regimens. Several strategies such as donor lymphocyte infusions (DLI), stem cell boost, or decreasing immune suppression are implemented with limited evidence to guide clinicians. We systematically assessed the effect of low mixed donor T chimerism on different HSCT morbidities and overall survival. At a single institution from 2012-2018 there were 112 HSCT for NMD. 88 patients were identified with 100% donor myeloid (CD33) chimerism at one month post-HSCT. Of the patients without 100% CD33 engraftment, 7 achieved and 9 failed to achieve 100% myeloid (CD33) chimerism one year post-HSCT. For the entire cohort 6 developed primary graft failure. CD3 and CD33 chimerisms were longitudinally assessed at 1, 3, 6, and 12 months post-HSCT. The analyzed cohort was further divided into subgroups (SG) of conditioning regimens: myeloablative busulfan (Bu) and cyclophosphamide (Cy) (SG1; n = 2), reduced toxicity myeloablative Bu-Cy-Fludarabine (Flu) (SG2; n = 35), Bu-Flu (SG3; n = 24), reduced intensity conditioning based on melphalan and Flu (SG4; n = 10), and Cy based immune-ablative regimens (SG5; n = 17). Acute and chronic graft versus host disease (GVHD), viral reactivation, need for DLI, and survival data were collected. The average age at HSCT was 8.8 years. The majority of patients received bone marrow grafts (4 cord and 7 peripheral stem cell infusions) and from a matched related donor (n = 51, 58%), MUD (n = 27, 31%), MMUD (n = 6, 7%), MMRD (n = 4, 5%). For the analyzed cohort overall survival was 95%. At 1 month post-HSCT, average T cell chimerism was lowest in SG3 (58.6%); other groups had similar higher T cell chimerism (SG1 84%, SG2 80.3%, SG4 86.8%, SG5 78.6%). When followed longitudinally, average T cell chimerism improved with time without need for additional intervention (Fig 1). Despite the disparity between T cell chimerism overall survival was not affected for SG3 (96%) and the rates of acute GVHD (37.5% v. 30.1%), chronic GVHD (8% v. 19%), and viral reactivation (8% v. 25%) was not significantly higher than rest of the analyzed cohort. Only 4 patients in the cohort were treated with DLI when the myeloid chimerism showed a decreasing trend (2 from SG3, 2 from SG4). Decreasing T cell chimerism can raise concern for impending graft failure in patients with NMD treated with RTM and RIC conditioning. In our cohort we have shown that in the majority of patients without pursuing DLI or a CD34 cell boost or changes in immune suppression, T cell chimerism continues to improve provided a robust myeloid graft. Patients with mixed T cell chimerism have an excellent survival rate, without increased second graft loss, GVHD, or viral reactivation. [ABSTRACT FROM AUTHOR]

The article presents information on diffusion measurements. Nuclear magnetic resonance (NMR) spectroscopy brings many advantages to the challenges faced by analytical chemists, such as mixture analysis. Many chromatographic techniques are routinely used to elicit information about mixture components. However, separation methods are both time-consuming and destructive to the sample. NMR spectroscopy isa non-destructive and quantitative analytical method that does not require pure standards for calibration. In addition, virtually all organic molecules have NMR-active nuclei thereby eliminating the need for sample derivatization.

Background: Adolescence is a period of heightened vulnerability to developing mental health problems, and rates of mental health disorder in this age group have increased in the last decade. Preventing mental health problems developing before they become entrenched, particularly in adolescents who are at high risk, is an important research and clinical target. Here, we report the protocol for the trial of the 'Building Resilience through Socioemotional Training' (ReSET) intervention. ReSET is a new, preventative intervention that incorporates individual-based emotional training techniques and group-based social and communication skills training. We take a transdiagnostic approach, focusing on emotion processing and social mechanisms implicated in the onset and maintenance of various forms of psychopathology. Methods: A cluster randomised allocation design is adopted with randomisation at the school year level. Five-hundred and forty adolescents (aged 12–14) will be randomised to either receive the intervention or not (passive control). The intervention is comprised of weekly sessions over an 8-week period, supplemented by two individual sessions. The primary outcomes, psychopathology symptoms and mental wellbeing, will be assessed pre- and post-intervention, and at a 1-year follow-up. Secondary outcomes are task-based assessments of emotion processing, social network data based on peer nominations, and subjective ratings of social relationships. These measures will be taken at baseline, post-intervention and 1-year follow-up. A subgroup of participants and stakeholders will be invited to take part in focus groups to assess the acceptability of the intervention. Discussion: This project adopts a theory-based approach to the development of a new intervention designed to target the close connections between young people's emotions and their interpersonal relationships. By embedding the intervention within a school setting and using a cluster-randomised design, we aim to develop and test a feasible, scalable intervention to prevent the onset of psychopathology in adolescence. Trial registration: ISRCTN88585916. Trial registration date: 20/04/2023. [ABSTRACT FROM AUTHOR]

Background Critically ill children are at risk of developing malnutrition, and undernutrition is a risk factor for morbidity and mortality. Objective The study evaluated changes in the energy and protein intake before and after implementation of nutrition support (NS) guidelines for a pediatric critical care unit (PICU). Design This retrospective study documented energy and protein intake for the first 8 days of PICU stay. Basal metabolic rate and protein needs were estimated by Schofield and American Society for Parenteral and Enteral Nutrition Guidelines, respectively. Participants/setting Three hundred thirty-five children from August to December 2012 (pre-implementation) and 185 from October to December 2013 (post-implementation). Intervention Implementation of NS Guidelines. Main outcome measures Changes in actual energy and protein intake in the post- compared with the pre-Implementation period. Statistical analysis performed Unpaired t tests, Pearson’s χ 2 (unadjusted analysis) were used. Logistic regressions were used to estimate odds ratios and 95% confidence intervals for protein and energy intake, adjusted for age, sex, and Pediatric Risk of Mortality score. Results After the implementation of guidelines, significant improvements were seen during days 5 through 8 in energy intake among children 2 years of age and older, and in protein intake in both age groups ( P <0.05). For the 8-day period, statistically or clinically significant improvements occurred in the cumulative protein deficit/kg/day, as follows: younger than 2-year-olds, −1.5±0.7 g/kg/day vs −1.3±0.8 g/kg/day, P =0.02; 2-year-olds or older, −1.0±0.6 g/kg/day vs −0.7±0.8 g/kg/day, P =0.01; and for the energy deficit/kg/d in 2-year-olds and older, −17.2±13.6 kcal/kg/day vs −13.3±18.1 kcal/kg/day, unpaired t test, P =0.07, in the pre- vs post-implementation period, respectively. Conclusions The implementation of NS guidelines was associated with improvements in total energy in 2-year-olds and older and protein in younger than 2 and 2 years and older children by days 5 through 8, and protein deficits were significantly lower in the post- vs the pre-implementation period. The implementation of NS guidelines may have had a positive effect on improving NS in critically ill children. [ABSTRACT FROM AUTHOR]

Purpose: T cell-Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis (T cell-EBV-HLH) is prevalent in East Asia and has poor prognosis. Understanding of this disease is limited, and literature regarding prevalence in North America is scarce. Herein, we summarize our experience. Methods: A retrospective analysis of T cell-EBV-HLH patients admitted to Children's Healthcare of Atlanta (GA, USA) from 2010 to 2020 was conducted. Additional immune studies were completed in a subset of patients. Results: We report 15 patients (10 months–19 years of age) diagnosed with T cell-EBV-HLH. Nine patients were Hispanic, and the majority did not have primary HLH (p-HLH) gene defects. Soluble interleukin-2 receptor levels in T cell-EBV-HLH were significantly higher than other forms of secondary-HLH but comparable to p-HLH, and it correlated with disease severity at presentation. Natural killer cell function was decreased in most patients despite a negative workup for p-HLH. Depending on disease severity, initial therapy included dexamethasone or dexamethasone and etoposide. Refractory patients were managed with blended regimens that included one or more of the following therapies: combination chemotherapy, alemtuzumab, emapalumab, and nivolumab. Rituximab did not appreciably decrease EBV viremia in most patients. Non-critically ill patients responded well to immunosuppressive therapy and are long-term survivors without undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Alemtuzumab resulted in inflammation flare in two of the three patients. Three patients underwent allogeneic HSCT, with disease relapse noted in one. At a median follow-up of 3 years, 10 of the 15 patients are alive. Conclusion: T cell-EBV-HLH occurs in the USA among the non-Asian populations, especially in those who are Hispanic. [ABSTRACT FROM AUTHOR]

The host-defense peptide (HDP) piscidin 1 (P1), isolated from the mast cells of striped bass, has potent activities against bacteria, viruses, fungi, and cancer cells and can also modulate the activity of membrane receptors. Given its broad pharmacological potential, here we used several approaches to better understand its interactions with multicomponent bilayers representing models of bacterial (phosphatidylethanolamine (PE)/phosphatidylglycerol) and mammalian (phosphatidylcholine/cholesterol (PC/Chol)) membranes. Using solid-state NMR, we solved the structure of P1 bound to PC/Chol and compared it with that of P3, a less potent homolog. The comparison disclosed that although both peptides are interfacially bound and α-helical, they differ in bilayer orientations and depths of insertion, and these differences depend on bilayer composition. Although Chol is thought to make mammalian membranes less susceptible to HDP-mediated destabilization, we found that Chol does not affect the permeabilization effects of P1. X-ray diffraction experiments revealed that both piscidins produce a demixing effect in PC/Chol membranes by increasing the fraction of the Chol-depleted phase. Furthermore, P1 increased the temperature required for the lamellar–to–hexagonal phase transition in PE bilayers, suggesting that it imposes positive membrane curvature. Patch-clamp measurements on the inner Escherichia coli membrane showed that P1 and P3, at concentrations sufficient for antimicrobial activity, substantially decrease the activating tension for bacterial mechanosensitive channels. This indicated that piscidins can cause lipid redistribution and restructuring in the microenvironment near proteins. We conclude that the mechanism of piscidin's antimicrobial activity extends beyond simple membrane destabilization, helping to rationalize its broader spectrum of pharmacological effects. [ABSTRACT FROM AUTHOR]

Abstract Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation. Highlights • Autoimmunity is a known manifestation of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. • Recurrent sinopulmonary infections and hypogammaglobinemia are not well recognized in IPEX syndrome. • IPEX, as other disorders involving regulatory T cells, can include a common variable immunodeficiency (CVID)-like presentation. • Expanded but dysregulated cTFH and B cell class switching defect could contribute to the development of hypogammaglobulinemia in some IPEX patients. [ABSTRACT FROM AUTHOR]

Abstract Anthrax toxin action requires triggering of natural endocytic transport mechanisms whereby the binding component of the toxin forms channels (PA 63) within endosomal limiting and intraluminal vesicle membranes to deliver the toxin's enzymatic components into the cytosol. Membrane lipid composition varies at different stages of anthrax toxin internalization, with intraluminal vesicle membranes containing ~70% of anionic bis(monoacylglycero)phosphate lipid. Using model bilayer measurements, we show that membrane lipids can have a strong effect on the anthrax toxin channel properties, including the channel-forming activity, voltage-gating, conductance, selectivity, and enzymatic factor binding. Interestingly, the highest PA 63 insertion rate was observed in bis(monoacylglycero)phosphate membranes. The molecular dynamics simulation data show that the conformational properties of the channel are different in bis(monoacylglycero)phosphate compared to PC, PE, and PS lipids. The anthrax toxin protein/lipid bilayer system can be advanced as a novel robust model to directly investigate lipid influence on membrane protein properties and protein/protein interactions. Graphical abstract Unlabelled Image Highlights • PA 63 channel activity, ion transport, AmPrβCD and LF N binding are lipid dependent. • In model bilayers, PA 63 activity is distinct in late endosomal DOBMP membranes. • MD simulations reveal different patterns in PA 63 conformational properties in DOBMP. • We propose a novel system to probe lipid influence on protein/protein interactions. [ABSTRACT FROM AUTHOR]

Tight regulation of pH is critical for the structure and function of cells and organelles. The pH environment changes dramatically along the endocytic pathway, an internalization transport process that is 'hijacked' by many intracellularly active bacterial exotoxins, including the anthrax toxin. Here, we investigate the role of pH on single-channel properties of the anthrax toxin protective antigen ( PA63). Using conductance and current noise analysis, blocker binding, ion selectivity, and poly(ethylene glycol) partitioning measurements, we show that the channel exists in two different open states ('maximum' and 'main') at pH ≥ 5.5, while only a maximum conductance state is detected at pH < 5.5. We describe two substantially distinct patterns of PA63 conductance dependence on KCl concentration uncovered at pH 6.5 and 4.5. [ABSTRACT FROM AUTHOR]