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Background: Apraxia of speech (AOS) is considered a disorder of speech planning or programming. Evidence for this stems from perceptual, acoustic, and electropalatographic investigations of articulation in AOS that revealed a delayed onset of anticipatory vowel gestures. Articulatory prolongation and syllable segregation have been attributed to a disturbance in anticipatory coarticulation. Aims: The aim of the current study was to investigate anticipatory lingual movement for consonantal gestures in AOS, and its impact on absolute and relative speech timing. Methods & Procedures: Tongue-tip movement and tongue-to-palate contact patterns were recorded for three speakers with AOS and a concomitant aphasia (age range = 35-63 years; M = 50.67 years; SD = 14.29) and five healthy talkers (age range = 29-65 years; M = 52.6 years; SD = 14.5) during the phrases 'a scarlet' and 'a sergeant', using electromagnetic articulography (EMA) (AG-200 system) and electropalatography (EPG) (Reading Electropalatograph system). Anticipatory lingual movement and speech timing were analysed during the final C1VC/C2 syllable in each of these phrases, where C represented an alveolar or postalveolar consonant. Specifically, tongue-tip displacement was calculated from the onset of release to the end of release of C1 to provide an indication of anticipatory lingual movement. With respect to speech timing, absolute (i.e., duration from time of maximum contact for C1 to time of maximum contact for C2) and relative (i.e., absolute duration expressed as a function of total syllable duration) durational measures were recorded, as was the stability of each. The results recorded for each of the participants with AOS were individually compared to those obtained by the control group. Outcomes & Results: The EMA results indicated that two participants with AOS exhibited reduced anticipatory lingual movement (i.e., greater tongue-tip displacement) during repetitions of 'sergeant'; however, all speakers produced a comparable tongue-tip displacement to that produced by the control group during the release of /l/ in 'scarlet'. The EPG results indicated that absolute duration was significantly prolonged during the final syllables of both stimuli for each of the apraxic speakers. Equivocal results were reported for relative timing and temporal stability. Conclusions: The results provide some preliminary evidence of reduced anticipatory lingual movement in AOS, and have demonstrated that this can have a significant impact on absolute speech timing. However, measures of relative timing were suggestive of either unimpaired or more extensive coarticulation. Additional research is required to resolve this issue. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to gather opinions and establish consensus among audiologists and patients on supporting individuals with mental health concerns in audiology settings., Design: Utilising a modified electronic Delphi survey, a panel of 25 experts engaged in three rounds of data collection over 12 weeks. Participants provided open-text responses in Round 1 describing "clinical practices that can be employed to support to patients presenting with mental health concerns", and the research team combined these with relevant clinical practices from literature searches. In subsequent rounds, panellists then rated their level of agreement with the combined list of statements; individually (Round 2) and again after seeing the panel's collated responses (Round 3)., Study Sample: Panel experts included 11 patients (adults with hearing loss; M age 73.8 years) and 14 audiologists (with M 11.8 years of experience working in audiology)., Results: Consensus was met for 123 items categorised into: Detection, Education, Effective Communication, Provision of Emotional Support, Personal Qualities and Attitudes of the Audiologist, Interventions, Connecting the Patient to Additional Support Services, Normal Processes that are Especially Important in these Cases, and Organisational Considerations., Conclusions: The study highlights the diversity of approaches audiologists can employ to support patients with mental health concerns.

Background: Mild traumatic brain injury (mTBI) affects 48 million people annually, with up to 30% experiencing long-term complaints such as fatigue, blurred vision, and poor concentration. Assessing neurophysiological features related to visual attention and outcome measures aids in understanding clinical symptoms and prognostication., Methods: We recorded EEG and eye movements in mTBI patients during a computerized task performed in the acute (< 24 h, TBI-A) and subacute phase (4-6 weeks thereafter). We estimated the posterior dominant rhythm, reaction times (RTs), fixation duration, and event-related potentials (ERPs). Clinical outcome measures were assessed using the Head Injury Symptom Checklist (HISC) and the Extended Glasgow Outcome Scale (GOSE) at 6 months post-injury. Similar analyses were performed in an age-matched control group (measured once). Linear mixed effect modeling was used to examine group differences and temporal changes within the mTBI group., Results: Twenty-nine patients were included in the acute phase, 30 in the subacute phase, and 19 controls. RTs and fixation duration were longer in mTBI patients compared to controls (p < 0.05), but not between TBI-A and TBI-S (p < 0.05). The frequency of the posterior dominant rhythm was significantly slower in TBI-A (0.6 Hz, p < 0.05) than TBI-S. ERP mean amplitude was significantly lower in mTBI patients than in controls. Neurophysiological features did not significantly relate to clinical outcome measures., Conclusion: mTBI patients demonstrate impaired processing speed and stimulus evaluation compared to controls, persisting up to 6 weeks after injury. Neurophysiological features in mTBI can assist in determining the extent and temporal progression of recovery., (© 2024. The Author(s).)

Objectives: The ask, inform, manage, encourage, refer (AIMER) program is a behavior change intervention designed to increase the frequency with which hearing healthcare clinicians (HHCs) ask about and provide information regarding mental wellbeing within adult audiology services. The objective of this study was to systematically evaluate the first iteration of the AIMER program to determine whether the intervention achieved the changes in HHC behaviors anticipated and to evaluate feasibility of implementing the AIMER program based on the implementation protocol., Design: The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to guide this evaluation. Data were collected from October 2020 to February 2022 and included both quantitative and qualitative measures (i.e., observation reports, staff surveys, clinical diaries, clinical file audits, and interviews)., Results: Comparison between pre- and post-implementation data showed that the AIMER intervention successfully increased: (i) HHC's skills and confidence for discussing mental wellbeing; (ii) how often HHCs ask about mental wellbeing within audiology consultations; (iii) how often HHCs provide personalized information and support regarding mental wellbeing within audiology consultations; and (iv) how often HHCs use mental wellbeing terms within clinical case notes and general practitioner reports. The factors affecting feasibility of implementing the AIMER program within the clinical setting could be classified into three major categories: (i) the AIMER program itself and its way of delivery to clinical staff; (ii) people working with the AIMER program; and (iii) contextual factors. Key recommendations to improve future implementation of the AIMER program were provided by the participants., Conclusions: The AIMER program was shown to be effective at increasing the frequency with which HHCs ask about and provide information regarding mental wellbeing within routine audiological service delivery. Implementation of the AIMER program was feasible but leaves room for improvement. Use of the reach, effectiveness, adoption, implementation, and maintenance framework facilitated systematic evaluation of multiple indicators providing a broad evaluation of the AIMER program. Our analysis helps to better understand the optimal levels of training and facilitation and provides recommendations to improve future scale-up of the AIMER program. The findings of this study will be used to further adapt and improve the AIMER program and to enhance program implementation strategies before its further dissemination., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [ 11 C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [ 11 C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [ 11 C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington's disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [ 11 C]BRD1158 human PET., Competing Interests: The authors declare the following competing financial interest(s): Dr. Jacob Hooker discloses the following relationships: Massachusetts Institute of Technology Consultant; American Chemical Society (ACS), ACS Publications, ACS Chemical Neuroscience Editorial Role; Eikonizo Therapeutics Co-Founder, Advisor; Sensorium Therapeutics Co-Founder, Advisor; Psy Therapeutics Consultant; Delix Therapeutics Advisor; Fuzionaire Diagnostics Advisor; Arclight Therapeutics Advisor; Proximity Therapeutics Advisor; Human Health Advisor, Rocket Science Health Advisor; Atai Life Sciences Sponsored research, training grant/gift. Dr. Beth Stevens discloses the following relationships: Beth Stevens serves on the scientific advisory board of Annexon Biosciences and is a minor shareholder of this company., (© 2024 The Authors. Published by American Chemical Society.)

Mycobacterium abscessus ( Mab ), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab Δ tetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab Δ tetV . These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti- Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections., Competing Interests: Competing interests statement:S.L.W., J.L., and R.E.L. disclose patent filings on this chemical series.

Objective: To explore the barriers and facilitators faced by hearing healthcare clinicians (HHCs) with respect to asking adults with hearing loss (HL) about their emotional well-being., Design: This qualitative study was conducted using semi-structured individual interviews and focus groups. The interview topic guide was developed based on the COM-B model., Study Sample: Fifteen HHCs of a single hearing services organisation in Western Australia across 13 clinic locations participated., Results: Barriers and facilitators that may influence HHCs' behaviour of routinely asking adults about their emotional well-being include having the knowledge and skills to ask about emotional well-being, forgetting to ask, awareness of the emotional impacts of HL, time and tools for asking, clients' reactions to being asked, supportive peers, normalisation of discussions relating to emotional well-being, presence of significant others, emotions associated with asking, being in the habit of asking, reminders, beliefs about consequences and confidence or capabilities, and scope of audiology practice., Conclusions: Application of the COM-B model identified barriers in capabilities (e.g. knowledge), opportunities (e.g. tools), and motivation (e.g. beliefs about benefits of asking about emotions) that need to be addressed for HHCs to ask their clients about their emotional well-being.

Objective: This study describes the development of an intervention to increase the frequency of audiologists' asking about and providing information regarding mental wellbeing within adult audiology services., Design: The Behaviour Change Wheel (BCW), an eight-step systematic process, was followed to develop the intervention. Reports describing the first four steps are published elsewhere. This report describes the final four steps and details the intervention developed., Results: A multifaceted intervention was developed to change audiologists' behaviours relating to providing mental wellbeing support to adults with hearing loss. Specifically, three behaviours were targeted: (1) asking clients about their mental wellbeing, (2) providing general information on the mental wellbeing impacts of hearing loss, and (3) providing personalised information on managing the mental wellbeing impacts of hearing loss. A variety of intervention functions and behaviour change techniques were incorporated into the intervention, including instruction and demonstration, information about others approval, adding objects to the environment, use of prompts/cues, and endorsement from credible sources., Conclusion: This study is the first to use the Behaviour Change Wheel to develop an intervention targeting mental wellbeing support behaviours in audiologists and confirms the usability and usefulness of the approach in a complex area of clinical care. The systematic development of the Ask, Inform, Manage, Encourage, Refer (AIMER) intervention will facilitate a thorough evaluation of its effectiveness in the next phase of this work., (© 2023. The Author(s).)

The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family, which includes JNK1-JNK3. Interestingly, JNK1 and JNK2 show opposing functions, with JNK2 activity favoring cell survival and JNK1 stimulating apoptosis. Isoform-selective small molecule inhibitors of JNK1 or JNK2 would be useful as pharmacological probes but have been difficult to develop due to the similarity of their ATP binding pockets. Here, we describe the discovery of a covalent inhibitor YL5084, the first such inhibitor that displays selectivity for JNK2 over JNK1. We demonstrated that YL5084 forms a covalent bond with Cys116 of JNK2, exhibits a 20-fold higher K inact / K I compared to that of JNK1, and engages JNK2 in cells. However, YL5084 exhibited JNK2-independent antiproliferative effects in multiple myeloma cells, suggesting the existence of additional targets relevant in this context. Thus, although not fully optimized, YL5084 represents a useful chemical starting point for the future development of JNK2-selective chemical probes.

Objective: To identify the barriers and facilitators of hearing healthcare clinicians (HHC) providing information to audiology consumers on (i) the mental health impacts of hearing loss, and (ii) management options for improving mental well-being., Design: A qualitative study using semi-structured individual and group interviews. Both the interview guide and the deductive process of data analysis were based on the COM-B model (Capabilities, Opportunities and Motivations required for Behaviour change)., Study Sample: Fifteen HHCs with between 2 and 25 years of clinical experience (mean 9.3)., Results: Psychological Capability barriers included lack of knowledge relating to mental health signs and symptoms, management options available, referral processes, and resources/tools to assist discussion of options. Social opportunity barriers included clients' lack of openness to receive mental health-related information from their HHC. Automatic motivation factors included feeling uncomfortable and helpless when discussing mental health. Reflective motivation factors included clinician's limiting beliefs concerning their role and responsibilities regarding provision of mental health support, and doubts about whether mental health services are truly beneficial for clients with hearing loss., Conclusion: Application of the COM-B model for behaviour change identified factors that need to be addressed to increase the provision of mental health information in the audiology setting.

Background: MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study., Objective: The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo., Methods: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension., Results: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks., Conclusions: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

There is a need for reliable predictors in patients with moderate to severe traumatic brain injury to assist clinical decision making. We assess the ability of early continuous EEG monitoring at the intensive care unit (ICU) in patients with traumatic brain injury (TBI) to predict long term clinical outcome and evaluate its complementary value to current clinical standards. We performed continuous EEG measurements in patients with moderate to severe TBI during the first week of ICU admission. We assessed the Extended Glasgow Outcome Scale (GOSE) at 12 months, dichotomized into poor (GOSE 1-3) and good (GOSE 4-8) outcome. We extracted EEG spectral features, brain symmetry index, coherence, aperiodic exponent of the power spectrum, long range temporal correlations, and broken detailed balance. A random forest classifier using feature selection was trained to predict poor clinical outcome based on EEG features at 12, 24, 48, 72 and 96 h after trauma. We compared our predictor with the IMPACT score, the best available predictor, based on clinical, radiological and laboratory findings. In addition we created a combined model using EEG as well as the clinical, radiological and laboratory findings. We included hundred-seven patients. The best prediction model using EEG parameters was found at 72 h after trauma with an AUC of 0.82 (0.69-0.92), specificity of 0.83 (0.67-0.99) and sensitivity of 0.74 (0.63-0.93). The IMPACT score predicted poor outcome with an AUC of 0.81 (0.62-0.93), sensitivity of 0.86 (0.74-0.96) and specificity of 0.70 (0.43-0.83). A model using EEG and clinical, radiological and laboratory parameters resulted in a better prediction of poor outcome (p < 0.001) with an AUC of 0.89 (0.72-0.99), sensitivity of 0.83 (0.62-0.93) and specificity of 0.85 (0.75-1.00). EEG features have potential use for predicting clinical outcome and decision making in patients with moderate to severe TBI and provide complementary information to current clinical standards., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome., Design, Setting, Participants, & Measurements: We randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 m 2 , to bardoxolone methyl ( n =77) or placebo ( n =80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight., Results: Patients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4; P <0.001] and 7.4 [95% confidence interval, 3.1 to 11.7; P =0.0008] ml/min per 1.73 m 2 , respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1; P <0.001) and 4.4 (95% confidence interval, 0.7 to 8.1; P =0.02) ml/min per 1.73 m 2 at 52 and 104 weeks, respectively. In a post hoc analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, -1.9 to 4.9] ml/min per 1.73 m 2 ). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure., Conclusions: In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different., Clinical Trial Registry Name and Registration Number: A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185., (Copyright © 2022 by the American Society of Nephrology.)

We compared intention to receive the seasonal influenza vaccine with a prospective coronavirus (COVID-19) vaccine among undecided or COVID-19 vaccine hesitant individuals to better understand the underlying differences and similarities in factors associated with vaccine intention. We delivered a cross-sectional online survey in October-November 2020. We included psychological constructs and sociodemographic variables informed by theory. We conducted pairwise comparisons and multiple linear regression models to explore associations between vaccine intention and psychological constructs. We recruited 1,660 participants, where 47.6% responded that they would likely receive the influenza vaccine, 31.0% that they would probably not accept the vaccination and 21.4% were unsure. In relation to the prospective COVID-19 vaccine, 39.0% responded that they would likely receive the vaccination, 23.7% that they would probably not accept the vaccination and 37.3% were unsure. Unique factors positively associated with COVID-19 vaccine intention were: perceived knowledge sufficiency about vaccine safety, beliefs about vaccine safety, and living in an area of low deprivation. The only unique factor positively associated with influenza intention was past influenza behavior. The strongest common predictors positively associated with intention were: favorable vaccine attitudes, the anticipated regret they may feel following infection if they were not to receive a vaccine, and the expectation from family or friends to accept the vaccine. Despite overall similarities in those factors associated with vaccination intention, we identified unique influences on intention. This additional insight will help support the planning and tailoring of future immunizations programmes for the respective viruses.

Toxoplasma gondii is a protozoan parasite capable of infecting any warm-blooded species and can increase risk-taking in intermediate hosts. Despite extensive laboratory research on the effects of T. gondii infection on behaviour, little is understood about the effects of toxoplasmosis on wild intermediate host behavior. Yellowstone National Park, Wyoming, USA, has a diverse carnivore community including gray wolves (Canis lupus) and cougars (Puma concolor), intermediate and definitive hosts of T. gondii, respectively. Here, we used 26 years of wolf behavioural, spatial, and serological data to show that wolf territory overlap with areas of high cougar density was an important predictor of infection. In addition, seropositive wolves were more likely to make high-risk decisions such as dispersing and becoming a pack leader, both factors critical to individual fitness and wolf vital rates. Due to the social hierarchy within a wolf pack, we hypothesize that the behavioural effects of toxoplasmosis may create a feedback loop that increases spatial overlap and disease transmission between wolves and cougars. These findings demonstrate that parasites have important implications for intermediate hosts, beyond acute infections, through behavioural impacts. Particularly in a social species, these impacts can surge beyond individuals to affect groups, populations, and even ecosystem processes., (© 2022. The Author(s).)

The peptide binding protein DppA is an ABC transporter found in prokaryotes that has the potential to be used as drug delivery tool for hybrid antibiotic compounds. Understanding the motifs and structures that bind to DppA is critical to the development of these bivalent compounds. This study focused on the biophysical analysis of the MtDppA from M. tuberculosis. Analysis of the crystal structure revealed a SVA tripeptide was co-crystallized with the protein. Further peptide analysis demonstrated MtDppA shows very little affinity for dipeptides but rather preferentially binds to peptides that are 3-4 amino acids in length. The structure-activity relationships (SAR) between MtDppA and tripeptides with varied amino acid substitutions were evaluated using thermal shift, SPR, and molecular dynamics simulations. Efforts to identify novel ligands for use as alternative scaffolds through the thermal shift screening of 35,000 compounds against MtDppA were unsuccessful, indicating that the MtDppA binding pocket is highly specialized for uptake of peptides. Future development of compounds that seek to utilize MtDppA as a drug delivery mechanism, will likely require a tri- or tetrapeptide component with a hydrophobic -non-acidic peptide sequence., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Fungal fatty acid (FA) synthase and desaturase enzymes are essential for the growth and virulence of human fungal pathogens. These enzymes are structurally distinct from their mammalian counterparts, making them attractive targets for antifungal development. However, there has been little progress in identifying chemotypes that target fungal FA biosynthesis. To accomplish this, we applied a whole-cell-based method known as Target Abundance-based FItness Screening using Candida albicans . Strains with varying levels of FA synthase or desaturase expression were grown in competition to screen a custom small-molecule library. Hit compounds were defined as preferentially inhibiting the growth of the low target-expressing strains. Dose-response experiments confirmed that 16 hits (11 with an acyl hydrazide core) differentially inhibited the growth of strains with an altered desaturase expression, indicating a specific chemical-target interaction. Exogenous unsaturated FAs restored C. albicans growth in the presence of inhibitory concentrations of the most potent acyl hydrazides, further supporting the primary mechanism being inhibition of FA desaturase. A systematic analysis of the structure-activity relationship confirmed the acyl hydrazide core as essential for inhibitory activity. This collection demonstrated broad-spectrum activity against Candida auris and mucormycetes and retained the activity against azole-resistant candida isolates. Finally, a preliminary analysis of toxicity to mammalian cells identified potential lead compounds with desirable selectivities. Collectively, these results establish a scaffold that targets fungal FA biosynthesis with a potential for development into novel therapeutics.

Early studies showed that 28-36% of UK adults were unsure or unwilling to be vaccinated against COVID-19. We wanted to identify which socio-demographic, socio-economic, personal health and psychological factors were associated with COVID-19 vaccine intentions (CVI) in adults living in England who did not want, yet to consider, or not sure whether to vaccinate. In October/November 2020, prior to vaccine availability, we surveyed adults stratified by gender, region, and deprivation, with additional purposive sampling of those aged 50 and over and those from an ethnic minority. Two hundred and ten did not want; 407 had yet to consider; and 1,043 were not sure whether to be vaccinated. Factors positively associated with CVI were: favorable vaccine views, trust in institutions associated with vaccine approval, vaccine subjective norms, anticipated regret of not having a vaccine, perceived vaccine benefits, perceived safety knowledge sufficiency, and a history of having an influenza vaccine. Factors negatively associated were: anti-lockdown views, and being a health or social care worker. Whilst showing significant relationships with CVI when analyzed in isolation, neighborhood deprivation and ethnicity did show an independent relationship to intention when all study measures were controlled for. Our findings suggest vaccine promotion focusing on the anticipated regret of not having a vaccine, the benefits of a mass COVID-19 immunization program, and the safety of a vaccine whilst ensuring or engendering trust in those bodies that brand a campaign may be most supportive of COVID-19 vaccine uptake.

Objective: Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA., Methods: We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks., Results: One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone., Interpretation: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

In a multinational placebo-controlled phase III clinical trial in 2,185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, treatment with the Nrf2 activator bardoxolone methyl increased estimated glomerular filtration rate, a measure of kidney function, but also resulted in increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase. These increases in liver enzyme level(s) were maximal after 4 weeks of treatment and reversible, trending back toward baseline through week 48. Total bilirubin concentrations did not increase, and no cases met Hy's Law criteria, although two subjects had ALT concentrations that exceeded 10 × the upper limit of the population reference range leading to discontinuation of treatment. Animal and cell culture experiments suggested that the increases in ALT and AST induced by bardoxolone methyl may be related to its pharmacological activity. Bardoxolone methyl significantly induced the mRNA expression of ALT and AST isoforms in cultured cells. Expression of ALT and AST isoforms in liver and kidney also positively correlated with Nrf2 status in mice. Overall, these data suggest that the increases in ALT and AST observed clinically were, at least in part, related to the pharmacological induction of aminotransferases via Nrf2 activation, rather than to any intrinsic form of hepatotoxicity., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome., Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR., Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy., Discussion/conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

In a globalized world, pandemics transmit impacts through markets. We document employment changes, coping strategies, and welfare of garment factory workers in Ethiopia's largest industrial park during the early stages of the Coronavirus Disease 2019 pandemic. We field a phone survey of female workers during a two month period in which cases are rapidly rising globally, but not locally. Our data suggest significant changes in employment, high levels of migration away from urban areas to rural areas if women are no longer working, and high levels of food insecurity. These findings compel a research and policy focus on documenting and mitigating the market-reach of pandemics on low-income workers at the margins., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Elsevier Ltd. All rights reserved.)

The cytoprotective transcriptor factor nuclear factor erythroid 2- related factor 2 (NRF2) is part of a complex regulatory network that responds to environmental cues. To better understand its role in a cluster of inflammatory and pro-oxidative burden of lifestyle diseases that accumulate with age, lessons can be learned from evolution, the animal kingdom and progeroid syndromes. When levels of oxygen increased in the atmosphere, mammals required ways to protect themselves from the metabolic toxicity that arose from the production of reactive oxygen species. The evolutionary origin of the NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signalling pathway from primitive origins has been a prerequisite for a successful life on earth, with checkpoints in antioxidant gene expression, inflammation, detoxification and protein homoeostasis. Examples from the animal kingdom suggest that superior antioxidant defense mechanisms with enhanced NRF2 expression have been developed during evolution to protect animals during extreme environmental conditions, such as deep sea diving, hibernation and habitual hypoxia. The NRF2-KEAP1 signalling pathway is repressed in progeroid (accelerated ageing) syndromes and a cluster of burden of lifestyle disorders that accumulate with age. Compelling links exist between tissue hypoxia, senescence and a repressed NRF2 system. Effects of interventions that activate NRF2, including nutrients, and more potent (semi)synthetic NRF2 agonists on clinical outcomes are of major interest. Given the broad-ranging actions of NRF2, we need to better understand the mechanisms of activation, biological function and regulation of NRF2 and its inhibitor, KEAP1, in different clinical conditions to ensure that modulation of this thiol-based system will not result in major adverse effects. Lessons from evolution, the animal kingdom and conditions of accelerated ageing clarify a major role of a controlled NRF2-KEAP1 system in healthy ageing and well-being., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Purpose: To evaluate the feasibility of Hear-Communicate-Remember, a training programme developed for family caregivers of people with dementia and hearing impairment that integrated hearing, communication and memory strategies, which was intended to be delivered via telehealth., Materials and Methods: Participants included six dyads consisting of adults with dementia and hearing impairment and their family caregivers. Data collection involved a combination of semi-structured interviews, self-report questionnaires and field notes., Results: Analysis of the qualitative interviews revealed four themes: appropriateness of intervention resources, considerations for the delivery of intervention via telehealth, knowledge and application of intervention strategies, and impact of the intervention on day-to-day life. Results from the satisfaction survey indicated that caregiver participants were mostly satisfied with all aspects of the intervention except the use of some technological components. The field notes described challenges with implementation via telehealth., Conclusions: Future research involving a cohort comparison study with a larger cohort of dyads is needed to establish treatment efficacy.

Objectives: Emotional and psychological well-being are essential to overall health, but there is little research showing how to approach emotional and psychological concerns in the audiological setting. This study investigated audiologists' self-reported clinical behaviors in response to emotional and psychological concerns and/or symptoms raised by audiology clients., Design: A sample of 83 Australia-based audiologists completed a survey including vignettes presenting older adults with hearing loss and experiencing symptoms consistent with either depression or grief. Content analysis was used to explore: (1) audiologists' self-reported usual response when clients present with emotional and psychological concerns and/or symptoms in the audiological setting; (2) audiologists' ability to identify and describe psychological symptoms; and (3) audiologists' self-reported clinical behaviors relating to client referral for psychological support., Results: When asked to describe their usual clinical course of action in response to the vignettes, over one half the audiologists described actions that address the clients concerns related to psychological well-being. Where audiologists described how they would provide psychological support, they described modifications to the audiological rehabilitation program including involving significant others in the rehabilitation process, recommending additional support outside of the audiology setting (such as General Practitioner or psychologists), and providing emotional support and counseling. When prompted, the majority of participants recognized the two cases with depression as having a mental health condition; however, 48% of participants indicated the control case as also having a mental health condition. When asked directly, the majority of audiologists indicated that they would refer the three vignettes for specialist support; however, less than one third described referral to a General Practitioner and less than 5% described referral to a mental health professional as their normal course of action in the open response item. Twenty-five different professions/people were reported as potential sources for referral., Conclusion: These findings support the need for further training and/or resources for audiologists to enable them to appropriately detect, describe and refer for emotional and psychological concerns and/or symptoms raised by clients' in the audiology setting.

Background: Echinochloa crus-galli (L.) Beauv. and Amaranthus palmeri S. Wats are two common and problematic weeds prevalent across the Midsouth of the USA. Herbicide absorption, translocation, and metabolism were investigated as potential sources of herbicide antagonism on A. palmeri and E. crus-galli using 14 C-labeled herbicides. Three 14 C-labeled herbicides, glyphosate, glufosinate, and dicamba, were utilized individually in separate experiments., Results: Uptake of 14 C-glyphosate in E. crus-galli was 15% of the total applied radioactivity for glyphosate/glufosinate (897 + 595 g a.i./a.e. ha -1 ) compared to 25% for glyphosate alone. Similarly, uptake of 14 C-glyphosate in A. palmeri reduced by 10% when applied with glufosinate. Applying glyphosate/dicamba (897/560 g a.e. ha -1 ) reduced 14 C-glyphosate uptake in both species. In the 14 C-glufosinate experiment, both species absorbed less 14 C-glufosinate when mixed with glyphosate compared to glufosinate alone. No metabolic degradation of glyphosate was observed in either species. E. crus-galli metabolized dicamba 23 times faster than A. palmeri. When glufosinate was applied with dicamba, metabolic degradation of 14 C-dicamba was limited in both species. For example, 99.9% of the applied radioactivity was recovered in A. palmeri as the parent compound when 14 C-glufosinate dicamba was applied with glufosinate, compared to 95.7% for dicamba alone., Conclusion: These findings demonstrate absorption, translocation, or metabolism of dicamba, glufosinate, and glyphosate can be affected by mixing with another herbicide. As mixing two herbicides is often a critical component of resistance management, careful investigation into the performance of these mixtures in the field is needed. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)

Purpose Emotional and mental health is essential to overall health, but there has been little research on how to approach emotional and mental health in the audiology setting. This study provides a preliminary investigation into the current knowledge, beliefs, and practices of Australian audiologists in addressing the emotional and mental health needs of adults with hearing loss. Method A 22-item survey using open- and closed-ended questions was completed by 95 Australian audiologists using a cross-sectional study design. Results Two thirds of audiologists described being underconfident and lacking the skills required to provide emotional support to people with hearing loss. Barriers to delivering emotional support included feeling out of their depth (56.6%), time/caseload pressures (55.3%), and the perception that the provision of emotional support was not within an audiologist's scope of practice (31.6%). Audiologists described a desire to refer clients to mental health professionals yet highlighted significant barriers, including not knowing who to refer to (54.7%), when to make a referral (49.3%), or how to make a referral (38.6%). Audiologists overwhelmingly (96%) indicated that they would like to develop their knowledge and skills associated with the provision of emotional and mental health support in the audiological setting. Conclusion Knowledge, skills, and time were identified as the key areas that require attention in order to allow audiologists to address the emotional and mental health needs of adults with hearing loss.

Background: Better outcome prediction could assist in reliable quantification and classification of traumatic brain injury (TBI) severity to support clinical decision-making. We developed a multifactorial model combining quantitative electroencephalography (qEEG) measurements and clinically relevant parameters as proof of concept for outcome prediction of patients with moderate to severe TBI., Methods: Continuous EEG measurements were performed during the first 7 days of ICU admission. Patient outcome at 12 months was dichotomized based on the Extended Glasgow Outcome Score (GOSE) as poor (GOSE 1-2) or good (GOSE 3-8). Twenty-three qEEG features were extracted. Prediction models were created using a Random Forest classifier based on qEEG features, age, and mean arterial blood pressure (MAP) at 24, 48, 72, and 96 h after TBI and combinations of two time intervals. After optimization of the models, we added parameters from the International Mission for Prognosis And Clinical Trial Design (IMPACT) predictor, existing of clinical, CT, and laboratory parameters at admission. Furthermore, we compared our best models to the online IMPACT predictor., Results: Fifty-seven patients with moderate to severe TBI were included and divided into a training set (n = 38) and a validation set (n = 19). Our best model included eight qEEG parameters and MAP at 72 and 96 h after TBI, age, and nine other IMPACT parameters. This model had high predictive ability for poor outcome on both the training set using leave-one-out (area under the receiver operating characteristic curve (AUC) = 0.94, specificity 100%, sensitivity 75%) and validation set (AUC = 0.81, specificity 75%, sensitivity 100%). The IMPACT predictor independently predicted both groups with an AUC of 0.74 (specificity 81%, sensitivity 65%) and 0.84 (sensitivity 88%, specificity 73%), respectively., Conclusions: Our study shows the potential of multifactorial Random Forest models using qEEG parameters to predict outcome in patients with moderate to severe TBI.

Multiple clinical studies have shown that bardoxolone methyl, a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with chronic kidney disease. However, whether an Nrf2 activator can protect tubules from proteinuria-induced tubular damage via anti-inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of Cancer Research-derived glomerulonephritis (ICGN) mouse model of nephrosis, we examined the effects of dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice. The tubular epithelial cells of ICGN mice showed a decrease in the size and number of mitochondria, as well as the breakdown of the crista structure, whereas the number and ultrastructure of mitochondria were maintained by the dh404 treatment. To further determine the effect of dh404 on mitochondrial function, we used human proximal tubular cells in vitro . Stimulation with albumin and free fatty acid increased mitochondrial reactive oxygen species (ROS). However, dh404 administration diminished mitochondrial ROS. Our data show that dh404 significantly reduced proteinuria-induced tubular cell mitochondrial damage, suggesting that improved redox balance and mitochondrial function and suppression of inflammation underlie the cytoprotective mechanism of Nrf2 activators, including bardoxolone methyl, in diabetic kidney disease.-Nagasu, H., Sogawa, Y., Kidokoro, K., Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., Kashihara, N. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.

Friedreich's Ataxia (FRDA) is a devastating and progressive ataxia, marked by mitochondrial dysfunction and oxidative stress. Nrf2 activators such as omaveloxolone (Omav) modulate antioxidative mechanisms, and thus may be viable therapeutic agents in FRDA., Competing Interests: Dr Zesiewicz has received personal compensation for serving on the advisory boards of Boston Scientific, Reata Pharmaceuticals, Inc, and Steminent Biotherapeutics. Dr Zesiewicz has received personal compensation as senior editor for Neurodegenerative Disease Management and as a consultant for Steminent Biotherapeutics. Dr Zesiewicz has received royalty payments as co-inventor of varenicline for treating imbalance (patent number 9463190) and nonataxic imbalance (patent number 9782404). Dr Zesiewicz has received research/grant support as principal investigator/investigator for studies from AbbVie Inc, Biogen, Biohaven Pharmaceutics, Boston Scientific, Bukwang Pharmaceuticals Co, Ltd, Cala Health, Inc, Cavion, Friedreich’s Ataxia Research Alliance, Houston Methodist Research Institute, National Institutes of Health (READISCA U01), Retrotope Inc, and Takeda Development Center Americas, Inc. Dr. Meyer is an employee of Reata Pharmaceuticals, Inc. The authors report no other conflicts of interest in this work., (© 2019 Ghanekar et al.)

Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: -0.035 [95% confidence interval -0.031 to -0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

New antibiotics that are active against multi-drug-resistant strains and difficult-to-treat bacterial infections are needed. Synthetic modification of spectinomycin, a bacterial protein synthesis inhibitor, has been shown to increase antibacterial activity compared with spectinomycin. Aminomethyl spectinomycins are active against Gram-negative and Gram-positive bacterial pathogens. In this study, the ability of aminomethyl spectinomycins to treat biothreat pathogens is examined by MIC profiling, synergy testing, and in vivo efficacy experiments. Compound 1950 exhibited potent antibacterial activity against Gram-negative pathogens Brucella spp., Burkholderia mallei, and Francisella tularensis, but showed little to no growth inhibition against Burkholderia pseudomallei, Bacillus anthracis, and Yersinia pestis. Combination testing in checkerboard assays revealed that aminomethyl spectinomycin-antibiotic combinations had mainly an additive effect against the susceptible biodefense pathogens. The in vivo efficacy of compound 1950 was also demonstrated in mice infected with B. mallei (FMH) or F. tularensis (SchuS4). These results suggest that aminomethyl spectinomycins are promising new candidates for development of therapeutics against biodefense bacterial agents.

Background: Clinical studies have found up to 90% of hearing aid owners demonstrate difficulty with basic hearing aid management tasks and almost 50% of hearing aid owners self-report not receiving enough practical help from their clinician regarding how to use their hearing aid. Although studies have highlighted the overwhelming amount of information and training required to learn how to use a hearing aid appropriately, a gap remains in the literature regarding the range of methods by which hearing aid owners acquire the knowledge and skills for hearing aid use, and whether these approaches are considered beneficial., Purpose: To gain insight into how both hearing aid owners and hearing health clinicians view the acquisition of hearing aid management skills and the efficacy of currently used methods of hearing aid training., Research Design: Concept mapping techniques were used to identify key themes, wherein participants generated, sorted, and rated the importance of statements in response to the question "How do hearing aid owners learn the skills required to use, handle, manage, maintain, and care for their hearing aids?", Study Sample: Twenty-four hearing aid owners (aged 56-91 years; 54.2% male) and 22 clinicians (aged 32-69 years; 9.1% male)., Data Collection and Analysis: Participant perspectives were collected via group concept mapping sessions in October 2015. Hierarchical cluster analysis was used to identify themes and develop a framework for understanding how skill acquisition occurs. Participants rated each method of hearing aid skill acquisition as to how beneficial it was and how often it was used., Results: Participants identified 75 unique items describing how hearing aid management skills are acquired within six concepts: (1) Relationship with the clinician, (2) clinician as a source of knowledge and support, (3) hands-on experience, (4) seeking additional information, (5) asking support people for help, and (6) external resources., Conclusions: The results of this study highlight the diverse methods and sources by which hearing aid owners learn the skills necessary to use, manage, and maintain their hearing aids. Significant emphasis was placed on the role of the hearing health clinician to provide training, support, and an ongoing professional relationship, with lesser roles played by family, friends, and other health professionals., (American Academy of Audiology.)

The most frequent ailment for which antibiotics are prescribed is otitis media (ear infections), which is most commonly caused by Haemophilus influenzae , Moraxella catarrhalis , and Streptococcus pneumoniae Treatment of otitis media is complicated by the fact that the bacteria in the middle ear typically form biofilms, which can be recalcitrant to antibiotic treatment. Furthermore, bacterial respiratory infections can be greatly exacerbated by viral coinfection, which is particularly evidenced by the synergy between influenza and S. pneumoniae In this study, we sought to ascertain the in vivo efficacy of aminomethyl spectinomycin lead 1950, an effective antibacterial agent both in vitro and in vivo against Streptococcus pneumoniae in the context of complex respiratory infections and acute otitis media. A single dose of 1950 significantly reduced bacterial burden in the respiratory tract for all three pathogens, even when species were present in a coinfection model. Additionally, a single dose of 1950 effectively reduced pneumococcal acute otitis media from the middle ear. The agent 1950 also proved efficacious in the context of influenza-pneumococcal super infection. These data further support the development of this family of compounds as potential therapeutic agents against the common causes of complex upper respiratory tract infections and acute otitis media., (Copyright © 2019 American Society for Microbiology.)