Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds.

The interleukin-4 (IL-4) cytokine plays a critical role in modulating immune homeostasis. Although there is great interest in harnessing this cytokine as a therapeutic in natural or engineered formats, the clinical potential of native IL-4 is limited by its instability and pleiotropic actions. Here, we design IL-4 cytokine mimetics (denoted Neo-4) based on a de novo engineered IL-2 mimetic scaffold and demonstrate that these cytokines can recapitulate physiological functions of IL-4 in cellular and animal models. In contrast with natural IL-4, Neo-4 is hyperstable and signals exclusively through the type I IL-4 receptor complex, providing previously inaccessible insights into differential IL-4 signaling through type I versus type II receptors. Because of their hyperstability, our computationally designed mimetics can directly incorporate into sophisticated biomaterials that require heat processing, such as three-dimensional-printed scaffolds. Neo-4 should be broadly useful for interrogating IL-4 biology, and the design workflow will inform targeted cytokine therapeutic development.

A qualitative investigation of the hearing and hearing-aid related emotional states experienced by adults with hearing loss.

OBJECTIVE: Despite previous research into the psychosocial impact of hearing loss, little detail is known regarding the hearing and hearing-aid-related emotional states experienced by adults with hearing loss in everyday life, and how they occur. DESIGN: Individual remote semi-structured interviews were audio-recorded, transcribed verbatim and qualitatively analysed with reflexive and inductive thematic analysis. STUDY SAMPLE: Seventeen participants (9 female) with hearing loss (age range 44-74 years) participated. Ten used bilateral hearing aids, four unilateral and three used no hearing aids at the time of interviews. RESULTS: The four main themes which emerged from the data were: identity and self-image, autonomy and control, personality and dominant emotional states and situational cost/benefit analysis with respect to use of hearing aids. CONCLUSIONS: This study goes beyond previous literature by providing a more detailed insight into emotions related to hearing and hearing-aids in adults. Hearing loss causes a multitude of negative emotions, while hearing aids generally reduce negative emotions and allow for more positive emotions. However, factors such as lifestyle, personality, situational control, the relationship with those in conversation and the attribution of blame are key to individual emotional experience. Clinical implications include the important role of social relationships in assessment and counselling.

Applications of qualitative grounded theory methodology to investigate hearing loss: protocol for a qualitative systematic review.

INTRODUCTION: Hearing loss is a chronic condition affecting 12 million individuals in the UK. People with hearing loss regularly experience difficulties interacting in everyday conversations. These difficulties in communication can result in a person with hearing loss withdrawing from social situations and becoming isolated. While hearing loss research has largely deployed quantitative methods to investigate various aspects of the condition, qualitative research is becoming more widespread. Grounded theory is a specific qualitative methodology that has been used to establish novel theories on the experiences of living with hearing loss. METHOD AND ANALYSIS: The aim of this systematic review is to establish how grounded theory has been applied to investigate the psychosocial aspects of hearing loss. Methods are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols 2015 checklist. Studies included in this review will have applied grounded theory as an overarching methodology or have grounded theory embedded among other methodologies. Studies included will have adult participants (≥18 years) who are either people with an acquired hearing loss, their family and friends (communication partners), or healthcare practitioners including audiologists, general practitioners, ear, nose and throat specialists and hearing therapists. The quality of application of grounded theory in each study will be assessed using the Guideline for Reporting and Evaluating Grounded Theory Research Studies. ETHICS AND DISSEMINATION: As only secondary data will be used in this systematic review, ethical approval is not required. No other ethical issues are foreseen. This review is registered with the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO). Findings will be disseminated via peer-reviewed publications and at relevant academic conferences. Findings may also be published in relevant professional and third sector newsletters and magazines as appropriate. Data will inform future research and guideline development. PROSPERO REGISTRATION NUMBER: CRD42019134197.

Applying the COM-B Model to Assess the Usability of Smartphone-Connected Listening Devices in Adults with Hearing Loss.

BACKGROUND: Unlike conventional hearing aids, smartphone-connected listening devices may require limited or no input from a trained audiologist in terms of device programming and adjustment. However, there is a lack of peer-reviewed evidence assessing the real-world perspectives of people living with hearing loss toward such technological innovations. PURPOSE: This study assessed the everyday experiences of adults living with hearing loss toward a range of smartphone-connected listening devices using the Capability, Opportunity, Motivation, Behaviour (COM-B) model as a theoretical framework. RESEARCH DESIGN: A qualitative study where participants trialed one of the following smartphone-connected listening devices for two weeks in their everyday lives: made-for-smartphone hearing aid, personal sound amplification product, and smartphone "hearing aid" app with wired earphones or wireless hearable. Individual semistructured interviews were conducted. STUDY SAMPLE: Twenty adults (13 male and 7 female; mean age = 62.25 years, SD = 11.59) with mild-to-moderate hearing loss (mean better ear pure-tone average = 30.49 dB HL, SD = 17.51) were recruited using a convenience sampling strategy. All participants owned conventional hearing aids. DATA ANALYSIS: The data were analyzed using an established deductive thematic analysis procedure within the context of the COM-B model. The model stipulates that for individuals to engage in a particular behavior (B), they must have sufficient capability (C), opportunity (O), and motivation (M). RESULTS: Capability: One of the key advantages facilitating use and adherence of smartphone-connected listening devices was the ability for participants to make fine-tune adjustments in any listening situation. Opportunity: Participants commented that these devices could address issues surrounding stigma as smartphones are ubiquitous in everyday life. Motivation: Participants consistently reported that the ability to make adjustments via a smartphone provided them with a greater sense of autonomy and empowerment. As a result, they felt more in control of their hearing loss. CONCLUSIONS: This study lays the foundation for further high-quality research to explore whether smartphone-connected technologies have the potential to yield optimum benefits for people living with hearing loss.

An X-linked Myh11-CreERT2 mouse line resulting from Y to X chromosome-translocation of the Cre allele.

The Myh11-CreERT2 mouse line (Cre+ ) has gained increasing application because of its high lineage specificity relative to other Cre drivers targeting smooth muscle cells (SMCs). This Cre allele, however, was initially inserted into the Y chromosome (X/YCre+ ), which excluded its application in female mice. Our group established a Cre+ colony from male ancestors. Surprisingly, genotype screening identified female carriers that stably transmitted the Cre allele to the following generations. Crossbreeding experiments revealed a pattern of X-linked inheritance for the transgene (k > 1000), indicating that these female carries acquired the Cre allele through a mechanism of Y to X chromosome translocation. Further characterization demonstrated that in hemizygous X/XCre+ mice Cre activity was restricted to a subset arterial SMCs, with Cre expression in arteries decreased by 50% compared to X/YCre+ mice. This mosaicism, however, diminished in homozygous XCre+ /XCre+ mice. In a model of aortic aneurysm induced by a SMC-specific Tgfbr1 deletion, the homozygous XCre+ /XCre+ Cre driver unmasked the aortic phenotype that is otherwise subclinical when driven by the hemizygous X/XCre+ Cre line. In conclusion, the Cre allele carried by this female mouse line is located on the X chromosome and subjected to X-inactivation. The homozygous XCre+ /XCre+ mice produce uniform Cre activity in arterial SMCs.

Smooth muscle cell-specific Tgfbr1 deficiency attenuates neointimal hyperplasia but promotes an undesired vascular phenotype for injured arteries.

Neointimal hyperplasia (NIH) and inward wall remodeling cause arterial restenosis and failure of bypass vein grafts. Previous studies from our group suggest that transforming growth factor (TGF) ß promotes these pathologies via regulating cell kinetics at the early stage and matrix metabolism at the late stage. Although these temporal TGFß effects may result from its signaling in different cell groups, the responsible cell type has not been identified. In the current study, we evaluated the effect of smooth muscle cell (SMC)-specific TGFß signaling through its type I receptor TGFBR1 on NIH and wall remodeling of the injured femoral arteries (FAs). An inducible Cre/loxP system was employed to delete SMC Tgfbr1 (Tgfbr1iko). Mice not carrying the Cre allele (Tgfbr1f/f) served as controls. The injured FAs were evaluated on d3, d7, and d28 postoperatively. Tgfbr1iko attenuated NIH by 92%, but had insignificant influence on arterial caliber when compared with Tgfbr1f/f controls on d28. This attenuation correlated with greater cellularity and reduced collagen content. Compared with Tgfbr1f/f FAs, however, Tgfbr1iko FAs exhibited persistent neointimal cell proliferation and cell apoptosis, with both events at a greater rate on d28. Tgfbr1iko FAs additionally contained fewer SMCs and more inflammatory infiltrates in the neointima and displayed a thicker adventitia than did Tgfbr1f/f FAs. More MMP9 proteins were detected in the adventitia of Tgfbr1iko FAs than in that of Tgfbr1f/f controls. Our results suggest that disruption of SMC Tgfbr1 inhibits arterial NIH in the short term, but the overall vascular phenotype may not favor long-term performance of the injured arteries.