Current approaches for Usher syndrome disease models and developing therapies.

Usher syndrome is a severely debilitating autosomal recessive disorder characterised by congenital or progressive hearing loss, gradual vision loss and in some subtypes, vestibular dysfunction. Much progress has been made in recent years in creating appropriate preclinical models for most subtypes of Usher syndrome to facilitate the development of novel therapies. In this review, we provide an update on new preclinical models of Usher syndrome, with a particular focus on induced pluripotent stem cells and new organoid models.

Cochlear Implantation in Australia: A Retrospective Analysis of 23 Years of Activity.

Objectives: To report the number of cochlear implantation procedures and recipients in Australia since 2000 by age, and to estimate the adult uptake of cochlear implants.

Methods: This was a retrospective analysis of data, using publicly available data on private and public hospital procedures undertaken in Australia between 2000/01 and 2022/23. The main outcome measures were: (i) Number of cochlear implants per financial year, by paediatric, adult, or 10-year age groups, and population adjusted.

Dizziness and imbalance and their association with general and mental health in a community-based cross-sectional study of middle-aged individuals: the Busselton healthy ageing study.

Background: Dizziness and imbalance are common symptoms among patients visiting healthcare providers. Current knowledge about their prevalence, impact on daily life, and associated factors is primarily based on selected samples from individuals seeking medical help, particularly older individuals. This study aimed to estimate the prevalence, symptoms, and impact of dizziness or imbalance symptoms, and to assess the association between these symptoms and their characteristics with demographic, general health, and mental health factors in middle-aged men and women from a representative, general population sample.

Generation of two induced pluripotent stem cell lines from an Usher syndrome type 1B patient with the homozygous c.496del MYO7A variant.

Usher syndrome (USH) is the most common cause of inherited deaf-blindness. Here, we produced the LEIi020-A and LEIi020-B induced pluripotent stem cell (iPSC) lines from dermal fibroblasts derived from a patient with USH1B caused by inheritance of homozygous c.496del variants in MYO7A using episomal plasmids encoding OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for TP53.

Recent Therapeutic Progress and Future Perspectives for the Treatment of Hearing Loss.

Up to 1.5 billion people worldwide suffer from various forms of hearing loss, with an additional 1.1 billion people at risk from various insults such as increased consumption of recreational noise-emitting devices and ageing.

Overcoming barriers: a review on innovations in drug delivery to the middle and inner ear.

Despite significant advances in the development of therapeutics for hearing loss, drug delivery to the middle and inner ear remains a challenge. As conventional oral or intravascular administration are ineffective due to poor bioavailability and impermeability of the blood-labyrinth-barrier, localized delivery is becoming a preferable approach for certain drugs. Even then, localized delivery to the ear precludes continual drug delivery due to the invasive and potentially traumatic procedures required to access the middle and inner ear.

Using x-ray micro computed tomography to quantify intracochlear fibrosis after cochlear implantation in a Guinea pig model.

Cochlear implants (CIs) allow individuals with profound hearing loss to understand speech and perceive sounds. However, not all patients obtain the full benefits that CIs can provide and the cause of this disparity is not fully understood. One possible factor for the variability in outcomes after cochlear implantation, is the development of fibrotic scar tissue around the implanted electrode.

Models of service delivery in adult cochlear implantation and evaluation of outcomes: A scoping review of delivery arrangements.

Background: This study aimed to describe available evidence of cochlear implantation delivery arrangements in adults and the outcomes by which these service models are measured.

Methods: Scoping review of English language, primary studies conducted on adults (≥18 years) with ten or more subjects, published between January 2000 and June 2022, which assessed the effects of delivery arrangements of cochlear implantation were included. MEDLINE, EMBASE, CINAHL Plus, AMED, PsycINFO, LILACS, KoreaMed, IndMed, Cochrane CRCT, ISRCTN registry, WHO ICTRP and Web of Science were systematically searched.

Factors Influencing Postoperative Experiences in Adult Cochlear Implant Recipients: A Multistakeholder Perspective.

Objective: To explore factors influencing postoperative experiences of adult cochlear implant (CI) recipients, determine the impact of each factor, and conceptualize recipients' postoperative journey.

Study Design: Participatory mixed methods; concept mapping.

Setting: Tertiary care (private and public).

Pharmacological Dose-Effect Profiles of Various Concentrations of Humanised Primary Bile Acid in Encapsulated Cells.

Bile acids (BA)s are known surfactants and well-documented to play a major role in food digestion and absorption. Recently, potential endocrinological and formulation-stabilisation effects of BAs have been explored and their pharmacological effects on supporting cell survival and functions have gained wide interest. Hence, this study aimed to explore the hyper-glycaemic dependent dose-effect of the BA chenodeoxycholic acid (CDCA) when encapsulated with pancreatic β-cells, allowing assessment of CDCA's impacts when encapsulated.

Biguanide Pharmaceutical Formulations and the Applications of Bile Acid-Based Nano Delivery in Chronic Medical Conditions.

Biguanides, particularly the widely prescribed drug metformin, have been marketed for many decades and have well-established absorption profiles. They are commonly administered via the oral route and, despite variation in oral uptake, remain commonly prescribed for diabetes mellitus, typically type 2. Studies over the last decade have focused on the design and development of advanced oral delivery dosage forms using bio nano technologies and novel drug carrier systems.

Single-Cellular Biological Effects of Cholesterol-Catabolic Bile Acid-Based Nano/Micro Capsules as Anti-Inflammatory Cell Protective Systems.

Recent studies in our laboratories have shown promising effects of bile acids in ➀ drug encapsulation for oral targeted delivery (via capsule stabilization) particularly when encapsulated with Eudragit NM30D and ➁ viable-cell encapsulation and delivery (via supporting cell viability and biological activities, postencapsulation). Accordingly, this study aimed to investigate applications of bile acid-Eudragit NM30D capsules in viable-cell encapsulation ready for delivery. Mouse-cloned pancreatic β-cell line was cultured and cells encapsulated using bile acid-Eudragit NM30D capsules, and capsules' images, viability, inflammation, and bioenergetics of encapsulated cells assessed.

The Effects of Primary Unconjugated Bile Acids on Nanoencapsulated Pharmaceutical Formulation of Hydrophilic Drugs: Pharmacological Implications.

Introduction: In a recent study, in our laboratory, primary unconjugated bile acids, commonly found in humans, chenodeoxycholic acid (CDCA), have been shown to improve stability of nanoencapsulated lipophilic drugs and improve their release profile after oral administration likely via electrokinetic stabilisation. Hence, this study aimed to examine the effects of CDCA on exerting similar effects on hydrophilic drugs.

Methods: Various CDCA-based formulations were produced for the orally administered hydrophilic drug, metformin.

Probucol Pharmacological and Bio-Nanotechnological Effects on Surgically Transplanted Graft Due to Powerful Anti-Inflammatory, Anti-Fibrotic and Potential Bile Acid Modulatory Actions.

Introduction: A major obstacle in islet transplantation and graft survival pre and post transplantation is islet apoptosis due to mainly inflammatory bio molecules released during islet harvesting and post graft transplantation and hence, subsequent graft fibrosis and failure. This study aimed to investigate if incorporation of the anti-inflammatory anti-hyperlipidaemic drug probucol (PB) would improve islet-graft survival and function, post transplantation in Type 1 diabetes (T1D).

Methods: T1D was induced in mice, and biological profiles of the diabetic mice transplanted PB-microencapsulated islets harvested from healthy syngeneic mice were measured.

Enhanced Bilosomal Properties Resulted in Optimum Pharmacological Effects by Increased Acidification Pathways.

Introduction: Recent studies in our laboratory have shown that some bile acids, such as chenodeoxycholic acid (CDCA), can exert cellular protective effects when encapsulated with viable β-cells via anti-inflammatory and anti-oxidative stress mechanisms. However, to explore their full potential, formulating such bile acids (that are intrinsically lipophilic) can be challenging, particularly if larger doses are required for optimal pharmacological effects. One promising approach is the development of nano gels.

Tinnitus and its associations with general health, mental health and hearing loss.

Background: A deeper knowledge of tinnitus is essential in order to better manage and treat tinnitus and its effects. Most studies to date are based on small samples and/or conducted in clinical settings. In this study we assessed the associations between tinnitus, general and mental health, hearing status and demographics in a large population cohort study.

Spontaneous Tegmen Tympani Dehiscence: Causes and Treatment of Conductive Hearing Loss.

Objective: Conductive hearing loss (CHL) commonly arises in patients with spontaneous dehiscence of the tegmen of the temporal bone with meningoencephalocele (SME). The aim of this study was to further investigate 1) the potential mechanisms for CHL in this setting; 2) hearing outcomes following surgery to address SME, and 3) the possible causes of persistent CHL following surgery.

Study Design: Retrospective case review.

Enhancing Resistance of Silk Fibroin Material to Enzymatic Degradation by Cross-Linking Both Crystalline and Amorphous Domains.

Silk fibroin (SF) membranes are finding widespread use as biomaterial scaffolds in a range of tissue engineering applications. The control over SF scaffold degradation kinetics is usually driven by the proportion of SF crystalline domains in the formulation, but membranes with a high β-sheet content are brittle and still contain amorphous domains, which are highly susceptible to enzymatic degradation. In this work, photo-cross-linking of SF using a ruthenium-based method, and with the addition of glycerol, was used to generate robust and flexible SF membranes for long-term tissue engineering applications requiring slow degradation of the scaffolds.

Generation of three induced pluripotent stem cell lines from a patient with Usher syndrome caused by biallelic c.949C > A and c.1256G > T mutations in the USH2A gene.

Mutations in the USH2A gene are the most common cause of Usher syndrome and autosomal recessive non-syndromic retinitis pigmentosa. Here, we describe the generation of three induced pluripotent stem cell lines from dermal fibroblasts derived from a patient carrying biallelic c.949C > A and c.

Hearing aids to support cognitive functions of older adults at risk of dementia: the HearCog trial- clinical protocols.

Background: Globally, about 50 million people were living with dementia in 2015, with this number projected to triple by 2050. With no cure or effective treatment currently insight, it is vital that factors are identified which will help prevent or delay both age-related and pathological cognitive decline and dementia. Observational data have suggested that hearing loss is a potentially modifiable risk factor for dementia, but no conclusive evidence from randomised controlled trials is currently available.

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy.

Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance. Three clinically distinct types of USH have been identified, decreasing in severity from Type 1 to 3, with symptoms of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP), and vestibular dysfunction. There are currently nine confirmed and two suspected USH-causative genes, and a further three candidate loci have been mapped.

What Influences Decision-Making for Cochlear Implantation in Adults? Exploring Barriers and Drivers From a Multistakeholder Perspective.

Objectives: To explore the factors influencing the uptake of cochlear implants in adults, determine the impact of each factor, and to conceptualize the journey to implantation from a multistakeholder perspective.

Design: Concept mapping was used to integrate input from multiple stakeholders, each with their own experience and expertise. This mixed participatory method collects qualitative and quantitative data collection and enables further quantitative analysis.

The effect of hearing loss configuration on cochlear implantation uptake rates: an Australian experience.

Recent changes to cochlear implant (CI) candidacy criteria have led to the inclusion of candidates with greater levels of hearing in the contralateral and/or implanted ear. This study assessed the impact of various hearing loss configurations on CI uptake rates (those assessed as eligible for CI, who proceed to CI). Retrospective cohort study.

Generation of two induced pluripotent stem cell lines from a patient with compound heterozygous mutations in the USH2A gene.

The human iPSC lines LEIi010-A and LEIi010-B were generated from the dermal fibroblasts of a patient with Usher syndrome using episomal plasmids containing OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for p53. These iPSC lines carry compound heterozygous mutations (c.949C > A and c.