Errata: Unleashing the Power of Test Box and Real-Ear Probe Microphone Measurement.

[This corrects the article DOI: 10.1055/s-0044-1786506.].

Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.

TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.

Chapter 2: My Hearing Aid Isn't Working Like It Used to .

This chapter will take you through specific patient complaints and the test box measures you can use to address these complaints. These measurements give you data that aid in your decision making about what is wrong, if anything, with the hearing aid and how you might address the problem. Before we discuss specific patient complaints and problems, let us review the American National Standard Institute (ANSI) guidelines for hearing aid testing in a test box.

Chapter 5: Setting the Hearing Aid Response and Verifying Signal Processing and Features with Real-Ear Probe Microphone Measures.

The real-ear probe microphone system provides a powerful tool to individual hearing aid fittings accounting for your patient's hearing and ear canal characteristics. The primary treatment for hearing loss is audibility, returning an audible signal across frequencies and input levels given the constraints of the hearing loss. This chapter will provide detailed information on the measures needed to individualize the hearing aid fitting and will present various clinical scenarios that will allow you to work with this information and see how you apply this knowledge clinically. You will explore the verification of signal processing and features that allow you to support your patients.

Chapter 4: Introduction and Getting Ready for Real-Ear Probe Microphone Measures.

Probe microphone measurements are an essential step in an individualized hearing aid fitting. These measurements allow audiologists to account for the individual's hearing and ear canal acoustics when programming hearing aids. An evidence-based hearing aid fitting includes matching the measured output of the hearing aids to targets for each input level and frequency. This allows the audiologist to confidently counsel the patient that the acoustic fitting is accurate, and the next step is for the individual to use the amplification during all waking hours to adapt to the newly amplified sounds. This also avoids mistakes such as overamplification or insufficient gain, which can endanger the patient and/or lead to a compromised fitting.

Chapter 3: Setting the Hearing Aid Response and Verifying Signal Processing and Features in the Test Box.

The test box can be used for fitting hearing aids (verifying audibility for the individual), for setting and fine-tuning specific signal processing (e.g., directional microphones, noise reduction, frequency lowering, telecoil responses), and for setting the response for specific accessories (e.g., remote microphones). If you have selected these features for your patient, it is important to make sure they are working properly and turned on. In addition, these tests can help you address specific patient complaints. Let us start by using the test box to pre-set a hearing aid and then we will move on to speech tests of signal processing and features.

Chapter 6: What Else Can I Do with This Equipment?

If there is sound in the ear canal, you can measure it with a probe microphone in the ear. The following are a few examples of how you might use your real-ear probe microphone measures beyond verifying hearing aid fittings, signal processing, and function of features. A process to simulate hearing loss to educate and support family members and patients is described.

Chapter 1: Introduction and Getting Ready for Hearing Aid Test Box Measures.

In this chapter you will be introduced to the hearing aid test box equipment and work through how to prepare the equipment so that it is ready to provide the testing you will use to evaluate, fit, and troubleshoot hearing aids and other amplifiers. At the end of this chapter, you will be familiar with terminology associated with hearing aid test box measures and the leveling required with the reference microphone and coupler microphone to ensure that your measurements are accurate and can be interpreted.

Biallelic FANCA variants detected in sisters with isolated premature ovarian insufficiency.

Premature ovarian insufficiency is a common form of female infertility affecting up to 4% of women and characterised by amenorrhea with elevated gonadotropin before the age of 40. Oocytes require controlled DNA breakage and repair for homologous recombination and the maintenance of oocyte integrity. Biallelic disruption of the DNA damage repair gene, Fanconi anemia complementation group A (FANCA), is a common cause of Fanconi anaemia, a syndrome characterised by bone marrow failure, cancer predisposition, physical anomalies and POI. There is ongoing dispute about the role of heterozygous FANCA variants in POI pathogenesis, with insufficient evidence supporting causation. Here, we have identified biallelic FANCA variants in French sisters presenting with POI, including a novel missense variant of uncertain significance and a likely pathogenic deletion that initially evaded detection. Functional studies indicated no discernible effect on DNA damage sensitivity in patient lymphoblasts. These novel FANCA variants add evidence that heterozygous loss of one allele is insufficient to cause DNA damage sensitivity and POI. We propose that intragenic deletions, that are relatively common in FANCA, may be missed without careful analysis, and could explain the presumed causation of heterozygous variants. Accurate variant curation is critical to optimise patient care and outcomes.

Barriers to Hearing Health Care for Aging Adults: Reframing the Conversation.

Untreated age-related hearing loss (ARHL) is associated with poor health and social outcomes. Treating hearing loss can mitigate these serious issues. Although there are documented barriers to care, we can look at these barriers and potential solutions differently if we view ARHL as a gradual onset, chronic condition. This provides a framework from which to solve problems in line with how other chronic health conditions experienced by aging adults are approached. With this lens, it becomes evident that early identification and treatment of ARHL can be supported by universal senior hearing screening, appropriate Medicare coverage for devices and services, and direct access to audiological care as well as avenues for self-care are necessary ingredients to change the hearing health care landscape.

Plain Language Summary: Age-Related Hearing Loss.

The plain language summary explains age-related hearing loss to patients, families, and care partners. The summary is for any patient aged 50 years and older, families, and care partners. It is based on the 2024 "Clinical Practice Guideline: Age-Related Hearing Loss." This plain language summary is a companion publication to the full guideline, which provides greater detail for clinicians. Guidelines and their recommendations may not apply to every patient, but they can be used to find best practices and quality improvement opportunities.

Clinical Practice Guideline: Age-Related Hearing Loss Executive Summary.

OBJECTIVE: Age-related hearing loss (ARHL) is a prevalent but often underdiagnosed and undertreated condition among individuals aged 50 and above. It is associated with various sociodemographic factors and health risks including dementia, depression, cardiovascular disease, and falls. While the causes of ARHL and its downstream effects are well defined, there is a lack of priority placed by clinicians as well as guidance regarding the identification, education, and management of this condition. PURPOSE: The purpose of this clinical practice guideline is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the identification and management of ARHL. These opportunities are communicated through clear actionable statements with an explanation of the support in the literature, the evaluation of the quality of the evidence, and recommendations on implementation. The target patients for the guideline are any individuals aged 50 years and older. The target audience is all clinicians in all care settings. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the Guideline Development Group (GDG). It is not intended to be a comprehensive, general guide regarding the management of ARHL. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. ACTION STATEMENTS: The GDG made strong recommendations for the following key action statements (KASs): (KAS 4) If screening suggests hearing loss, clinicians should obtain or refer to a clinician who can obtain an audiogram. (KAS 8) Clinicians should offer, or refer to a clinician who can offer, appropriately fit amplification to patients with ARHL. (KAS 9) Clinicians should refer patients for an evaluation of cochlear implantation candidacy when patients have appropriately fit amplification and persistent hearing difficulty with poor speech understanding. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should screen patients aged 50 years and older for hearing loss at the time of a health care encounter. (KAS 2) If screening suggests hearing loss, clinicians should examine the ear canal and tympanic membrane with otoscopy or refer to a clinician who can examine the ears for cerumen impaction, infection, or other abnormalities. (KAS 3) If screening suggests hearing loss, clinicians should identify sociodemographic factors and patient preferences that influence access to and utilization of hearing health care. (KAS 5) Clinicians should evaluate and treat or refer to a clinician who can evaluate and treat patients with significant asymmetric hearing loss, conductive or mixed hearing loss, or poor word recognition on diagnostic testing. (KAS 6) Clinicians should educate and counsel patients with hearing loss and their family/care partner(s) about the impact of hearing loss on their communication, safety, function, cognition, and quality of life. (KAS 7) Clinicians should counsel patients with hearing loss on communication strategies and assistive listening devices. (KAS 10) For patients with hearing loss, clinicians should assess if communication goals have been met and if there has been improvement in hearing-related quality of life at a subsequent health care encounter or within 1 year. The GDG offered the following KAS as an option: (KAS 11) Clinicians should assess hearing at least every 3 years in patients with known hearing loss or with reported concern for changes in hearing.

Clinical Practice Guideline: Age-Related Hearing Loss.

OBJECTIVE: Age-related hearing loss (ARHL) is a prevalent but often underdiagnosed and undertreated condition among individuals aged 50 and above. It is associated with various sociodemographic factors and health risks including dementia, depression, cardiovascular disease, and falls. While the causes of ARHL and its downstream effects are well defined, there is a lack of priority placed by clinicians as well as guidance regarding the identification, education, and management of this condition. PURPOSE: The purpose of this clinical practice guideline is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the identification and management of ARHL. These opportunities are communicated through clear actionable statements with explanation of the support in the literature, evaluation of the quality of the evidence, and recommendations on implementation. The target patients for the guideline are any individuals aged 50 years and older. The target audience is all clinicians in all care settings. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group (GDG). It is not intended to be a comprehensive, general guide regarding the management of ARHL. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. ACTION STATEMENTS: The GDG made strong recommendations for the following key action statements (KASs): (KAS 4) If screening suggests hearing loss, clinicians should obtain or refer to a clinician who can obtain an audiogram. (KAS 8) Clinicians should offer, or refer to a clinician who can offer, appropriately fit amplification to patients with ARHL. (KAS 9) Clinicians should refer patients for an evaluation of cochlear implantation candidacy when patients have appropriately fit amplification and persistent hearing difficulty with poor speech understanding. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should screen patients aged 50 years and older for hearing loss at the time of a health care encounter. (KAS 2) If screening suggests hearing loss, clinicians should examine the ear canal and tympanic membrane with otoscopy or refer to a clinician who can examine the ears for cerumen impaction, infection, or other abnormalities. (KAS 3) If screening suggests hearing loss, clinicians should identify sociodemographic factors and patient preferences that influence access to and utilization of hearing health care. (KAS 5) Clinicians should evaluate and treat or refer to a clinician who can evaluate and treat patients with significant asymmetric hearing loss, conductive or mixed hearing loss, or poor word recognition on diagnostic testing. (KAS 6) Clinicians should educate and counsel patients with hearing loss and their family/care partner(s) about the impact of hearing loss on their communication, safety, function, cognition, and quality of life (QOL). (KAS 7) Clinicians should counsel patients with hearing loss on communication strategies and assistive listening devices. (KAS 10) For patients with hearing loss, clinicians should assess if communication goals have been met and if there has been improvement in hearing-related QOL at a subsequent health care encounter or within 1 year. The GDG offered the following KAS as an option: (KAS 11) Clinicians should assess hearing at least every 3 years in patients with known hearing loss or with reported concern for changes in hearing.

Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.

CLPB is a mitochondrial intermembrane space AAA+ domain-containing disaggregase. CLPB mutations are associated with 3-methylglutaconic aciduria and neutropenia; however, the molecular mechanism underscoring disease and the contribution of CLPB substrates to disease pathology remains unknown. Interactions between CLPB and mitochondrial quality control (QC) factors, including PARL and OPA1, have been reported, hinting at dysregulation of organelle QC in disease. Utilizing proteomic and biochemical approaches, we show a stress-specific aggregation phenotype in a CLPB-null environment and define the CLPB substrate profile. We illustrate an interplay between intermembrane space proteins including CLPB, HAX1, HTRA2, and the inner membrane quality control proteins (STOML2, PARL, YME1L1; SPY complex), with CLPB deficiency impeding SPY complex function by virtue of protein aggregation in the intermembrane space. We conclude that there is an interdependency of mitochondrial QC components at the intermembrane space/inner membrane interface, and perturbations to this network may underscore CLPB disease pathology.

A data-driven approach to identify a rapid screener for auditory processing disorder testing referrals in adults.

Hearing thresholds form the gold standard assessment in Audiology clinics. However, ~ 10% of adult patients seeking audiological care for self-perceived hearing deficits have thresholds that are normal. Currently, a diagnostic assessment for auditory processing disorder (APD) remains one of the few viable avenues of further care for this patient population, yet there are no standard guidelines for referrals. Here, we identified tests within the APD testing battery that could provide a rapid screener to inform APD referrals in adults. We first analyzed records from the University of Pittsburgh Medical Center (UPMC) Audiology database to identify adult patients with self-perceived hearing difficulties despite normal audiometric thresholds. We then looked at the patients who were referred for APD testing. We examined test performances, correlational relationships, and classification accuracies. Patients experienced most difficulties within the dichotic domain of testing. Additionally, accuracies calculated from sensitivities and specificities revealed the words-in-noise (WIN), the Random Dichotic Digits Task (RDDT) and Quick Speech in Noise (QuickSIN) tests had the highest classification accuracies. The addition of these tests have the greatest promise as a quick screener during routine audiological assessments to help identify adult patients who may be referred for APD assessment and resulting treatment plans.

Human Tim8a, Tim8b and Tim13 are auxiliary assembly factors of mature Complex IV.

Human Tim8a and Tim8b are paralogous intermembrane space proteins of the small TIM chaperone family. Yeast small TIMs function in the trafficking of proteins to the outer and inner mitochondrial membranes. This putative import function for hTim8a and hTim8b has been challenged in human models, but their precise molecular function(s) remains undefined. Likewise, the necessity for human cells to encode two Tim8 proteins and whether any potential redundancy exists is unclear. We demonstrate that hTim8a and hTim8b function in the assembly of cytochrome c oxidase (Complex IV). Using affinity enrichment mass spectrometry, we define the interaction network of hTim8a, hTim8b and hTim13, identifying subunits and assembly factors of the Complex IV COX2 module. hTim8-deficient cells have a COX2 and COX3 module defect and exhibit an accumulation of the Complex IV S2 subcomplex. These data suggest that hTim8a and hTim8b function in assembly of Complex IV via interactions with intermediate-assembly subcomplexes. We propose that hTim8-hTim13 complexes are auxiliary assembly factors involved in the formation of the Complex IV S3 subcomplex during assembly of mature Complex IV.

Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome.

The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.

Hearing screening and amplifier uptake results in a multidisciplinary head and neck cancer survivorship clinic.

PURPOSE: Hearing loss and tinnitus are prevalent among survivors of head and neck cancer (HNC), but auditory issues are under-addressed in the survivorship literature. The purpose of this study was to describe the hearing loss and management experience of a group of survivors provided with a hearing screening and amplifier assistance if needed during their visit. METHODS: A retrospective chart review of 1176 individuals seen in the HNC Survivorship Clinic between December 2016 and October 2020 who interacted with audiology was performed. RESULTS: Of these survivors, 72% failed the 30-dB HL hearing screening at one or more frequencies. Thirty-three percent of the sample reported tinnitus. Consistent with the general population, this group has a low prevalence of hearing aid use. In this clinic, individuals who fail the hearing screening at all frequencies are offered a simple, non-custom amplifier for use during their visit. Thirty-one percent of individuals offered the amplifier used it during their Survivorship Clinic visit to enhance communication and reduce listening effort. Only 54% of individuals who failed the hearing screening self-reported hearing loss. The poor sensitivity and specificity associated with the self-perception of hearing loss data support the need for hearing screening that consists of responding to tones. Of individuals who received a recommendation for a comprehensive hearing test, 21% received a hearing test with 68% of these individuals receiving the hearing test the same day of their Survivorship Clinic visit. CONCLUSIONS: The data from 1176 survivors of HNC seen by audiology over the past few years as part of the UPMC HNC Survivorship Clinic support the need for hearing management in this population to improve communication during and after the Survivorship Clinic visit. IMPLICATIONS FOR CANCER SURVIVORS: Survivors of HNC have a high prevalence of greater than mild hearing loss and tinnitus (both issues known to negatively impact health-related communication and quality of life). This manuscript describes a hearing screening program within a Survivorship Clinic that identifies individuals in need of non-custom amplification during their appointment to support effective communication. Survivors should be referred to audiologists for evaluation and management of treatment-related issues of hearing.