Highly variable hearing loss due to POU4F3 (c.37del) is revealed by longitudinal, frequency specific analyses.

Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15.

Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene.

Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3' UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.

Telepsychology May Improve Treatment Adherence in Patients with Psychogenic Nonepileptic Seizures.

Introduction: Access to mental health care is a significant challenge in patients with psychogenic nonepileptic seizures (PNES). Telepsychology can curb the access barriers and improve adherence but the role of telepsychology in improving adherence has not been well investigated. The current study examines the utility of telepsychology during the COVID-19 pandemic and treatment adherence in PNES patients. Materials and Methods: Patients with PNES admitted to a 12-week counseling program were offered two visit types: telepsychology and in-office. Visit type, visit status, and demographic information were obtained from department database. Follow-up visits in 6 months were used to examine the effect of visit type on visit status. Adherence to treatment was measured by higher attendance of scheduled visits and less cancellation and no-show rates. Results: Two hundred fifty-seven (n) patients who scheduled virtual or telepsychology visits were included in the study. After adjusting for demographic variables, and accounting for repeated measures, telepsychology visits were significantly more likely to be attended (odds ratio [OR] = 2.40, 95% confidence interval [CI] = 1.69-3.41, p < 0.001) and were significantly less likely to be canceled (OR = 0.43, 95% CI = 0.29-0.64, p < 0.001). The regression model showed patients in the telepsychology visit group attended more than three times as many visits as in-office patients (incidence rate ratios = 3.16, 95% CI = 2.13-4.73, p < 0.001). Conclusions: Patients with PNES have logistical and psychological barriers that can impede their ability to attend counseling treatment. Receiving care remotely may have been associated with higher engagement with mental health treatment compared to having to travel to counseling clinics. Considering the symptom-related restrictions patients with PNES have and the barriers presented by the COVID-19 pandemic, telepsychology played a key role for continuation of mental health treatment.

A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

Bridging the gap in epilepsy care: A single-center experience of 3700 outpatient tele-epilepsy visits.

We describe the largest-to-date single-center implementation of tele-epilepsy. Beginning in 2017, all patients at a single tertiary care academic epilepsy center were offered the option to complete outpatient follow-up visits via video-conferencing using personal devices. A retrospective review of all patients who self-selected virtual visits over nearly 3 years showed 2140 patients completed 3698 tele-epilepsy visits, with 41% completing more than one visit during the study period. Based on the distance from the center to the home address, 26.7% of patients were local (≤50 miles), 30.5% were near regional (51-150 miles), 20.1% were far regional (151-270 miles), and 22.7% were remote (>270 miles), from 43 different states. An estimated 928 696 miles of travel was prevented, with a median travel distance saved of 124.5 miles (interquartile range = 45.0-253.0). The mean visit time was 15.7 (±10.4) minutes. More than 90% of patients gave the visit and provider experience the maximum rating, with a nearly 60% response rate on the post-visit survey. Virtual outpatient follow-up care provides a convenient way to connect with epilepsy specialists and reduce the burden of care by cutting travel time. Our experience demonstrates that outpatient tele-epilepsy is feasible, sustainable, and scalable.

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect.

Genetic isolates provide unprecedented opportunities to identify pathogenic mutations and explore the full natural history of clinically heterogeneous phenotypes such as hearing loss. We noticed a unique audioprofile, characterized by prelingual and rapid deterioration of hearing thresholds at frequencies >0.5 kHz in several adults from unrelated families from the island population of Newfoundland. Targeted serial Sanger sequencing of probands for deafness alleles (n = 23) that we previously identified in this founder population was negative. Whole exome sequencing in four members of the largest family (R2010) identified a CLDN14 (DFNB29) variant [c.488C>T; p. (Ala163Val)], likely pathogenic, sensorineural hearing loss, autosomal recessive. Although not associated with deafness or disease, CLDN14 p.(Ala163Val) has been previously reported as a variant of uncertain significance (VUS). Targeted sequencing of 169 deafness probands identified one homozygote and one heterozygous carrier. Genealogical studies, cascade sequencing and haplotype analysis across four unrelated families showed all subjects with the unique audioprofile (n = 12) were also homozygous for p.(Ala163Val) and shared a 1.4 Mb DFNB29-associated haplotype on chromosome 21. Most significantly, sequencing 175 population controls revealed 1% of the population are heterozygous for CLDN14 p.(Ala163Val), consistent with a major founder effect in Newfoundland. The youngest CLDN14 [c.488C>T; p.(Ala163Val)] homozygote passed newborn screening and had normal hearing thresholds up to 3 years of age, which then deteriorated to a precipitous loss >1 kHz during the first decade. Our study suggests that genetic testing may be necessary to identify at-risk children in time to prevent speech, language and developmental delay.

X-linked hearing loss: two gene mutation examples provide generalizable implications for clinical care.

PURPOSE: To describe the inheritance patterns and auditory phenotype features of 3 Canadian families with mutations in 2 X-linked "deafness" genes (DFNX). METHOD: Audiological, medical, and family histories were collected and family members interviewed to compare hearing thresholds and case histories between cases with mutations in SMPX versus POU3F4. RESULTS: The family pedigrees reveal characteristic X-linked inheritance patterns. Phenotypic features associated with the SMPX (DFNX4) mutation include early onset in males with rapid progression from mild and flat to sloping sensorineural loss, with highly variable onset and hearing loss severity in females. In contrast, phenotypic features associated with the POU3F4 (DFNX2) mutation are characterized by an early onset, mixed hearing loss with fluctuation in males, and a normal hearing phenotype reported for females. CONCLUSIONS: The study shows how this unique inheritance pattern and both gender and mutation-specific phenotype variations can alert audiologists to the presence of X-linked genetic etiologies in their clinical practice. By incorporating this knowledge into clinical decision making, audiologists can facilitate the early identification of X-linked hearing loss and contribute to the effective team management of affected families.

Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL.

Autosomal dominant sensorineural hearing loss (ADSNHL) is extremely genetically heterogeneous, making it difficult to molecularly diagnose. We identified a multiplex (n=28 affected) family from the genetic isolate of Newfoundland, Canada with variable SNHL and used a targeted sequencing approach based on population-specific alleles in WFS1, TMPRSS3 and PCDH15; recurrent mutations in GJB2 and GJB6; and frequently mutated exons of KCNQ4, COCH and TECTA. We identified a novel, in-frame deletion (c.806_808delCCT: p.S269del) in the voltage-gated potassium channel KCNQ4 (DFNA2), which in silico modeling predicts to disrupt multimerization of KCNQ4 subunits. Surprisingly, 10/23 deaf relatives are non-carriers of p.S269del. Further molecular characterization of the DFNA2 locus in deletion carriers ruled out the possibility of a pathogenic mutation other than p.S269del at the DFNA2A/B locus and linkage analysis showed significant linkage to DFNA2 (maximum LOD=3.3). Further support of genetic heterogeneity in family 2071 was revealed by comparisons of audio profiles between p.S269del carriers and non-carriers suggesting additional and as yet unknown etiologies. We discuss the serious implications that genetic heterogeneity, in this case observed within a single family, has on molecular diagnostics and genetic counseling.

Workers' perspectives on self-directing mainstream return to work following acute mental illness: reflections on partnerships.

OBJECTIVE: To examine barriers and facilitators influencing self-direction of return to mainstream work following acute mental illness. PARTICIPANTS: Five individuals who had attempted return to mainstream work following acute mental illness. METHODS: In depth, semi-structured qualitative interviews with the five participants selected through purposive sampling. RESULTS: The three main themes related to the workers' self-direction of their return to work experience were (a) worker self-management, (b) workers' 'personal' partnerships and (c) workplace partnerships. CONCLUSION: Personal and workplace partnerships are integral to supporting workers as they take ownership of their full potential and self-direct return to mainstream work.

A couple-based intervention for female breast cancer.

OBJECTIVE: Although women's breast cancer affects both women and their male partners, as well as their relationships, few interventions have been developed to work with couples confronting breast cancer. The current investigation presents the pilot results from a new couple-based intervention program for breast cancer that teaches couples how to minimize negative effects and maximize positive functioning during this difficult time. METHOD: In this pilot study, 14 couples in which the wife had early stage breast cancer were randomly assigned to one of the two treatment conditions: Couple-based relationship enhancement (RE) or treatment-as-usual (TAU). RESULTS: The results from this study suggest that compared with couples receiving treatment-as-usual, both women and men in the RE condition experienced improved functioning on individual psychological variables as well as relationship functioning at posttest and 1-year follow-up. In addition, women in RE show fewer medical symptoms at both time periods. CONCLUSIONS: In this pilot study, the couple-based intervention, RE, has shown promise in improving individual, medical, and relationship functioning for couples in which the woman is facing breast cancer, and therefore merits further investigation on a larger scale.

Observed emotional involvement and overinvolvement in families of patients with bipolar disorder.

Many studies have examined the construct validity of the criticism component of expressed emotion, but little work has been done on clarifying the emotional overinvolvement (EOI) construct. In a sample of 115 recently episodic patients with bipolar disorder, the authors of the present study examined the construct validity of an observational coding system for both appropriate and inappropriate emotional involvement that permitted separate ratings for relatives' intrusiveness, self-sacrificing behaviors, and distress related to the patient's well-being. Findings support the measure's reliability and convergent validity and are moderately supportive of the measure's discriminant validity. Results also suggest that Camberwell Family Interview (C. E. Vaughn & J. P. Leff, 1976) EOI ratings do not discriminate among the different dimensions of the emotional involvement construct (or their appropriateness or inappropriateness) as revealed in laboratory-based interactions. The findings suggest that clinicians working with such families might consider differentiating among the various ways in which family members are involved with the patient and helping them learn to judge under what circumstances such involvement is appropriate and inappropriate.

Factors associated with physiotherapists' interest in cardiorespiratory continuing education using computer-assisted learning: a survey.

PURPOSE: To determine factors associated with Canadian physiotherapists' interest in undertaking continuing education in various cardiorespiratory content areas and their willingness to complete a portion of study within each of these content areas via computer-assisted learning (CAL). METHODS: In a six-page mailed questionnaire, 1,426 potential participants were asked to indicate their interest in 11 cardiorespiratory content areas, their continuing-education preferences, and their access and willingness to do continuing education by CAL. Demographic data were also collected from respondents. RESULTS: Respondents included 285 physiotherapists from cardiorespiratory interest groups (CRGs) and 447 from the licensing bodies' sample (overall response rate = 56%). Physiotherapists in public employment and practice areas other than orthopaedics had increased interest in all cardiorespiratory content areas except Exercise Physiology. Membership in a CRG increased their likelihood to be willing to learn the cardiorespiratory content area via CAL. CONCLUSIONS: In developing content and determining the accessibility of cardiorespiratory continuing education, educators should consider the type of employer and area of practice of interested attendees as well as the lack of willingness to use CAL by those not involved in CRGs.

A case for genetics education: collaborating with speech-language pathologists and audiologists.

Because speech-language pathologists (SLPs) and audiologists (AUDs) are among the first referrals for parents of children exhibiting feeding, speech, language, hearing, and balance difficulties, it is important for SLP and AUD professionals to recognize genetic causes of and contributions to complex and Mendelian communication disorders. We review genetics in the curricula of speech-language pathology and audiology programs and obstacles to its integration throughout curricula. We present suggestions about how SLPs and AUDs can aid in diagnosis and contribute their clinical expertise in characterizing phenotypes, followed with a review of a new genetics-education website developed by the National Coalition for Health Professional Education in Genetics (NCHPEG), the University of Cincinnati, and the National Society of Genetic Counselors. The need to integrate genetics content into curricula and continuing education across disciplines is clear, as is the need for and benefit of multidisciplinary collaboration in patient care. The NCHPEG site for speech-language pathology and audiology begins to address those needs and may serve as a practical model for future multidisciplinary collaborations between genetics professionals and other health professions.

N-Acetyl L-cysteine does not protect against premature age-related hearing loss in C57BL/6J mice: a pilot study.

A compound capable of preventing age-related hearing loss would be very useful in an aging population. N-acetyl-L-cysteine (L-NAC) has been shown to be protective against noise exposure, a condition that leads to increased oxidative stress. Not withstanding environmental factors, there is evidence that age-related hearing loss (AHL) in the mouse is linked to more than one genetic loci and, by extension, in humans. Our hypothesis is that AHL defect results in increased sensitivity to oxidative stress and L-NAC would be able to protect the hearing of a mouse model of pre-mature AHL, the C57BL/6J (B6) mouse strain. L-NAC was added to the regular water bottle of B6 mice (experimental group) and available ad lib. The other group received normal tap water. Hearing was tested monthly by the ability to generate the auditory brainstem response (ABR). After the final ABR test, mice were sacrificed by an overdose of Avertin, ears were harvested and hair cell loss was quantified. There was no difference in ABR thresholds or in histopathology between the control group and the group receiving L-NAC in their drinking water. In contrast to the protective effects of L-NAC against noise-induced hearing loss, the lack of protective effect in this study may be due to (i) the dosage level; (ii) the duration of treatment; (iii) the biochemical mechanisms underlying age-induced hearing loss; or (iv) how the mouse metabolizes L-NAC.

Couples' reports of support for smoking cessation predicting women's late pregnancy cessation.

PURPOSE: Although social support has been linked to smoking cessation, no studies have examined whether social support predicts women's late pregnancy cessation. Further, few have included reports from both support recipients and providers. DESIGN: Longitudinal. SUBJECTS: Pregnant couples (n = 394) reported support for cessation in early (13-20 weeks) and late (28 weeks) pregnancy. MEASURES: Different measures of couples' support were tested for predicting women's late pregnancy, cessation. Measures of couples' support that were calculated included: summative (added women's and male partners' support scores, possible range 2-10), difference (subtracted the lower score from the higher, possible range 0-4), strong link (used higher positive or lower negative score, possible range 1-5), weak link (lower positive or higher negative score, possible range 1-5), and female and male reports alone (possible ranges 1-5). Covariate-adjusted odds ratios for the association of these various measures of couples' support with women's late pregnancy cessation were calculated. RESULTS: Of the 12 scores (6 positive, 6 negative), only summative (p = .03) and weak link (p = .05) for positive support predicted women's quitting. CONCLUSION: Neither women's nor male partners' reports alone predicted women's cessation; only when both scores were considered, either by adding the scores or by taking the lower score, was the positive support score predictive. Future studies of social support should include support recipients' and providers' perspectives.

Rated helpfulness and partner-reported smoking cessation support across the pregnancy-postpartum continuum.

Support interventions have not changed smoking cessation rates significantly. The pregnancy-postpartum continuum presents a unique opportunity to examine patterns of support. Expectant couples (N = 477) were surveyed twice during pregnancy and 3 times postpartum. Partners reported positive and negative smoking-specific support; women reported the helpfulness of partner support. Linear trends suggest that women viewed support as more helpful during pregnancy than during postpartum. Partners' provision of positive support across the continuum depended on their smoking; provision of negative support depended on women's smoking. Partners who smoked provided lower levels of both positive and negative support, especially postpartum. Women who smoked throughout the pregnancy perceived their partner's negative support as helpful. Implications are that partners who smoke may need help staying engaged in the support process. Partners may provide negative support in response to women's smoking cues. Women who are struggling with cessation may not view negative support as negative.

Hearing screening outcomes in infants of pregestational diabetic mothers.

PURPOSE: Hearing screening results for newborns of diabetic mothers were compared with those of nondiabetic controls. METHOD: This study was a retrospective chart review of mothers with pregestational diabetes mellitus and their neonates (n=73) who received newborn hearing screening between January 1, 2000, and May 1, 2002. A group of nondiabetic mothers and their infants (n=73), with birth dates that matched the diabetic group, served as controls. A 2-tiered hearing screening protocol, employing distortion product otoacoustic emission (DPOAE) and automated auditory brainstem response (A-ABR) screening techniques, was used. RESULTS: The DPOAE screening failure rate was 5.5% (4/73) for babies in the nondiabetic control group and 11.0% (8/73) for infants of diabetic mothers; this difference was not statistically significant. The A-ABR failure rate was 9.1% (1/11) for the diabetic group compared with 0% (0/4) for the controls, but the A-ABR was measured for only a small number of participants in each group. The frequency of premature birth and abnormal birth weight was significantly greater for the infants of diabetic mothers compared with controls. CONCLUSIONS: Given the greater frequency of prematurity and abnormal birth weight in the population of neonates born to diabetics, additional research using A-ABR is recommended.

Methodologically sound, cost-effective research on the outcome of couple therapy.

Because of its potential to answer pressing applied questions about what treatments to use with which couples as well as its potential to answer basic questions about couple functioning, outcome research on couple therapy is vital to the field. This article describes the primary methodological issues that an investigator faces in conducting outcome research during treatment development, efficacy testing, and effectiveness evaluation. Descriptions of what has been done in the past are integrated with recommendations about what should be done in the future. Mindful of the potential expense of outcome research, the authors suggest ways in which questions can be investigated cost effectively.