Neural Correlates of Speech Processing in Prelingually Deafened Children and Adolescents with Cochlear Implants

Prelingually deafened children with cochlear implants stand a good chance of developing satisfactory speech performance. Nevertheless, their eventual language performance is highly variable and not fully explainable by the duration of deafness and hearing experience. In this study, two groups of cochlear implant users (CI groups) with very good basic hearing abilities but non-overlapping speech performance (very good or very bad speech performance) were matched according to hearing age and age at implantation. We assessed whether these CI groups differed with regard to their phoneme discrimination ability and auditory sensory memory capacity, as suggested by earlier studies. These functions were measured behaviorally and with the Mismatch Negativity (MMN). Phoneme discrimination ability was comparable in the CI group of good performers and matched healthy controls, which were both better than the bad performers. Source analyses revealed larger MMN activity (155–225 ms) in good than in bad performers, which was generated in the frontal cortex and positively correlated with measures of working memory. For the bad performers, this was followed by an increased activation of left temporal regions from 225 to 250 ms with a focus on the auditory cortex. These results indicate that the two CI groups developed different auditory speech processing strategies and stress the role of phonological functions of auditory sensory memory and the prefrontal cortex in positively developing speech perception and production

Unraveling haplotype errors in the DFNA33 locus

Genetic heterogeneity makes it difficult to identify the causal genes for hearing loss. Studies from previous decades have mapped numerous genetic loci, providing critical supporting evidence for gene discovery studies. Despite widespread sequencing accessibility, many historically mapped loci remain without a causal gene. The DFNA33 locus was mapped in 2009 and coincidentally contains ATP11A, a gene recently associated with autosomal dominant hearing loss and auditory neuropathy type 2. In a rare opportunity, we genome-sequenced a member of the original family to determine whether the DFNA33 locus may also be assigned to ATP11A. We identified a deep intronic variant in ATP11A that showed evidence of functionally normal splicing. Furthermore, we re-assessed haplotypes from the originally published DFNA33 family and identified two double recombination events and one triple recombination event in the pedigree, a highly unlikely occurrence, especially at this scale. This brief research report also serves as a call to the community to revisit families who have previously been involved in gene mapping studies, provide closure, and resolve these historical loci

TIMELESS Forms a Complex with PARP1 Distinct from Its Complex with TIPIN and Plays a Role in the DNA Damage Response

SummaryPARP1 is the main sensor of single- and double-strand breaks in DNA and, in building chains of poly(ADP-ribose), promotes the recruitment of many downstream signaling and effector proteins involved in the DNA damage response (DDR). We show a robust physical interaction between PARP1 and the replication fork protein TIMELESS, distinct from the known TIMELESS-TIPIN complex, which activates the intra-S phase checkpoint. TIMELESS recruitment to laser-induced sites of DNA damage is dependent on its binding to PARP1, but not PARP1 activity. We also find that the PARP1-TIMELESS complex contains a number of established PARP1 substrates, and TIMELESS mutants unable to bind PARP1 are impaired in their ability to bind PARP1 substrates. Further, PARP1 binding to certain substrates and their recruitment to DNA damage lesions is impaired by TIMELESS knockdown, and TIMELESS silencing significantly impairs DNA double-strand break repair. We hypothesize that TIMELESS cooperates in the PARP1-mediated DDR

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment

When Hearing Is Tricky: Speech Processing Strategies in Prelingually Deafened Children and Adolescents with Cochlear Implants Having Good and Poor Speech Performance

Cochlear implants provide individuals who are deaf with access to speech. Although substantial advancements have been made by novel technologies, there still is high variability in language development during childhood, depending on adaptation and neural plasticity. These factors have often been investigated in the auditory domain, with the mismatch negativity as an index for sensory and phonological processing. Several studies have demonstrated that the MMN is an electrophysiological correlate for hearing improvement with cochlear implants. In this study, two groups of cochlear implant users, both with very good basic hearing abilities but with non-overlapping speech performance (very good or very poor speech performance), were matched according to device experience and age at implantation. We tested the perception of phonemes in the context of specific other phonemes from which they were very hard to discriminate (e.g., the vowels in /bu/ vs. /bo/). The most difficult pair was individually determined for each articipant. Using behavioral measures, both cochlear implants groups performed worse than matched controls, and the good performers performed better than the poor performers. Cochlear implant groups and controls did not differ during time intervals typically used for the mismatch negativity, but earlier: source analyses revealed increased activity in the region of the right supramarginal gyrus (220±260 ms) in good performers. Poor performers showed increased activity in the left occipital cortex (220±290 ms), which may be an index for cross-modal perception. The time course and the neural generators differ from data from our earlier studies, in which the same phonemes were assessed in an easy-to-discriminate context. The results demonstrate that the groups used different language processing strategies, depending on the success of language development and the particular language context. Overall, our data emphasize the role of neural plasticity and use of adaptive strategies for successful language development with cochlear implants.</p

Recommendations for Age-Appropriate Testing, Timing, and Frequency of Audiologic Monitoring during Childhood Cancer Treatment: An International Society of Paediatric Oncology Supportive Care Consensus Report

Importance: Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on. Objective: To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice. Methods: An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel. Findings: The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources. Conclusions and Relevance: This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens

Recommendations for Age-Appropriate Testing, Timing, and Frequency of Audiologic Monitoring During Childhood Cancer Treatment An International Society of Paediatric Oncology Supportive Care Consensus Report

IMPORTANCE Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on. OBJECTIVE To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice. METHODS An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel. FINDINGS The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources. CONCLUSIONS AND RELEVANCE This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens

PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents

Aims: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies. Methods: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning. Results: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors. Conclusions: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being