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BACKGROUND AND PURPOSE: Although psychiatric diagnoses are recognized in idiopathic dystonia, no previous studies have examined the temporal relationship between idiopathic dystonia and psychiatric diagnoses at scale. Here, we determine rates of psychiatric diagnoses and psychiatric medication prescription in those diagnosed with idiopathic dystsuponia compared to matched controls. METHODS: A longitudinal population-based cohort study using anonymized electronic health care data in Wales (UK) was conducted to identify individuals with idiopathic dystonia and comorbid psychiatric diagnoses/prescriptions between 1 January 1994 and 31 December 2017. Psychiatric diagnoses/prescriptions were identified from primary and secondary health care records. RESULTS: Individuals with idiopathic dystonia (n = 52,589) had higher rates of psychiatric diagnosis and psychiatric medication prescription when compared to controls (n = 216,754, 43% vs. 31%, p < 0.001; 45% vs. 37.9%, p < 0.001, respectively), with depression and anxiety being most common (cases: 31% and 28%). Psychiatric diagnoses predominantly predated dystonia diagnosis, particularly in the 12 months prior to diagnosis (incidence rate ratio [IRR] = 1.98, 95% confidence interval [CI] = 1.9-2.1), with an IRR of 12.4 (95% CI = 11.8-13.1) for anxiety disorders. There was, however, an elevated rate of most psychiatric diagnoses throughout the study period, including the 12 months after dystonia diagnosis (IRR = 1.96, 95% CI = 1.85-2.07). CONCLUSIONS: This study suggests a bidirectional relationship between psychiatric disorders and dystonia, particularly with mood disorders. Psychiatric and motor symptoms in dystonia may have common aetiological mechanisms, with psychiatric disorders potentially forming prodromal symptoms of idiopathic dystonia.
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Distonia , Distúrbios Distônicos , Transtornos Mentais , Humanos , Estudos de Coortes , Distúrbios Distônicos/complicações , Transtornos Mentais/psicologia , ComorbidadeRESUMO
BACKGROUND AND PURPOSE: Accurate epidemiological information is essential for the improved understanding of dystonia syndromes, as well as better provisioning of clinical services and providing context for diagnostic decision-making. Here, we determine epidemiological, social deprivation, and mortality characteristics of adult-onset idiopathic dystonia in the Welsh population. METHODS: A retrospective population-based cohort study using anonymized electronic health care data in Wales was conducted to identify individuals with dystonia between 1 January 1994 and 31 December 2017. We developed a case-ascertainment algorithm to determine dystonia incidence and prevalence, as well as characterization of the dystonia cohort, based on social deprivation and mortality. RESULTS: The case-ascertainment algorithm (79% sensitivity) identified 54,966 cases; of these cases, 41,660 had adult-onset idiopathic dystonia (≥20 years). Amongst the adult-onset form, the median age at diagnosis was 41 years, with males significantly older at time of diagnosis compared to females. Prevalence rates ranged from 0.02% in 1994 to 1.2% in 2017. The average annual incidence was 87.7/100,000/year, increasing from 49.9/100,000/year (1994) to 96.21/100,000/year (2017). In 2017, people with dystonia had a similar life expectancy to the Welsh population. CONCLUSIONS: We have developed a case-ascertainment algorithm, supported by the introduction of a neurologist-reviewed validation cohort, providing a platform for future population-based dystonia studies. We have established robust population-level prevalence and incidence values for adult-onset idiopathic forms of dystonia, with this reflecting increasing clinical recognition and identification of causal genes. Underlying causes of death mirrored those of the general population, including circulatory disorders, respiratory disorders, cancers, and dementia.
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Distonia , Distúrbios Distônicos , Adulto , Estudos de Coortes , Distonia/epidemiologia , Distúrbios Distônicos/epidemiologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Privação SocialRESUMO
PURPOSE OF REVIEW: To review recent literature evaluating psychiatric and cognitive symptoms in dystonia, the two non-motor symptom groups most frequently evaluated in dystonia research and recognised in clinical practice. RECENT FINDINGS: Recent work has embedded clinical recognition of psychiatric symptoms in dystonia, with depressive and anxiety-related symptoms routinely observed to be the most common. Less explored symptoms, such as self-harm, suicidal ideation, and substance abuse, represent newer areas of investigation, with initial work suggesting higher rates than the background population. Investigation of cognitive function has provided less consistent results, both within individual dystonia subtypes and across the spectrum of dystonias, partly reflecting the heterogeneity in approaches to assessment. However, recent work indicates impairments of higher cognitive function, e.g. social cognition, and disrupted visual and auditory sensory processing. Dystonia demonstrates psychiatric and cognitive symptom heterogeneity, with further work needed to recognise endophenotypes and improve diagnostic accuracy, symptom recognition, and management.
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Distonia , Distúrbios Distônicos , Transtornos Mentais , Humanos , Distonia/genética , Distúrbios Distônicos/complicações , Distúrbios Distônicos/diagnóstico , Transtornos Mentais/complicações , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , CogniçãoRESUMO
Sleep and circadian rhythm disturbances are central features of many movement disorders, exacerbating motor and non-motor symptoms and impairing quality of life. Understanding these disturbances to sleep is clinically important and may further our understanding of the underlying movement disorder. This review evaluates the current anatomical and neurochemical understanding of normal sleep and the recognised primary sleep disorders. In addition, we undertook a systematic review of the evidence for disruption to sleep across multiple movement disorders. Rapid eye movement sleep behaviour disorder has emerged as the most reliable prodromal biomarker for the alpha synucleinopathies, including Parkinson's disease and multiple system atrophy, often preceding motor symptom onset by several years. Abnormal sleep has also been described for many other movement disorders, but further evidence is needed to determine whether this is a primary or secondary phenotypic component of the underlying condition. Medication used in the treatment of motor symptoms also affects sleep and can aggravate or cause certain sleep disorders. Within the context of movement disorders, there is also some suggestion of a shared underlying mechanism for motor and sleep pathophysiology, with evidence implicating thalamic and brainstem structures and monoaminergic neurotransmission. This review highlights the need for an understanding of normal and abnormal sleep within the movement disorder clinic, an ability to screen for specific causes of poor sleep and to treat sleep disturbance to improve quality of life. Key sleep disorders also act as important biomarkers and have implications in diagnosis, prognosis and the development of future therapies.
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Ritmo Circadiano/fisiologia , Transtornos dos Movimentos/complicações , Transtornos do Sono-Vigília/etiologia , Sono/fisiologia , Humanos , Transtornos dos Movimentos/fisiopatologia , Qualidade de Vida , Transtornos do Sono-Vigília/fisiopatologiaRESUMO
Coral reefs, one of the world's most productive and diverse ecosystems, are currently threatened by a variety of stressors that result in increased prevalence of both bleaching and disease. Therefore, understanding the molecular mechanisms involved in these responses is critical to mitigate future damage to the reefs. One group of genes that is potentially involved in cnidarian immunity and symbiosis is GTPases of immunity associated proteins (GIMAP). In vertebrates, this family of proteins is involved in regulating the fate of developing lymphocytes and interacts with proteins involved in apoptosis and autophagy. As apoptosis, autophagy and immunity have previously been shown to be involved in cnidarian symbiosis and disease, the goal of this research was to determine the role of cnidarian GIMAPs in these processes using the anemone Exaiptasia pallida To do so, GIMAP genes were characterized in the E. pallida genome and changes in gene expression were measured using qPCR in response to chemical induction of apoptosis, autophagy and treatment with the immune stimulant lipopolysaccharide (LPS) in both aposymbiotic and symbiotic anemones. The results revealed four GIMAP-like genes in E. pallida, referred to as Ep_GIMAPs Induction of apoptosis and autophagy resulted in a general downregulation of Ep_GIMAPs, but no significant changes were observed in response to LPS treatment. This indicates that Ep_GIMAPs may be involved in the regulation of apoptosis and autophagy, and therefore could play a role in cnidarian-dinoflagellate symbiosis. Overall, these results increase our knowledge on the function of GIMAPs in a basal metazoan.
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Dinoflagellida , Anêmonas-do-Mar , Animais , Apoptose/genética , Autofagia/genética , Ecossistema , GTP Fosfo-Hidrolases , Anêmonas-do-Mar/genética , SimbioseRESUMO
While motor and psychiatric phenotypes in idiopathic dystonia are increasingly well understood, a few studies have examined the rate, type, and temporal pattern of other clinical co-morbidities in dystonia. Here, we determine the rates of clinical diagnoses across 13 broad systems-based diagnostic groups, comparing an overall idiopathic dystonia cohort, and sub-cohorts of cervical dystonia, blepharospasm, and dystonic tremor, to a matched-control cohort. Using the SAIL databank, we undertook a longitudinal population-based cohort study (January 1st 1994-December 31st 2017) using anonymised electronic healthcare records for individuals living in Wales (UK), identifying those diagnosed with dystonia through use of a previously validated algorithm. Clinical co-morbid diagnoses were identified from primary health care records, with a 10% prevalence threshold required for onward analysis. Using this approach, 54,166 dystonia cases were identified together with 216,574 matched controls. Within this cohort, ten of the main ICD-10 diagnostic codes exceeded the 10% prevalence threshold over the 20-year period (infection, neurological, respiratory, gastrointestinal, genitourinary, dermatological, musculoskeletal, circulatory, neoplastic, and endocrinological). In the overall dystonia cohort, musculoskeletal (aOR: 1.89, aHR: 1.74), respiratory (aOR: 1.84; aHR: 1.65), and gastrointestinal (aOR: 1.72; aHR: 1.6) disorders had the strongest associations both pre- and post-dystonia diagnosis. However, variation in the rate of association of individual clinical co-morbidities was observed across the cervical, blepharospasm, and tremor dystonia groups. This study suggests an increased rate of specific co-morbid clinical disorders both pre- and post-dystonia diagnosis which should be considered during clinical assessment of those with dystonia to enable optimum symptomatic management.
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Comorbidade , Distúrbios Distônicos , Humanos , Prevalência , Masculino , Feminino , Pessoa de Meia-Idade , Distúrbios Distônicos/epidemiologia , Adulto , Idoso , Estudos Longitudinais , Estudos de Coortes , Adolescente , Adulto Jovem , Reino Unido/epidemiologia , Idoso de 80 Anos ou mais , País de Gales/epidemiologiaRESUMO
Risky alcohol use and alcohol use disorders (AUD) are a rising problem in women, yet a major disparity in our understanding of what drives alcohol consumption in women remains. Historically biomedical research has focused on male subjects; however, recent increases in reporting of females, have highlighted major differences between the sexes. Here we review the current literature of the effect of gonadal steroid hormones (estrogens, androgens, and progestins), neurosteriods, and neurobiological factors on alcohol use in clinical and preclinical studies of both sexes. Further, we briefly discuss how fundamental sex differences in genetics, metabolism, neuroimmune, and stress responses may influence sex differences in alcohol intake. Comparing the sexes could aid in the discovery of novel therapeutics to treat AUD, and implementation of current treatment options in women.
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Consumo de Bebidas Alcoólicas , Hormônios Esteroides Gonadais , Caracteres Sexuais , Humanos , Feminino , Masculino , Hormônios Esteroides Gonadais/metabolismo , Animais , AlcoolismoRESUMO
BACKGROUND: Dystonia is a hyperkinetic movement disorder with key motor network dysfunction implicated in pathophysiology. The UK Biobank encompasses > 500,000 participants, of whom 42,565 underwent brain MRI scanning. This study applied an optimized pre-processing pipeline, aimed at better accounting for artifact and improving data reliability, to assess for grey and white matter structural MRI changes between individuals diagnosed with primary dystonia and an unaffected control cohort. METHODS: Individuals with dystonia (n = 76) were identified from the UK Biobank using published algorithms, alongside an age- and sex-matched unaffected control cohort (n = 311). Grey matter morphometric and diffusion measures were assessed, together with white matter diffusion tensor and diffusion kurtosis metrics using tractography and tractometry. Post-hoc Neurite Orientation and Density Distribution Imaging (NODDI) was also undertaken for tracts in which significant differences were observed. RESULTS: Grey matter tremor-specific striatal differences were observed, with higher radial kurtosis. Tractography identified no white matter differences, however segmental tractometry identified localised differences, particularly in the superior cerebellar peduncles and anterior thalamic radiations, including higher fractional anisotropy and lower orientation distribution index in dystonia, compared to controls. Additional tremor-specific changes included lower neurite density index in the anterior thalamic radiations. CONCLUSIONS: Analysis of imaging data from one of the largest dystonia cohorts to date demonstrates microstructural differences in cerebellar and thalamic white matter connections, with architectural differences such as less orientation dispersion potentially being a component of the morphological structural changes implicated in dystonia. Distinct tremor-related imaging features are also implicated in both grey and white matter.
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Distonia , Distúrbios Distônicos , Substância Branca , Humanos , Encéfalo , Imagem de Tensor de Difusão/métodos , Bancos de Espécimes Biológicos , Reprodutibilidade dos Testes , Tremor , Biobanco do Reino Unido , Substância Branca/diagnóstico por imagem , Distúrbios Distônicos/diagnóstico por imagem , Imagem de Difusão por Ressonância MagnéticaRESUMO
Background: In the UK, a robust childhood immunisation programme ensures children are offered protection against serious infections; identifying inequalities in vaccination coverage is essential. This is one of the first data linkage studies to examine coverage of primary, as well as pre-school booster and second dose of MMR vaccines, in children receiving support from social care services across Wales. Methods: By accessing records held within the Secure Anonymised Information Linkage (SAIL) Databank, vaccination status of children receiving social care and support between April 2016 and March 2021 (n = 24,540) was ascertained. This was achieved through linkage of the Children Receiving Care and Support (CRCS) Census and National Community Child Health Database which holds vaccination records for all children in Wales registered for NHS care. This sample was split into three groups - those children who had never been recorded on the Child Protection Register (CPR) or as 'Looked After' but in CRCS (n = 12,480), children ever on the CPR (n = 6,225) and those ever recorded as 'Looked After' but who were never on the CPR (n = 5,840). The comparison group of children and young people (CYP) never receiving welfare support consisted of 624,905 children. Results: Children receiving care or support were more likely to be up-to-date with all six vaccines (no recorded vaccines: 0.6-6.3%) compared to children in the comparison group (no recorded vaccines: 3-10.3%). However, of those who were vaccinated, they were less likely to be vaccinated in a timely manner; both early (5.2% vs. 22.2%; margin of error [ME] = 0.52, 95% CI [confidence interval] = -0.18 - -0.17, p < 0.001) and delayed vaccinations were more common (62.7% vs. 71.3%; ME = 0.58, 95% CI = 0.08-0.09, p < 0.001). Validation of the CRCS immunisation flag showed moderate levels of accuracy. Around 70% of immunisation flags were correct across all three groups. Discussion: Findings suggest a positive association between receiving services under a care and support plan and being up-to-date with immunisations; children receiving support under a care and support plan were more likely to have experienced early or late vaccinations, demonstrating that there is still more inter-disciplinary co-ordination and planning needed to improve these outcomes. Thus, identifying inequalities in vaccination coverage is essential to target interventions and to prioritise geographic areas for catch-up.
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Cobertura Vacinal , Vacinação , Humanos , Criança , Pré-Escolar , Adolescente , País de Gales , Vacina contra Sarampo-Caxumba-Rubéola/uso terapêutico , Bases de Dados FactuaisRESUMO
BACKGROUND: Sleep disturbance is an increasingly recognized non-motor trait in dystonia, with varying findings reported to date. Here, we examine sleep in a UK Biobank derived dystonia cohort using subjective self-reported sleep symptoms and objective accelerometer-derived sleep measures, with comparison to a control population. METHODS: A total of 241 dystonia cases were compared to 964 matched controls in analysis of self-reported sleep symptoms and changes in sleep architecture using wrist-worn triaxial accelerometers. RESULTS: Dystonia participants had poorer self-reported sleep patterns compared to controls. Accelerometery measurements demonstrated later sleep times, reduced time in bed, and shifts in circadian rhythm. No association was observed with pain, and only limited relationships with psychiatric symptoms. DISCUSSION: This study demonstrates the utility of accelerometers in longer term evaluation of sleep in dystonia, for measurement of disturbance and response to treatment. Compared to controls, altered sleep and circadian rhythm were more common in dystonia patients which may contribute to the clinical phenotype.
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Distonia , Distúrbios Distônicos , Humanos , Estudos de Coortes , Bancos de Espécimes Biológicos , Sono/fisiologia , Acelerometria , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Up to 70% of individuals diagnosed with adult-onset idiopathic focal cervical dystonia (AOIFCD) report difficulties with sleep. Larger cohort studies using wrist-worn accelerometer devices have emerged as an alternative to smaller polysomnography studies, in order to evaluate sleep architecture. METHODS: To measure activity during the sleep/wake cycle, individuals wore a consumer-grade wrist device (Garmin vivosmart 4) continuously over 7 days on their non-dominant wrist, while completing a daily sleep diary and standardised sleep and non-motor questionnaires via a dedicated app. Sleep measures were derived from the captured raw triaxial acceleration and heart rate values using previously published validated algorithms. RESULTS: Data were collected from 50 individuals diagnosed with AOIFCD and 47 age- and sex-matched controls. Those with AOIFCD self-reported significantly higher levels of excessive daytime sleepiness (p = 0.04) and impaired sleep quality (p = 0.03), while accelerometer measurements found the AOIFCD cohort to have significantly longer total sleep times (p = 0.004) and time spent in NREM sleep (p = 0.009), compared to controls. Overall, there was limited agreement between wearable-derived sleep parameters, and self-reported sleep diary and visual analogue scale records. DISCUSSION: This study shows the potential feasibility of using consumer-grade wearable devices in estimating sleep measures at scale in dystonia cohorts. Those diagnosed with AOIFCD were observed to have altered sleep architecture, notably longer total sleep time and NREM sleep, compared to controls. These findings suggest that previously reported disruptions to brainstem circuitry and serotonin neurotransmission may contribute to both motor and sleep pathophysiology.
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Distúrbios Distônicos , Torcicolo , Dispositivos Eletrônicos Vestíveis , Humanos , Adulto , Polissonografia , Qualidade do Sono , Sono/fisiologiaRESUMO
Introduction: Necrotizing enterocolitis (NEC) is a potentially fatal intestinal disease primarily affecting preterm infants. Early diagnosis of neonates with NEC is crucial to improving outcomes; however, traditional diagnostic tools remain inadequate. Biomarkers represent an opportunity to improve the speed and accuracy of diagnosis, but they are not routinely used in clinical practice. Methods: In this study, we utilized an aptamer-based proteomic discovery assay to identify new serum biomarkers of NEC. We compared levels of serum proteins in neonates with and without NEC and identified ten differentially expressed serum proteins between these groups. Results: We detected two proteins, C-C motif chemokine ligand 16 (CCL16) and immunoglobulin heavy constant alpha 1 and 2 heterodimer (IGHA1 IGHA2), that were significantly increased during NEC and eight that were significantly decreased. Generation of receiver operating characteristic (ROC) curves revealed that alpha-fetoprotein (AUC = 0.926), glucagon (AUC = 0.860), and IGHA1 IGHA2 (AUC = 0.826) were the proteins that best differentiated patients with and without NEC. Discussion: These findings indicate that further investigation into these serum proteins as a biomarker for NEC is warranted. In the future, laboratory tests incorporating these differentially expressed proteins may improve the ability of clinicians to diagnose infants with NEC rapidly and accurately.
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The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case-control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC > 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. Combination with genetic data highlights phenotypic subgroups consistent with the heterogeneity observed in clinical practice.
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Distúrbios Distônicos , Torcicolo , Humanos , Bancos de Espécimes Biológicos , Distúrbios Distônicos/genética , Distúrbios Distônicos/diagnóstico , Dor , Reino Unido/epidemiologia , AnoctaminasRESUMO
BACKGROUND: Non-motor symptoms are well established phenotypic components of adult-onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non-motor phenotypic features to identify possible AOIFCD subgroups. METHODS: Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non-motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self-completed questionnaires or face-to-face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between non-motor symptoms and determine evidence of phenotypic subgroups. RESULTS: Independent cluster analysis of the two cohorts suggests two predominant phenotypic subgroups, one consisting of approximately a third of participants in both cohorts, experiencing increased levels of depression, anxiety, sleep impairment, and pain catastrophizing, as well as, decreased quality of life. The Bayesian approach reinforced this with the primary axis, which explained the majority of the variance, in each cohort being associated with psychiatric symptomology, and also sleep impairment and pain catastrophizing in the Dystonia Wales cohort. CONCLUSIONS: Non-motor symptoms accompanying AOIFCD parse into two predominant phenotypic sub-groups, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention.
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Distúrbios Distônicos , Torcicolo , Adulto , Teorema de Bayes , Humanos , Fenótipo , Qualidade de Vida , Torcicolo/epidemiologiaRESUMO
Coral disease is a major threat to reef ecosystems and therefore, understanding the cellular pathways underlying disease progression and resistance is critical to mitigating future outbreaks. This study focused on tyrosinase-like proteins in cnidarians, which contribute to melanin synthesis, an invertebrate innate immune defense. Specifically, characterization and phylogenetic analysis of cnidarian tyrosinases were performed, and their role in symbiosis and a "mystery disease" in the anemone Exaiptasia pallida was investigated using qPCR. The results reveal a diversity of tyrosinase-like proteins in cnidarians that separate into two major clades on a phylogenetic tree, suggesting functional divergence. Two E. pallida sequences, Ep_Tyr1 and Ep_Tyr2, were further investigated, and qPCR results revealed no gene expression differences as a function of symbiotic state, but decreased expression in late disease stages. Overall this work provides evidence for the participation of tyrosinases in the cnidarian immune response.
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Monofenol Mono-Oxigenase/imunologia , Anêmonas-do-Mar/imunologia , Animais , Monofenol Mono-Oxigenase/genética , Anêmonas-do-Mar/genética , Anêmonas-do-Mar/microbiologia , SimbioseRESUMO
Hearing loss is widespread and persistent because mature mammalian auditory hair cells (HCs) are nonregenerative. In mice, the ability to regenerate HCs from surrounding supporting cells (SCs) declines abruptly after postnatal maturation. We find that combining p27Kip1 deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27Kip1 deletion, independent of canonical effects on Rb-family proteins, upregulated GATA3, a co-factor for ATOH1 that is lost from SCs with age. Co-activation of GATA3 or POU4F3 and ATOH1 promoted conversion of SCs to HCs in adult mice. Activation of POU4F3 alone also converted mature SCs to HCs in vivo. These data illuminate a genetic pathway that initiates auditory HC regeneration and suggest p27Kip1, GATA3, and POU4F3 as additional therapeutic targets for ATOH1-mediated HC regeneration.