E ora come si fa? Realizzare una tesi di laurea multidisciplinare in ambito audio-otologico, radiologico e pediatrico

L\u2019Organizzazione Mondiale della Sanit\ue0 (OMS) ha posto in evidenza la dimensione sociale della disabilit\ue0 fin dagli anni \u201880, e, nel 2001, ne ha successivamente rivoluzionato l\u2019approccio, guardando alla disabilit\ue0 non come una lineare e logica conseguenza della menomazione, ma come il risultato di un\u2019interazione tra lo stato di salute della persona e l\u2019ambiente in cui vive. Nonostante quest\u2019ultima visione della disabilit\ue0 sia oggi universalmente condivisa, il pensiero e la pratica medica, l\u2019organizzazione sanitaria ospedaliera e le successive strategie socio-assistenziali, faticano ancor\u2019oggi a staccarsi da un sistema tradizionale, che mette maggiormente a fuoco la diagnosi, il trattamento e il generale \u201csupporto\u201d alle patologie croniche, trascurando la prospettiva orientata allo sviluppo e alla disabilit\ue0 nella sua accezione compiuta. In sintonia con i principi emergenti in sanit\ue0, e cio\ue8 la centralit\ue0 del paziente e della sua rete di cura, il termine disabilit\ue0 vuole in definitiva evidenziare che il deficit e l\u2019eventuale presenza di patologie associate non sono i soli elementi da prendere in considerazione nel trattamento. L\u2019approccio di cura alle condizioni croniche deve diventare multi-prospettico: non solo biomedico, anche individuale, sociale, ambientale. Queste considerazioni risultano valere ancor di pi\uf9 quando si curano ipoacusie e sordit\ue0 congenite o preverbali, condizioni che si manifestano all\u2019inizio o precocemente nella vita di un bambino, e che durano per tutta la vita, con conseguenze funzionali che possono fortemente condizionare le traiettorie dello sviluppo. Il contributo pi\uf9 specifico del sottoscritto \ue8 nel paragrafo: "E ora come si fa? Realizzare una tesi di laurea multidisciplinare in ambito Audio-Otologico, Radiologico e Pediatrico

Copy number variation, gene expression and histological localization of human beta-defensin 2 in patients with adeno-tonsillar hypertrophy

Both bacterial infections and innate oral immunity response participate in development of adeno-tonsillar hypertrophy (ATH). ATH can lead to obstructive sleep apnea. We investigated the beta-defensin 2 (hBD-2) encoding gene, DEFB4, by analyzing the copy number variations (CNVs) of the defensin gene cluster in patients with ATH and by correlating CNV with DEFB4 gene expression. We enrolled 79 patients with ATH, 21 of whom presented with only adenoid hypertrophy, while 58 exhibited hypertrophy of both adenoid and tonsil. CNVs of the defensin gene cluster, DEFB4 mRNA, and hBD-2 protein expression were assessed. Also, beta-defensin 2 was localized histologically using immunohistochemistry. The distribution of defensin gene cluster CNV was similar among the 79 subjects. DEFB4 expression analysis exhibited considerable inter-individual variability, but with neither specific differences among subjects nor correlation with the CNV number. Immunohistochemistry enabled localization of hBD-2 in the tonsil and adenoid epithelium. No differences in localization between the two ATH presentations were found. Inducible antimicrobial defensin peptides exhibited great inter-individual variability in terms of both CNV and gene expression, but no correlation with presentation of ATH was found

Proteomic study identifies glycolytic and inflammation pathways involved in recurrent otitis media

Recurrent acute otitis media (RAOM) in children is clinically defined as the occurrence of at least three episodes of acute otitis media over a course of 6 months. A further common pathological condition of interest in the context of pediatric otolaryngology is adenotonsillar hypertrophy (ATH), a common cause of obstructive sleep apnea syndrome. Aimed at unraveling the differential modulation of proteins in the two pathologies and at understanding the possible pathways involved in their onset, we analyzed the proteomic profile of the adenoids from 14 RAOM and ATH patients by using two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). The 2-DE coupled with MS allowed us to identify 23 spots with significant (p-value < 0.05) changes in protein amount, recognizing proteins involved in neutrophil degranulation and glycolysis pathways.This research was funded by I.R.C.C.S. “B. G.”, grant number RC 02/20 and RC 15/17

Left atrial geometric and functional remodeling parameters by cardiac magnetic resonance imaging and outcome prediction in patients with severe aortic stenosis

BACKGROUND: Emerging studies are beginning to shape the role of afflicted left atrium’s (LA) function and strain in cardiovascular diseases including aortic stenosis (AS), especially for risk stratification and outcome prediction. Cardiac magnetic resonance imaging (CMR) is becoming increasingly useful in determining parameters of LA, however, in patients with AS, this has not been yet approached. AIMS: The study sought to evaluate the role of CMR in characterizing LA geometry and function in patients with severe AS. METHODS: We prospectively evaluated 70 patients with symptomatic severe AS and 70 controls. LA volumes, function and strain were determined using CMR. A composite outcome (cardiac death, ventricular tachyarrhythmias, and heart failure hospitalization) was evaluated over a median of 13 months. Time-to-event outcomes were analyzed accordingly. RESULTS: Besides increased LA volumes (LAVs) and LA sphericity index (LASI) (P &lt;0.001), LA phasic functions and strain were considerably defective in patients with AS (all P &lt;0.001). LV mass (LVM), end-diastolic and end-systolic volumes were also significantly associated withal LA strain parameters (P &lt;0.001). Regarding outcome prediction, decreased total (LA-et), active (LA-ea) and passive strain (LA-ep), along with enhanced LASI were independently associated with outcome (P &lt;0.001). Time-to-event analysis showed significantly higher risk to reach the composite outcome for LA-et &lt;31.1% [HR=6.981; 95%CI (2.74–17.77),  P &lt;0.001)], LA-ep &lt;14.5% [HR = 2.68; 95% CI (1.00–7.18), P&lt;0.01)], and LA-ea &lt;21.2% [HR = 2.02; 95% CI (1.07–3.83), P &lt;0.03]. CONCLUSION: Patients with severe AS have significantly remodelled LA, with impaired phasic function and strain. Amongst all CMR parameters, LAVmin, LASI, LAPF and LA-ep appear to be independent predictors for outcome

Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations

Hereditary hearing loss (HHL) is a common disorder characterized by a huge genetic heterogeneity. The definition of a correct molecular diagnosis is essential for proper genetic counseling, recurrence risk estimation, and therapeutic options. From 20 to 40% of patients carry mutations in GJB2 gene, thus, in more than half of cases it is necessary to look for causative variants in the other genes so far identified (~100). In this light, the use of next-generation sequencing technologies has proved to be the best solution for mutational screening, even though it is not always conclusive. Here we describe a combined approach, based on targeted re-sequencing (TRS) of 96 HHL genes followed by high-density SNP arrays, aimed at the identification of the molecular causes of non-syndromic HHL (NSHL). This strategy has been applied to study 103 Italian unrelated cases, negative for mutations in GJB2, and led to the characterization of 31% of them (i.e., 37% of familial and 26.3% of sporadic cases). In particular, TRS revealed TECTA and ACTG1 genes as major players in the Italian population. Furthermore, two de novo missense variants in ACTG1 have been identified and investigated through protein modeling and molecular dynamics simulations, confirming their likely pathogenic effect. Among the selected patients analyzed by SNP arrays (negative to TRS, or with a single variant in a recessive gene) a molecular diagnosis was reached in ~36% of cases, highlighting the importance to look for large insertions/deletions. Moreover, copy number variants analysis led to the identification of the first case of uniparental disomy involving LOXHD1 gene. Overall, taking into account the contribution of GJB2, plus the results from TRS and SNP arrays, it was possible to reach a molecular diagnosis in ~51% of NSHL cases. These data proved the usefulness of a combined approach for the analysis of NSHL and for the definition of the epidemiological picture of HHL in the Italian population

Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment

Correlation of cochlear aperture stenosis with cochlear nerve deficiency in congenital unilateral hearing loss and prognostic relevance for cochlear implantation

The use of neonatal hearing screening has enabled the identifcation of congenital unilateral sensorineural hearing loss (USNHL) immediately after birth, and today there are several intervention options available to minimize potential adverse efects of this disease, including cochlear implantation. This study aims to analyze the characteristics of the inner ear of a homogeneous group of congenital non-syndromic USNHL to highlight the features of the inner ear, which can help in clinical, surgical, and rehabilitative decision-making. A retrospective chart review was carried out at a tertiary referral center. Systematic diagnostic work-up and rigorous inclusion\u2013exclusion criteria were applied to 126 children with unilateral hearing impairment, leading to a selection of 39 strictly congenital and non-syndromic USNHL cases, undergoing computed tomography (CT) and magnetic resonance (MR) imaging studies. The frequency and type of malformations of the inner ear in USNHL and unafected contralateral ears were assessed, with an in-depth analysis of the defciency of the cochlear nerve (CND), the internal auditory canal (IAC) and the cochlear aperture (CA). Inner ear anomalies were found in 18 out of 39 (46%) of the USNHL patients. In 1 subject, the anomalies were bilateral, and the CND resulted in the predominant identifed defect (78% of our abnormal case series), frequently associated with CA stenosis. Only 3 out of 14 children with CND presented stenosis of the IAC. CND and CA stenosis (and to a much lesser extent IAC stenosis) are a frequent association within congenital and non-syndromic USNHL that could represent a distinct pathological entity afecting otherwise healthy infants. In the context of a diagnostic work-up, the evaluation with CT and MRI measurements should take place in a shared decision-making setting with thorough counseling. Both imaging techniques have proven useful in differentiating the cases that will most likely beneft from the cochlear implant, from those with potentially poor implant performance

Modeling postnatal hearing case finding within the Italian National Health System

Objective: Despite the successful implementation of newborn hearing screening (NHS), a debate is emerging as to what should be the best means of enabling timely diagnosis and intervention for preschoolers with educationally significant sensorineural or conductive hearing impairment (HI) missed at the time of NHS or occurred after birth. Our study aims to document the proportion and characteristics of HIs diagnosed in children in need of audiologic assessment, in order to outline the optimization areas of an operational framework for auditory surveillance during preschool age. Method: The referral routes and outcomes of 730 audiological assessments performed in 3 years within the framework of the early hearing identification program in Trieste (Italy) were retrospectively analyzed. Results: Among 570/595 completed evaluations, an HI was diagnosed in 114 children, 73.7% of which presenting an exclusively conductive HI due to middle ear effusion. HIs were found in 36/141 who failed NHS, and 60/385 preschoolers who were referred by the primary care pediatrician's surveillance activity during well-child visits, with diagnostic yield of 25.5 and 15.5%, respectively. Conclusion: Ongoing preschool surveillance in primary care setting integrated into a NHS program is feasible to conduct and may effectively identify HIs that missed NHS or were related with a risk factor. New triage instruments and protocols for immediate audiology referral could allow to obtain the diagnosis of educationally significant conductive and sensorineural HIs ahead of the development concern and in the same way reduce patient mobility, thus optimizing timing efficiency and economic impact of the program

Spontaneous head movements support accurate horizontal auditory localization in a virtual visual environment

This study investigates the relationship between auditory localization accuracy in the horizontal plane and the spontaneous translation and rotation of the head in response to an acoustic stimulus from an invisible sound source. Although a number of studies have suggested that localization ability improves with head movements, most of them measured the perceived source elevation and front-back disambiguation. We investigated the contribution of head movements to auditory localization in the anterior horizontal field in normal hearing subjects. A virtual reality scenario was used to conceal visual cues during the test through a head mounted display. In this condition, we found that an active search of the sound origin using head movements is not strictly necessary, yet sufficient for achieving greater sound source localization accuracy. This result may have important implications in the clinical assessment and training of adults and children affected by hearing and motor impairments

Assessment of Communication Abilities in Four Children with Early Bilateral CIs in Clinical and Home Environments with LENA System: A Case Report

Children’s language acquisition is underpinned by the quantity and quality of linguistic stimulation. Early diagnosis and cochlear implantation (CI), along with a family-centered intervention, are regarded as critical factors in providing appropriate language stimulation and thus supporting successful language outcomes in children with sensory neural hearing loss (SNHL). Considering the lack of tools to assess early language skills and open issues regarding the early predictors of CI outcomes, our goal was to evaluate the potential usability of the Language ENvironment Analysis (LENA) system as an early assessment and/or predictive tool. Clinical video recordings, LENA home recordings, and vocabulary scores were used to assess the progression of communication abilities of four children with CIs (6–35 m.o.). The data revealed a positive correlation between the estimated mean length of utterance (EMLU), vocal conversational turns (CT) in clinical video recordings, and receptive vocabulary, as well as the CT count in LENA being a significant predictor of productive vocabulary. These findings lead us to conclude that the LENA system has the potential to be used as an additional (tele-)measure in the early assessment of communication abilities of children with CI, as well as as a tool in the research of early predictors of CI outcomes