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Abstract Background Individuals with thiamine-responsive megaloblastic anemia (TRMA) mainly manifest macrocytic anemia, sensorineural deafness, ocular complications, and nonautoimmune diabetes. Macrocytic anemia and diabetes may be responsive to high-dosage thiamine treatment, in contrast to sensorineural deafness. Little is known about the efficacy of thiamine treatment on ocular manifestations. Cases presentation Our objective is to report data from four Italian TRMA patients: in Cases 1, 2 and 3, the diagnosis of TRMA was made at 9, 14 and 27 months. In 3 out of 4 subjects, thiamine therapy allowed both normalization of hyperglycemia, with consequent insulin suspension, and macrocytic anemia. In all Cases, thiamine therapy did not resolve the clinical manifestation of deafness. In Cases 2 and 3, follow-up showed no blindness, unlike Case 4, in which treatment was started for megaloblastic anemia at age 7 but was increased to high doses only at age 25, when the genetic diagnosis of TRMA was performed. Conclusions Early institution of high-dose thiamine supplementation seems to prevent the development of retinal changes and optic atrophy in TRMA patients. The spectrum of clinical manifestations is broad, and it is important to describe known Cases to gain a better understanding of this rare disease.

IntroductionSensorineural hearing loss (SNHL) has been suggested to be possibly related to congenital toxoplasmosis (CT), although its prevalence varies from 0% to 26%. This variance appears to be dependent especially on early timing of treatment. However, the available data are based on outdated studies conducted on small groups of patients that lack homogeneity. Therefore, to establish evidence-based guidelines for audiologic monitoring in CT, we conducted a comprehensive evaluation of a large case series over a long period of time.Patients and methodsThis is a single-center, retrospective cohort that enrolled all infants and children who were exposed in utero to Toxoplasma gondii and/or congenitally infected between September 1980 and December 2022. They underwent standard serial audiological evaluations to detect possible SNHL at an early stage. The first evaluation was performed during the initial assessment to define the onset of congenital toxoplasmosis, with another evaluation conducted at least at 12 months of life.ResultsWe collected data from 1,712 patients, and 183 (10.7%) were diagnosed with CT. Among these cases, 78 children (42.6%) presented with symptomatic CT at the onset, exhibiting ocular findings (21.1%), clinical cerebral manifestations (6.1%), and/or abnormal findings on neuroimaging (35.5%). Therapy was administrated at the onset in 164 patients (89.6%) with 115 of them starting treatment prior to 2.5 months of age (0–388, median 32.00 ± 92.352 days of life). Only one patient presented with SNHL at the onset, but this was apparently unrelated to CT. The median number of audiological assessments was 2.2 ± 1.543 (2–10). No patients developed any grade of delayed hearing loss, both in treated and untreated groups. The median age at last audiological evaluation was 2.3 ± 2.18 years (1–8), although the median follow-up period was 12.4 years (±6.3), ranging from 1 to 27 years.ConclusionsBased on these data, it appears that SNHL may be less frequent in CT than previously assumed. We recommend conducting an audiological assessment at the onset (within the first 2.5 months of life) to comprehensively define the type of CT onset, and then conducting another evaluation within 9 months of life.

Background and Aims: Perianal fistula represents one of the most disabling manifestations of Crohn′s disease (CD) due to complete destruction of the affected mucosa, which is replaced by granulation tissue and associated with changes in tissue organization. To date, the molecular mechanisms underlying perianal fistula formation are not well defined. Here, we dissected the tissue changes in the fistula area and addressed whether a dysregulation of extracellular matrix (ECM) homeostasis can support fistula formation. Methods: Surgical specimens from perianal fistula tissue and the surrounding region of fistulizing CD were analyzed histologically and by RNA sequencing. Genes significantly modulated were validated by real-time polymerase chain reaction, Western blot, and immunofluorescence assays. The effect of the protein product of TNF-stimulated gene-6 (TSG-6) on cell morphology, phenotype, and ECM organization was investigated with endogenous lentivirus-induced overexpression of TSG-6 in Caco-2 cells and with exogenous addition of recombinant human TSG-6 protein to primary fibroblasts from region surrounding fistula. Proliferative and migratory assays were performed. Results: A markedly different organization of ECM was found across fistula and surrounding fistula regions with an increased expression of integrins and matrix metalloproteinases and hyaluronan (HA) staining in the fistula, associated with increased newly synthesized collagen fibers and mechanosensitive proteins. Among dysregulated genes associated with ECM, TNFAI6 (gene encoding for TSG-6) was as significantly upregulated in the fistula compared with area surrounding fistula, where it promoted the pathological formation of complexes between heavy chains from inter-alpha-inhibitor and HA responsible for the formation of a crosslinked ECM. There was a positive correlation between TNFAI6 expression and expression of mechanosensitive genes in fistula tissue. The overexpression of TSG-6 in Caco-2 cells promoted migration, epithelial–mesenchymal transition, transcription factor SNAI1, and HA synthase (HAs) levels, while in fibroblasts, isolated from the area surrounding the fistula, it promoted an activated phenotype. Moreover, the enrichment of an HA scaffold with recombinant human TSG-6 protein promoted collagen release and increase of SNAI1, ITGA4, ITGA42B, and PTK2B genes, the latter being involved in the transduction of responses to mechanical stimuli. Conclusions: By mediating changes in the ECM organization, TSG-6 triggers the epithelial–mesenchymal transition transcription factor SNAI1 through the activation of mechanosensitive proteins. These data point to regulators of ECM as new potential targets for the treatment of CD perianal fistula.

Abstract Tumor‐associated macrophages (TAMs) have a unique favorable effect on the prognosis of colorectal cancer (CRC), although their association with stage‐specific outcomes remains unclear. We assessed the densities of CD68+ and CD163+ TAMs at the invasive front of resected CRC stage III CRC from 236 patients, 165 of whom received post‐surgical FOLFOX treatment, and their relationship with disease‐free survival (DFS). Associations between macrophage mRNAs and clinical outcome were investigated in silico in 59 stage III CRC and FOLFOX‐treated patients from The Cancer Genome Atlas (TCGA). Biological interactions of SW480 and HT29 cells and macrophages with FOLFOX were tested in co‐culture models. Low TAM densities were associated with shorter DFS among patients receiving FOLFOX (CD68+, p = 0.0001; CD163+, p = 0.0008) but not among those who were untreated. By multivariate Cox analysis, only low TAM (CD68+, p = 0.001; CD163+, p = 0.002) and nodal status (CD68+, p = 0.009; CD163+, p = 0.007) maintained an independent predictive value. In the TCGA cohort, high CD68 mRNA levels were associated with better outcome (p = 0.02). Macrophages enhanced FOLFOX cytotoxicity on CRC cells (p

Background: An early hearing detection and intervention program (EHDI) is the first step for the habilitation of children with permanent hearing impairment (PHI). Actually, early intervention programs have increasingly shifted toward family involvement, emphasizing that the child’s family should take an active role in the habilitation process. Therefore, familiar empowerment is the best way to improve a child’s emerging abilities. The aim of this study was to investigate parental self-efficacy beliefs and involvement as well as the language skills of deaf or hard of hearing DHH children who were habilitated with hearing aids and followed using the T.A.T.A web app (NeonaTal Assisted TelerehAbilitation), an example of asynchronous telepractice. Methods: The study describes the early stages of the habilitation program of 15 PHI children followed through the T.A.T.A. web app, which empowers families through a weekly questionnaire submitted during the first 270 to 360 days of their child’s life, for 14 weeks. The family involvement rate scale (FIRS) was used to evaluate parental compliance, and all children received in-person visits at the beginning and at the end of the training period. Results: The children showed greater auditory perceptual skills at the end of the training period on the basis of both the Infant Listening Progress Profile (ILiP) score and the Categories of Auditory Performance (CAP) and FIRS scales. In other words, the auditory skills improved with age as well as with parental participation. Conclusions: The T.A.T.A. web app promotes a proactive management and a tailored habilitation through an active familiar involvement, easily achieved in clinical routine and in emergency settings without additional costs.

With more than 466 million people affected, hearing loss represents the most common sensory pathology worldwide. Despite its widespread occurrence, much remains to be explored, particularly concerning the intricate pathogenic mechanisms underlying its diverse phenotypes. In this context, metabolomics emerges as a promising approach. Indeed, lying downstream from molecular biology’s central dogma, the metabolome reflects both genetic traits and environmental influences. Furthermore, its dynamic nature facilitates well-defined changes during disease states, making metabolomic analysis a unique lens into the mechanisms underpinning various hearing impairment forms. Hence, these investigations may pave the way for improved diagnostic strategies, personalized interventions and targeted treatments, ultimately enhancing the clinical management of affected individuals. In this comprehensive review, we discuss findings from 20 original articles, including human and animal studies. Existing literature highlights specific metabolic changes associated with hearing loss and ototoxicity of certain compounds. Nevertheless, numerous critical issues have emerged from the study of the current state of the art, with the lack of standardization of methods, significant heterogeneity in the studies and often small sample sizes being the main limiting factors for the reliability of these findings. Therefore, these results should serve as a stepping stone for future research aimed at addressing the aforementioned challenges.

Abstract GPR120 (encoded by FFAR4 gene) is a receptor for long chain fatty acids, activated by ω-3 Polyunsaturated Fatty Acids (PUFAs), and expressed in many cell types. Its role in the context of colorectal cancer (CRC) is still puzzling with many controversial evidences. Here, we explored the involvement of epithelial GPR120 in the CRC development. Both in vitro and in vivo experiments were conducted to mimic the conditional deletion of the receptor from gut epithelium. Intestinal permeability and integrity of mucus layer were assessed by using Evans blue dye and immunofluorescence for MUC-2 protein, respectively. Microbiota composition, presence of lipid mediators and short chain fatty acids were analyzed in the stools of conditional GPR120 and wild type (WT) mice. Incidence and grade of tumors were evaluated in all groups of mice before and after colitis-associated cancer. Finally, GPR120 expression was analyzed in 9 human normal tissues, 9 adenomas, and 17 primary adenocarcinomas. Our work for the first time highlights the role of the receptor in the progression of colorectal cancer. We observed that the loss of epithelial GPR120 in the gut results into increased intestinal permeability, microbiota translocation and dysbiosis, which turns into hyperproliferation of epithelial cells, likely through the activation of β -catenin signaling. Therefore, the loss of GPR120 represents an early event of CRC, but avoid its progression as invasive cancer. these results demonstrate that the epithelial GPR120 receptor is essential to maintain the mucosal barrier integrity and to prevent CRC developing. Therefore, our data pave the way to GPR120 as an useful marker for the phenotypic characterization of CRC lesions and as new potential target for CRC prevention.

Background: The aim of this study was to compare, in users of bimodal cochlear implants, the performance obtained using their own hearing aids (adjusted with the standard NAL-NL1 fitting formula) with the performance using the Phonak Naìda Link Ultra Power hearing aid adjusted with both NAL-NL1 and a new bimodal system (Adaptive Phonak Digital Bimodal (APDB)) developed by Advanced Bionics and Phonak Corporations. Methods: Eleven bimodal users (Naìda CI Q70 + contralateral hearing aid) were enrolled in our study. The users’ own hearing aids were replaced with the Phonak Naìda Link Ultra Power and fitted following the new formula. Speech intelligibility was assessed in quiet and noisy conditions, and comparisons were made with the results obtained with the users’ previous hearing aids and with the Naída Link hearing aids fitted with the NAL-NL1 generic prescription formula. Results: Using Phonak Naìda Link Ultra Power hearing aids with the Adaptive Phonak Digital Bimodal fitting formula, performance was significantly better than that with the users’ own rehabilitation systems, especially in challenging hearing situations for all analyzed subjects. Conclusions: Speech intelligibility tests in quiet settings did not reveal a significant difference in performance between the new fitting formula and NAL-NL1 fittings (using the Naída Link hearing aids), whereas the performance difference between the two fittings was very significant in noisy test conditions.

IntroductionSeveral studies and meta-analyses suggested the role of vitamin D 25OH in preventing severe forms of coronavirus disease 2019 (COVID-19). However, the evidence on the clinical benefits of vitamin D 25OH adequacy in patients hospitalized for COVID-19 remain conflicting and speculative. We aimed to investigate the association between vitamin D 25OH serum levels and mortality in hospitalized patients with moderate to severe COVID-19.MethodThis prospective observational multicentre study included 361 consecutive patients with moderate to severe COVID-19 admitted to the Italian hospitals involved in the NUTRI-COVID19 trial from March to August 2020. For each patient, serum vitamin D 25OH levels were assessed 48 h since admission and classified as deficient (

Permanent childhood hearing impairment (PCHI) represents the most frequent sensory pathology at birth. PCHI has a relevant psychological impact on the life of both the affected children and their families. Thus, the aim of this work is to explore the degree of parental distress felt by mothers of a deaf or hard-of-hearing child, to determine if this stress is associated with variables related to the children’s health (e.g., the severity of hearing loss, presence of other conditions, difficulty with treatment options, difficulty with rehabilitation) or family characteristics such as socio-economic and educational status. The study used the Parenting Stress Index–Short Form (PSI-SF) questionnaire administered to mothers. The results were analyzed in relation to variables such as parents’ education level, number of children, severity of hearing loss, presence of other chronic conditions, presence of cognitive delay, familiarity with hearing loss, time of diagnosis, use of prosthetics, and start in a rehabilitation program. The data indicate a correlation between maternal stress levels and low-educational levels, as well as the presence of congenital infections and cognitive delay. These results highlight the need for a comprehensive physical and psychological approach for hearing-impaired children, as stress factors can affect the adherence to effective rehabilitation.

Background and Objectives: Midlife hearing loss (HL) has been considered as a major modifiable risk factor for a later-life progression to dementia. Our aim was to detect a link between precocious sensorineural hearing loss (SNHL) and mild cognitive impairment (MCI) and their association to putative risk factors for a common pathology. Materials and methods: In this study, a retrospective case-control study was carried out. A total of 112 patients were enrolled as following: 81 patients with bilateral SNHL and 31 subjects with normal hearing, whose ages ranged from 50 to 65 years. Both groups performed pure tone audiometry, a tinnitus handicap inventory (THI), Mini-Mental State examination (MMSE), and the Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS-A and HADS-D). Results: The mean age was 58 ± 5.2 in SNHL patients and 53.2 ± 4.8 in the control group. The mean pure tone average in the SNHL group was 40.2 ± 18.7 dB HL on the right side and 41.2 ± 17.2 dB HL on the left side, while in the control group it was 12.5 ± 2.8 dB HL on right side and 12.4 ± 3.1 dB HL on left side. About 64% of patients with SNHL exhibited comorbidities, and the most common condition was hypertension. Altered MoCA test scores were significantly related to the pure tone averages in patients with SNHL compared to the control group (p = 0.0004), while the differences in the HADS-A and HADS-D were not significant. Furthermore, a significant correlation was observed in SNHL patients between an altered MoCA test and hypercholesterolemia (p = 0.043). Conclusions: Hearing impairment and screening tests to detect MCI should be considered in the midlife in order to carry out strategies to prevent the progression to dementia. Hypertension and hypercholesterolemia are two risk factors in the development of endothelial dysfunction, oxidative stress, and vascular inflammation, and may represent the common pathology linking the inner ear and brain damage.

Background: Currently, the novel coronavirus (SARS-CoV-2) causes an acute respiratory illness named COVID-19 and is a controversial risk factor for hearing loss (HL). Herein, we aim to describe the associated symptoms and to evaluate hearing function in the COVID-19 pediatric population. Methods: A retrospective cross-sectional observational study was carried out on 37 children who contracted COVID-19 infection with no previous audio-vestibular disorders. Clinical data on the infections were collected, and an audiological assessment of all affected children was performed by using different diagnostic protocols according to their age. Results: Fever, upper respiratory and gastrointestinal manifestations were common presentations of infection. Audiological function was normal in 30 (81.08%) children, while 7 children showed an increased hearing threshold: 6 (16.21%) had transient conductive hearing loss (CHL) due to middle ear effusion and normalized at the follow-up and 1 had sensorineural hearing loss (SNHL). A single child was affected by bilateral SNHL (2.7%); however, he underwent a complete audiological work-up leading to a diagnosis of genetic HL due to a MYO6 gene mutation which is causative of progressive or late onset SNHL. Conclusions: HL needs to be considered among the manifestations of COVID-19 in children, nevertheless, we found cases of transient CHL. The onset of HL during or following COVID-19 infection does not eliminate the indication for maintaining audiological surveillance and audiological work-ups, including genetic diagnosis, to avoid the risk of mistaking other causes of HL.

Abstract Objectives Tinnitus is a common symptom largely impactful on quality of life, especially in the elderly. Our aim was to evaluate the efficacy of self‐administered screening tests to correlate the severity of subjective perception of tinnitus with emotional disorders and the overall cognitive status. Methods Patients aged ≥ 55 years with chronic tinnitus were recruited and submitted to a complete audiological evaluation; Tinnitus Handicap inventory (THI); Hospital Anxiety and Depression Scale (HADS‐A and HADS‐D) and Mini‐Mental State Examination (MMSE). Demographic and audiological features of patients with and without cognitive impairment (MMSE score cut‐off of 24/30) were analyzed in order to reveal the relationship among tinnitus, emotional disorders, and cognitive dysfunction. Results 102 patients were recruited (mean age: 70.4 ± 9.6). THI score was directly related to HADS‐A score (r = .63) HADS‐D score (r = .66), whereas there was no relationship between tinnitus severity and MMSE (r = .13). CI and n‐CI groups did not differ in the characteristics of tinnitus (p > .05), however, hearing threshold (p = .049) and anxious depressive traits measured with HADS‐A (p = .044) and HADS‐D (p = .016) were significantly higher in the group with cognitive impairment. Furthermore, age ≥ 75 years (p = .002, OR = 13.8), female sex (p = .032; OR = 6.5), severe hearing loss (p = .036; OR = 2.3), and anxiety (p = .029; OR = 9.2) resulted risk factors for CI. Therefore, in CI group MMSE score was inversely related to age (r = −.84). Conclusions Cognitive impairment and psychiatric discomfort should be considered in tinnitus patients, related to increasing age, female sex, and severe hearing loss. Thus, self‐administered questionnaires can be useful in addressing clinical approach.

Background: Objectives of the present work were to analyze the prevalence of hearing loss in our population of screened newborns during the first 9 years of the universal newborn hearing screening (UNHS) program at University Hospital Sassari (Italy) (AOU Sassari), to analyze the risk factors involved, and to analyze our effectiveness in terms of referral rates and dropout rates. Methods: Monocentric retrospective study whose target population included all the newborns born or referred to our hospital between 2011 and 2019. Results: From 2011 to 2019, a total of 11,688 babies were enrolled in our screening program. In total, 3.9‰ of wellborn babies and 3.58% of neonatal intensive care unit (NICU) babies had some degree of hearing loss. The most frequently observed risk factors among non-NICU babies were family history of hearing loss (3.34%) and craniofacial anomalies (0.16%), among NICU babies were low birth weight (54.91%) and prematurity (24.33%). In the multivariate analysis, family history of hearing loss (p < 0.001), NICU (p < 0.001), craniofacial anomalies (p < 0.001), low birth weight (p = 0.04) and HIV (p = 0.03) were confirmed as risk factors. Conclusions: Our data are largely consistent with the literature and most results were expected, one relevant exception being the possible role of NICU as a confounding factor and the limited number of risk factors confirmed in the multivariate analysis.

Background and Aim: Cytomegalovirus (CMV) is the main cause of congenital infection in developed countries leading to deafness but the burden of sensorineural hearing loss (SNHL) in asymptomatic children remains incompletely characterized. Aim of this study was to evaluate the long-term audiological outcome in this group of patients.Methods: Consecutive neonates with congenital CMV infection were followed from 2002 to 2018. Patients were considered asymptomatic if free from any clinical and instrumental impairment at referral and underwent serial clinical exams, audiological evaluations and CMV-PCR determinations.Results: A cohort of 258 children was analyzed and the disease onset was asymptomatic in 125 (48%) infants. Among these, we studied 102 patients with a follow-up longer than 1 year and a median observation period of 2.8 years (range: 1–10.3 years). No patient developed a stable delayed SNHL but only 14 (14%) presented a variable hearing impairment, seven of which bilateral. The unstable SNHL was mild in 12 infants and moderate in two. Patients with fluctuating SNHL had significantly higher urine viral load (p 0.002) and more often positive viremia (p 0.015) than babies with stable normal hearing.Conclusions: CMV infected, asymptomatic neonates have a low risk of transient SNHL later in infancy. Positive viremia and high urine viral load at onset are significant risk factors for delayed fluctuating SNHL. These data are relevant for an appropriate follow up plan of these patients.

Resembling the development of cancer by multistep carcinogenesis, the evolution towards metastasis involves several passages, from local invasion and intravasation, encompassing surviving anoikis into the circulation, landing at distant sites and therein establishing colonization, possibly followed by the outgrowth of macroscopic lesions. Within this cascade, epithelial to mesenchymal transition (EMT) works as a pleiotropic program enabling cancer cells to overcome local, systemic, and distant barriers against diffusion by replacing traits and functions of the epithelial signature with mesenchymal-like ones. Along the transition, a full-blown mesenchymal phenotype may not be accomplished. Rather, the plasticity of the program and its dependency on heterotopic signals implies a pendulum with oscillations towards its reversal, that is mesenchymal to epithelial transition. Cells in intermixed E⇔M states can also display stemness, enabling their replication together with the epithelial reversion next to successful distant colonization. If we aim to include the EMT among the hallmarks of cancer that could modify clinical practice, the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers needs to be filled. We review the knowledge on EMT, derived from models and mechanistic studies as well as from translational studies, with an emphasis on gastrointestinal cancers (GI).

The review begins with molecular genetics, which hit the field unveiling the involvement of oncogenes and tumor suppressor genes in the pathogenesis of colorectal cancer (CRC) and uncovering genetic predispositions. Then the notion of molecular phenotypes with different clinical behaviors was introduced and translated in the clinical arena, paving the way to next-generation sequencing that captured previously unrecognized heterogeneity. Among other molecular regulators of CRC progression, the extent of host immune response within the tumor micro-environment has a critical position. Translational sciences deeply investigated the field, accelerating the pace toward clinical transition, due to its strong association with outcomes. While the perturbation of gut homeostasis occurring in inflammatory bowel diseases can fuel carcinogenesis, micronutrients like vitamin D and calcium can act as brakes, and we discuss underlying molecular mechanisms. Among the components of gut microbiota, Fusobacterium nucleatum is over-represented in CRC, and may worsen patient outcome. However, any translational knowledge tracing the multifaceted evolution of CRC should be interpreted according to the prognostic and predictive frame of the TNM-staging system in a perspective of clinical actionability. Eventually, we examine challenges and promises of pharmacological interventions aimed to restrain disease progression at different disease stages.