Exposure to urban particulate matter alters responses of olfactory mucosal cells to SARS-CoV-2 infection.

Respiratory viruses have a significant impact on health, as highlighted by the COVID-19 pandemic. Exposure to air pollution can contribute to viral susceptibility and be associated with severe outcomes, as suggested by recent epidemiological studies. Furthermore, exposure to particulate matter (PM), an important constituent of air pollution, is linked to adverse effects on the brain, including cognitive decline and Alzheimer's disease (AD). The olfactory mucosa (OM), a tissue located at the rooftop of the nasal cavity, is directly exposed to inhaled air and in direct contact with the brain. Increasing evidence of OM dysfunction related to neuropathogenesis and viral infection demonstrates the importance of elucidating the interplay between viruses and air pollutants at the OM. This study examined the effects of subacute exposure to urban PM 0.2 and PM 10-2.5 on SARS-CoV-2 infection using primary human OM cells obtained from cognitively healthy individuals and individuals diagnosed with AD. OM cells were exposed to PM and subsequently infected with the SARS-CoV-2 virus in the presence of pollutants. SARS-CoV-2 entry receptors and replication, toxicological endpoints, cytokine release, oxidative stress markers, and amyloid beta levels were measured. Exposure to PM did not enhance the expression of viral entry receptors or cellular viral load in human OM cells. However, PM-exposed and SARS-CoV-2-infected cells showed alterations in cellular and immune responses when compared to cells infected only with the virus or pollutants. These changes are highly pronounced in AD OM cells. These results suggest that exposure of human OM cells to PM does not increase susceptibility to SARS-CoV-2 infection in vitro, but it can alter cellular immune responses to the virus, particularly in AD. Understanding the interplay of air pollutants and COVID-19 can provide important insight for the development of public health policies and interventions to reduce the negative influences of air pollution exposure.

Human-derived air-liquid interface cultures decipher Alzheimer's disease-SARS-CoV-2 crosstalk in the olfactory mucosa.

BACKGROUND: The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD. METHODS: To address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air-liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing. RESULTS: Results indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation. CONCLUSIONS: The study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection.

Spoken Language Skills in Children With Bilateral Hearing Aids or Bilateral Cochlear Implants at the Age of Three Years.

OBJECTIVES: Early hearing aid (HA) fitting and cochlear implants (CIs) aim to reduce the effects of hearing loss (HL) on spoken language development. The goals of this study were (1) to examine spoken language skills of children with bilateral HAs and children with bilateral CIs; (2) to compare their language skills to the age-norms of peers with normal hearing (NH); and (3) to investigate factors associated with spoken language outcomes. DESIGN: Spoken language results of 56 Finnish children with HL were obtained from a nationwide prospective multicenter study. Children with HL comprised two groups: children with mild-to-severe HL who used bilateral HAs (BiHA group, n = 28) and children with profound HL who used bilateral CIs (BiCI group, n = 28). Children's spoken language comprehension, expressive and receptive vocabulary, and phonological skills were compared with normative values of children with NH at the age of three years. Odds ratio (OR) was calculated to compare proportions of children below age-norms in BiHA and BiCI groups. Factors associated with spoken language outcomes were modeled with analysis of covariance. RESULTS: At the age of 3 years, 50%-96% of children with HL performed 1 SD or more below the mean of the normative sample of age-peers with NH in spoken language skills, depending on the language domain. Receptive vocabulary and phonological skills were the most vulnerable language domains. In receptive vocabulary, 82% of the children in the BiHA group and 50% of the children in the BiCI group scored 1 SD or more below the normative mean. The BiHA group was 4.4 times more likely to have poorer receptive vocabulary than the BiCI group. In phonological skills, 96% of children in the BiHA group and 60% of the children in the BiCI group scored 1 SD or more below the normative mean. The BiHA group was 18.0 times more likely to have poorer phonological skills than the BiCI group. The analysis of covariance models showed that unaided pure-tone average, PTA0.5-4 kHz, had a significant effect on spoken language comprehension in the BiHA group. For the BiCI group, age at HL diagnosis and age at CI activation had a significant effect on expressive vocabulary. High maternal level of education had a significant effect on language comprehension and expressive vocabulary and female gender on phonological skills. CONCLUSIONS: At the age of 3 years, especially receptive vocabulary and phonological skills caused difficulties for children with HL showing also considerable individual variation. Children with bilateral HAs seemed to be more likely to have poorer receptive vocabulary and phonological skills than children with bilateral CIs. A variety of factors was associated with outcomes in both groups. Close monitoring of spoken language skills of children with HL is important for ensuring similar opportunities for all children with HL and timely intervention, when needed.

The effect of virtual reality on temporal bone anatomy evaluation and performance.

PURPOSE: There is only limited data on the application of virtual reality (VR) for the evaluation of temporal bone anatomy. The aim of the present study was to compare the VR environment to traditional cross-sectional viewing of computed tomography images in a simulated preoperative planning setting in novice and expert surgeons. METHODS: A novice (n = 5) and an expert group (n = 5), based on their otosurgery experience, were created. The participants were asked to identify 24 anatomical landmarks, perform 11 distance measurements between surgically relevant anatomical structures and 10 fiducial markers on five cadaver temporal bones in both VR environment and cross-sectional viewings in PACS interface. The data on performance time and user-experience (i.e., subjective validation) were collected. RESULTS: The novice group made significantly more errors (p < 0.001) and with significantly longer performance time (p = 0.001) in cross-sectional viewing than the expert group. In the VR environment, there was no significant differences (errors and time) between the groups. The performance of novices improved faster in the VR. The novices showed significantly faster task performance (p = 0.003) and a trend towards fewer errors (p = 0.054) in VR compared to cross-sectional viewing. No such difference between the methods were observed in the expert group. The mean overall scores of user-experience were significantly higher for VR than cross-sectional viewing in both groups (p < 0.001). CONCLUSION: In the VR environment, novices performed the anatomical evaluation of temporal bone faster and with fewer errors than in the traditional cross-sectional viewing, which supports its efficiency for the evaluation of complex anatomy.

Biometal Dyshomeostasis in Olfactory Mucosa of Alzheimer's Disease Patients.

Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer's disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to be altered in the brains of AD patients. Little is known about elemental homeostasis in the AD patient olfactory mucosa. Here we aimed to assess whether the disease-related alterations to biometal homeostasis observed in the brain are also reflected in the olfactory mucosa. We applied RNA sequencing to discover gene expression changes related to metals in olfactory mucosal cells of cognitively healthy controls, individuals with mild cognitive impairment and AD patients, and performed analysis of the elemental content to determine metal levels. Results demonstrate that the levels of zinc, calcium and sodium are increased in the AD olfactory mucosa concomitantly with alterations to 17 genes related to metal-ion binding or metal-related function of the protein product. A significant elevation in alpha-2-macroglobulin, a known metal-binding biomarker correlated with brain disease burden, was observed on the gene and protein levels in the olfactory mucosa cells of AD patients. These data demonstrate that the olfactory mucosa cells derived from AD patients recapitulate certain impairments of biometal homeostasis observed in the brains of patients.

Perceptual Assessment and Acoustic Voice Analysis as Screening Tests for Vocal Fold Paresis After Thyroid or Parathyroid Surgery.

BACKGROUND: The aim of this study was to evaluate the reliability of clinician-based perceptual assessment of voice and computerized acoustic voice analysis as screening tests for vocal fold paresis or paralysis (VFP) after thyroid and parathyroid surgery. METHODS: This was a prospective study of 181 patients undergoing thyroid or parathyroid procedure with pre and postoperative laryngoscopic vocal fold inspection, perceptual voice assessment using grade, roughness, breathiness, asthenia, and strain (GRBAS) scale and acoustic voice analysis using the multi-dimensional voice program (MDVP). Patients were divided into 2 groups for comparison; those with new postoperative VFP and those without. Potential screening tools were evaluated using the receiving operating characteristic (ROC) analysis. RESULTS: Fourteen (6.6%) patients had a new postoperative VFP. Postoperative GRBAS scores were significantly (P < 0.05) higher in patients with VFP compared to those without. However, there were no statistically significant differences in MDVP values between the groups. Postoperative GRBAS grade score (cut off > 0) had the best sensitivity, 93%, for predicting VFP, but the specificity was only 50%. Postoperative jitter (cut off > 1.60) in MDVP had a good specificity, 90%, but only 50% sensitivity. Combining all the GRBAS and MDVP variables with P < 0.05 in the ROC analysis yielded a test with 100% sensitivity and 55% specificity. CONCLUSIONS: Physician-based perceptual voice assessment has a high sensitivity for detecting postoperative VFP, but the specificity is poor. The risk of VFP is low in patients with completely normal voice at discharge. However, routine laryngoscopy after thyroid and parathyroid surgery is still the most reliable exam for VFP screening.

Virtual reality improves the accuracy of simulated preoperative planning in temporal bones: a feasibility and validation study.

PURPOSE: Consumer-grade virtual reality (VR) has recently enabled various medical applications, but more evidence supporting their validity is needed. We investigated the accuracy of simulated surgical planning in a VR environment (VR) with temporal bones and compared it to conventional cross-sectional image viewing in picture archiving and communication system (PACS) interface. METHODS: Five experienced otologic surgeons measured significant anatomic structures and fiducials on five fresh-frozen cadaveric temporal bones in VR and cross-sectional viewing. Primary image data were acquired by computed tomography. In total, 275 anatomical landmark measurements and 250 measurements of the distance between fiducials were obtained with both methods. Distance measurements between the fiducials were confirmed by physical measurement obtained by Vernier caliper. The experts evaluated the subjective validity of both methods on a 5-point Likert scale qualitative survey. RESULTS: A strong correlation based on intraclass coefficient was found between the methods on both the anatomical (r > 0.900) and fiducial measurements (r > 0.916). Two-tailed paired t-test and Bland-Altman plots demonstrated high equivalences between the VR and cross-sectional viewing with mean differences of 1.9% (p = 0.396) and 0.472 mm (p = 0.065) for anatomical and fiducial measurements, respectively. Gross measurement errors due to the misidentification of fiducials occurred more frequently in the cross-sectional viewing. The mean face and content validity rating for VR were significantly better compared to cross-sectional viewing (total mean score 4.11 vs 3.39, p < 0.001). CONCLUSION: Our study supports good accuracy and reliability of VR environment for simulated surgical planning in temporal bones compared to conventional cross-sectional visualization.

Facial nerve function and hearing after microsurgical removal of sporadic vestibular schwannomas in a population-based cohort.

BACKGROUND: Vestibular schwannoma (VS) is a benign tumor originating from the vestibulocochlear nerve. The optimal treatment strategy is debated, since surgery may result in iatrogenic facial nerve injury. We report the results of VS surgery in a population-based unselected cohort in a center with access to Cyber Knife (CK) radiosurgery. METHODS: We reviewed 117 consecutive operations and found 95 patients who had their primary operation due to vestibular schwannoma between 2001 and 2017. Facial nerve function was evaluated with the House-Brackmann (HB) scale and hearing with the EU classification. RESULTS: The population consisted of 37 males and 58 females with a median age of 54 years (range 19-79). One year after surgery 67% of patients had a good outcome (HB 1-2). The rate of good outcome was 90% if no facial nerve damage was observed during intraoperative monitoring, the size of the tumor was under 30 mm and no hydrocephalus was present. During the study period, the treatment strategy changed from total to near-total resection after the introduction of CK radiosurgery, which could be used as a second-line treatment in case of residual tumor regrowth. This resulted in an improvement of outcomes (0% HB 5-6) despite the larger tumor sizes (25 ± 14 mm vs. 31 ± 9 mm, p < 0.05). Hearing preservation rates did not increase. CONCLUSIONS: Near-total resection and subsequent CK radiosurgery in case of residual tumor regrowth during follow-up seems to provide a good outcome of facial nerve function even in large VSs.

Preservation of residual hearing after cochlear implant surgery with slim modiolar electrode.

PURPOSE: To evaluate the insertion results and hearing preservation of a novel slim modiolar electrode (SME) in patients with residual hearing. METHODS: We retrospectively collected the data from the medical files of 17 patients (18 ears) implanted with a SME. All patients had functional low frequency hearing (PTA (0.125-0.5 kHz) ≤ 80 dB HL). The insertion results were re-examined from the postoperative cone-beam computed tomography scans. Postoperative thresholds were obtained at the time of switch-on of the sound processors (mean 43 days) and at latest follow-up (mean 582 days). The speech recognition in noise was measured with the Finnish matrix sentence test preoperatively and at follow-up. RESULTS: The mean insertion depth angle (IDA) was 395°. Neither scala dislocations nor tip fold over were detected. There were no total hearing losses. Functional low-frequency hearing was preserved in 15/18 (83%) ears at switch-on and in 14/17 (82%) ears at follow-up. According to HEARRING classification, 55% (10/18) had complete HP at switch-on and 41% (7/17) still at follow-up. Thirteen patients (14 ears) were initially fitted with electric-acoustic stimulation and seven patients (8 ears) continued to use it after follow-up. CONCLUSIONS: The preliminary hearing preservation results with the SME were more favorable than reported for other perimodiolar electrodes. The results show that the array may also be feasible for electro-acoustic stimulation; it is beneficial in that it provides adequate cochlear coverage for pure electrical stimulation in the event of postoperative or progressive hearing loss.

The long-term learning effect related to the repeated use of the Finnish matrix sentence test and the Finnish digit triplet test.

Objectives: To assess are there learning-related improvements in the speech reception thresholds (SRTs) for the Finnish matrix sentence test (FMST) and the Finnish digit triplet test (FDTT) in repeated use over 12 months.Design: Test sessions were scheduled at 0, 1, 3, 6 and 12 months, and each session included five FMST measurements and four FDTT measurements. The within-session and inter-session improvements in SRTs were analysed with a linear mixed model.Study sample: Fifteen young normal-hearing participants.Results: Statistically significant mean improvements of 2.0 dB SNR and 1.2 dB SNR were detected for the FMST and the FDTT, respectively, over the 12-month follow-up period. For the FMST, majority of the improvement occurred during the first two test sessions. For the FDTT, statistically significant differences were detected only in comparison to the first test session and to the first test measurement of every session over the 12-month follow-up.Conclusions: Repeated use of the FMST led to significant learning-related improvements, but the improvements appeared to plateau by the third test session. For the FDTT, the overall improvements were smaller, but a significant within-session difference between the first and consecutive FDTT measurements persisted throughout the test sessions.

The Finnish simplified matrix sentence test for the assessment of speech intelligibility in the elderly.

Objective: A simplified version of the Finnish matrix sentence test (FMST) was developed to improve the reliability of hearing diagnostic for children and for patients with limited working memory capacity and/or vocabulary.Design: Study 1 evaluated the word matrix of the Finnish simplified matrix sentence test (FINSIMAT) to rule out systematic differences between the new FINSIMAT test lists, and to provide reference values for normal-hearing (NH) young adults (YA). In Study 2, the FINSIMAT and the FMST were evaluated in elderly listeners with mild-to-moderate hearing impairment (HI).Study sample: Twenty NH YAs participated in Study 1, and 16 elderly HI adults participated in Study 2.Results: For NH YAs, the reference speech reception threshold (SRT50) estimate and the slope for the FINSIMAT were -11.2 ± 1.0 dB signal-to-noise ratio (SNR) and 19.4 ± 1.9%/dB SNR. For the elderly HI listeners, the mean SRT50 estimates for the FINSIMAT and FMST were -4.1 and -3.6 dB SNR, respectively. The correlation between the FMST and FINSIMAT results was strong (r2 = 0.78, p < 0.001).Conclusion: The FINSIMAT showed comparable characteristics to the FMST and proved feasible for measurements in elderly HI listeners.

Incidence, Risk Factors, and Natural Outcome of Vocal Fold Paresis in 920 Thyroid Operations with Routine Pre- and Postoperative Laryngoscopic Evaluation.

BACKGROUND: The aim of this study was to determine the incidence, risk factors, and spontaneous recovery rate of vocal fold paresis (VFP) with routine laryngoscopy before and after thyroid surgery. METHODS: All consecutive patients undergoing primary or redo thyroid surgery between years 2011-2016 were prospectively registered in an electronic database, and scheduled for pre- and postoperative laryngoscopic vocal fold inspection by otolaryngologists independently of the surgical team. RESULTS: A total of 920 thyroid operations with 1296 nerves at risk were performed in 866 patients. Pre- and postoperative laryngoscopy was done in 95% and 98%, respectively. Preoperative VFP was detected in 24 (2.8%) patients. New postoperative VFP was found in 53 of 920 operations (5.8%) and in 55 of 1296 nerves at risk (4.2%). After 12 months, 14 had recovered full vocal fold function and eight had near-complete recovery. VFP was permanent after 29 operations (3.2%); two patients were lost to follow-up with uncertain outcome. Of the 1296 nerves at risk, injury was permanent in 30 (2.3%). In multivariate analysis, patients operated for recurrent goiter had nearly nine times higher risk of new VFP (23% rate), whereas patients with malignant histology had three times higher risk of postoperative VFP (up to 22% rate). CONCLUSION: VFP continues to be a serious complication of thyroid surgery, especially in operations for redo goiter and thyroid malignancy. The incidence of VFP may be underestimated unless laryngoscopic examinations are performed routinely.

Electrode migration after cochlear implant surgery: more common than expected?

The overall complication rate of cochlear implant surgery is low and so-called electrode failures (electrode migration, misplacement, etc.,) account for only a minority of all complications. The aim of this study was to explore the prevalence of electrode migration as the cause for increased impedance values and non-auditory stimulation in the basal channels. Within the scope of a quality control process, the cochlear implant database of the Kuopio University Hospital (Finland) was reviewed. Patients with gradual elevation of impedance values and/or non-auditory stimulation of the basal electrode channels were re-examined and cone-beam computed tomography was administered. There were 162 cochlear implant recipients and 201 implanted devices registered in the database. A total of 18 patients (18 devices) were identified having significantly increased impedance values or non-auditory stimulation of the basal electrodes. Cone-beam computed tomography revealed extra-cochlear electrodes in 12 of these patients due to the migration of the electrode array. All extruded electrodes were lateral wall electrodes, i.e., straight electrode arrays (Cochlear CI422 and Med-El devices). The most common feature of electrode migration was the gradual increase of the impedance values in the basal electrodes, even though telemetry could also be unsuspicious. Electrode migration after cochlear implant surgery may be more common than previously reported. At surgery, special attention should be paid to the reliable fixation of the electrode array. This study underlines the importance of postoperative imaging after cochlear implant surgery.

Insertion characteristics and placement of the Mid-Scala electrode array in human temporal bones using detailed cone beam computed tomography.

The aim of this study was to evaluate the insertion results and placement of the new Advanced Bionics HiFocus Mid-Scala (HFms) electrode array, inserted through the round window membrane, in eight fresh human temporal bones using cone beam computed tomography (CBCT). Pre- and post-insertion CBCT scans were registered to create a 3D reconstruction of the cochlea with the array inserted. With an image fusion technique both the bony edges of the cochlea and the electrode array in situ could accurately be determined, thus enabling to identify the exact position of the electrode array within the scala tympani. Vertical and horizontal scalar location was measured at four points along the cochlea base at an angular insertion depth of 90°, 180° and 270° and at electrode 16, the most basal electrode. Smooth insertion through the round window membrane was possible in all temporal bones. The imaging results showed that there were no dislocations from the scala tympani into the scala vestibule. The HFms electrode was positioned in the middle of the scala along the whole electrode array in three out of the eight bones and in 62 % of the individual locations measured along the base of the cochlea. In only one cochlea a close proximity of the electrode with the basilar membrane was observed, indicating possible contact with the basilar membrane. The results and assessments presented in this study appear to be highly accurate. Although a further validation including histopathology is needed, the image fusion technique described in this study represents currently the most accurate method for intracochlear electrode assessment obtainable with CBCT.

The development and design of the European Board of Otorhinolaryngology-Head and Neck Surgery Examination (EBEORL-HNS).

The UEMS Otorhinolaryngology-Head and Neck Surgery section is a dedicated body formed to promote the standardisation and harmonisation of European Otorhinolaryngology (ORL). The European Examination Board of Otorhinolaryngology and Head and Neck Surgery was created to establish a supranational final exam and accreditation for ORL Surgeons. It is open to candidates both from the European Union and outside the EU. The exam is composed of a written examination to assess mainly the theoretical knowledge of Otorhinolaryngological diseases. The second part, a viva voce examination, is designed to test the clinical application of knowledge based on case scenarios and clinical conditions presented to the candidates. The inaugural examination written component took place in Mannheim/Germany in 2009 and the inaugural Viva Voce examination in Vienna/Austria in 2010. Up to and including the year 2013, 858 participants have attempted one of the two exam components. Of the 858 participants, 305 were successful in both examinations and obtained the accreditation of the European Diploma (European Board Certification). The historical origins, development of the examination, its formal arrangements and the format of the examination are presented in this article.

[Herpes zoster in the pharynx]. / Vyöruusu nielussa.

A 74-year-old woman was suspected of having a peritonsillar abscess. She had a light-coloured coating on the pharynx and the larynx, bordering to the left of the median line, as well as laryngeal edema on the side of the lesion. On the basis of precisely unilateral findings we arrived at pharyngeal herpes zoster as the working diagnosis. The diagnosis was further supported by the detection of varicella-zoster virus DNA in the mucosa and the presence of positive IgM antibody levels. The patient was treated with an antiviral drug, an antimicrobial drug and a glucocorticoid. Mucosal lesions and edema returned to normal, and the patient was discharged. The precise unilaterality of the symptoms is essential to the diagnosis.

Development of Social-Pragmatic Understanding in Children With Congenital Hearing Loss and Typical Hearing Between the Ages of 4 and 6 Years.

PURPOSE: This prospective longitudinal study aimed to explore (a) the development of social-pragmatic understanding of children with bilateral hearing aids (BiHAs), bilateral cochlear implants (BiCIs), and typical hearing (TH) between the ages of 4 and 6 years and (b) group differences between children with BiHAs, BiCIs, and TH. METHOD: The Pragma test was used for a comprehensive assessment of social-pragmatic understanding of a total of 86 children: 19 children with BiHAs, 22 children with BiCIs, and 45 children with TH. The Pragma test requires answering socially and contextually demanding questions and explaining the right answers. The explanation tasks are targeted at studying the participant's own awareness of the inferencing process. The children in this study were assessed yearly at the ages of 4, 5, and 6 years. RESULTS: The participants with BiHAs, BiCIs, and TH showed significant development in their social-pragmatic understanding between the ages of 4 and 6 years, but most children with hearing loss (HL) still did not meet age expectations at the age of 6 years. Children with BiHAs and BiCIs both showed large-scale inferential difficulties, including utilizing theory of mind, utilizing verbal and visual information, and understanding conversational norms and emotions in context. CONCLUSIONS: Children with BiHAs and BiCIs are at risk of delays in social-pragmatic understanding despite early detection of HL, early amplification, and cochlear implantation. Therefore, the social-pragmatic abilities of children with HL should be assessed regularly, and the children with HL should have early access to social-pragmatic interventions where utilizing contextual information is practiced comprehensively.

Development of Lyophilised Eudragit® Retard Nanoparticles for the Sustained Release of Clozapine via Intranasal Administration.

Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the i.m. route is often painful, with low patient compliance and requiring specialised personnel. Moreover, CZP has a very low aqueous solubility. This study proposes the intranasal route as an alternative route of administration for CZP, through its encapsulation in polymeric nanoparticles (NPs) based on Eudragit® RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400-500 nm were formulated to reside and release CZP in the nasal cavity, where it can be absorbed through the nasal mucosa and reach the systemic circulation. CZP-EUD-NPs showed a controlled release of CZP for up to 8 h. Furthermore, to reduce mucociliary clearance and increase the residence time of NPs in the nasal cavity to improve drug bioavailability, mucoadhesive NPs were formulated. This study shows that the NPs already exhibited strong electrostatic interactions with mucin at time zero due to the presence of the positive charge of the used copolymers. Furthermore, to improve the solubility, diffusion and adsorption of CZPs and the storage stability of the formulation, it was lyophilised using 5% (w/v) HP-ß-CD as a cryoprotectant. It ensured the preservation of the NPs' size, PDI and charge upon reconstitution. Moreover, physicochemical characterisation studies of solid-state NPs were performed. Finally, toxicity studies were performed in vitro on MDCKII cells and primary human olfactory mucosa cells and in vivo on the nasal mucosa of CD-1 mice. The latter showed non-toxicity of B-EUD-NPs and mild CZP-EUD-NP-induced tissue abnormalities.

Emissions from modern engines induce distinct effects in human olfactory mucosa cells, depending on fuel and aftertreatment.

Ultrafine particles (UFP) with a diameter of ≤0.1 µm, are contributors to ambient air pollution and derived mainly from traffic emissions, yet their health effects remain poorly characterized. The olfactory mucosa (OM) is located at the rooftop of the nasal cavity and directly exposed to both the environment and the brain. Mounting evidence suggests that pollutant particles affect the brain through the olfactory tract, however, the exact cellular mechanisms of how the OM responds to air pollutants remain poorly known. Here we show that the responses of primary human OM cells are altered upon exposure to UFPs and that different fuels and engines elicit different adverse effects. We used UFPs collected from exhausts of a heavy-duty-engine run with renewable diesel (A0) and fossil diesel (A20), and from a modern diesel vehicle run with renewable diesel (Euro6) and compared their health effects on the OM cells by assessing cellular processes on the functional and transcriptomic levels. Quantification revealed all samples as UFPs with the majority of particles being ≤0.1 µm by an aerodynamic diameter. Exposure to A0 and A20 induced substantial alterations in processes associated with inflammatory response, xenobiotic metabolism, olfactory signaling, and epithelial integrity. Euro6 caused only negligible changes, demonstrating the efficacy of aftertreatment devices. Furthermore, when compared to A20, A0 elicited less pronounced effects on OM cells, suggesting renewable diesel induces less adverse effects in OM cells. Prior studies and these results suggest that PAHs may disturb the inflammatory process and xenobiotic metabolism in the OM and that UFPs might mediate harmful effects on the brain through the olfactory route. This study provides important information on the adverse effects of UFPs in a human-based in vitro model, therefore providing new insight to form the basis for mitigation and preventive actions against the possible toxicological impairments caused by UFP exposure.