Age‐related hearing loss frequently precedes or coexists with mild cognitive impairment and dementia. The role specific neuropathologies play in this association, as either a cause or a consequence, is unclear. We therefore aimed to investigate whether specific dementia related neuropathologies were associated with hearing impairment in later life. We analysed data on ante‐mortem hearing impairment with post‐mortem neuropathological data for 442 participants from the Brains for Dementia Research Cohort. Binary logistic regression models were used to estimate the association of hearing impairment with the presence of each dementia‐related neuropathology overall, and with specific staged changes. All analyses adjusted for age and sex, and several sensitivity analyses were conducted to test the robustness of findings. Presence and density of neuritic plaques were associated with higher odds of hearing impairment ante‐mortem . Presence of any LB disease was likewise associated with hearing impairment , but this did not increase with higher cortical pathology . Nonspecific amyloid deposition, neurofibrillary tangle staging, overall AD neuropathology level, and cerebrovascular disease were not clearly associated with increased risks of hearing impairment. Our results provide some support for an association between dementia‐related neuropathology and hearing loss and suggest that hearing loss may be associated with a high neuritic plaque burden and more common in Lewy body disease. Photomicrographs taken from the temporal cortex. Case 20174966 exhibits severe tau pathology as neurofibrillary tangles (a ‐ arrow) and frequent neuritic plaques (a ‐ arrowhead), abundant amyloid beta plaques (b ‐ arrows) and severe cerebral amyloid angiopathy  is 100 μm and is valid for images a and b. EvidencA factor also worth considering in terms of what may cause hearing loss to lead to cognitive impairment is social withdrawal. In a cross‐sectional survey of 3613 older adults (age >50), hearing impairment was an independent, positive correlate for isolation and loneliness . LonelinConversely, hearing impairment may be a consequence of neurodegeneration‐related cognitive impairment. The ‘cognitive ear’—the interface between auditory and cognitive processing—, 14 enabTo better understand the routes through which ARHL is associated with cognitive dysfunction the relationship between ARHL and dementia‐related neuropathological changes—including Alzheimer's‐related amyloid and tau pathology, Lewy body pathology, and cerebrovascular disease, have to be clarified.Previous research examining the associations between ARHL, and suspected Alzheimer's pathology have applied PET imaging of amyloid and tau in individuals with ARHL– , 21, 22.Whilst PET imaging is superior to clinical evaluation alone for the detection of Alzheimer or Lewy pathology  it is stTwo studies interrogated the association between hearing impairment and post‐mortem neuropathological data. The largest comprises of 2755 individuals from the National Alzheimer's Coordinating Centre (NACC) database. Impaired hearing was associated with higher Braak NFT stage in cognitively healthy older adults, higher neocortical LB presence in MCI, and micro infarcts in dementia, but negatively correlated with neuritic plaque density in the latter . The othThe aim of our study, therefore, was to further elucidate whether the presence of dementia related neuropathology is associated with hearing impairment in later life. We have used clinical and post‐mortem neuropathological data from the Brains for Dementia Research (BDR) programme.22.1Participants were identified from the United Kingdom BDR cohort, which recruited from six regional centres: Oxford, Bristol, Newcastle, Cardiff, London and Manchester. Four hundred and forty‐two participants were eligible for inclusion who had hearing function reported ante‐mortem, and comprehensive neuropathological assessment post‐mortem.Participants provided written, informed consent prior to assessment and eventual brain tissue donation.2.2During life, participants in the BDR cohort underwent repeated clinical assessment, approximately annually. These clinical assessments gather data on ethnicity, comorbidities, any sensory impairment, smoking, socioeconomic status, education level and cognitive/dementia status—and were conducted by research psychologists or research nurses. Where available, assessments included informants (friends or family members) to provide additional data.Participants were classified as having dementia, having MCI or being cognitively normal in accordance with methods outlined in McAleese et al paper . This cl2.3Participants' hearing status was rated by the researcher at interview, incorporating information from the participant and any informants, as well as their own observations:0—Normal hearing, no hearing aid used;1—Hears normally with a hearing aid;2—Slightly impaired hearing even with a hearing aid;3—Very impaired hearing even with a hearing aid;4—Impaired hearing, but no hearing aid used.n = 279) and all other ratings as evidence of impaired hearing (n = 153).For our analyses, those with a rating of 0 were classified as having unimpaired hearing , and different severity of Lewy body pathology .3Baseline characteristics of the cohort are presented in Table 3.1Presence of moderate neuritic plaques (C2) and frequent neuritic plaques (C3) both had a significant association with hearing impairment– and , respectively. However, for sparse neuritic plaques (C1), the result was non‐significant , intermediate  and high  levels of AD‐related neuropathological change were not associated with significantly increased odds of hearing impairment in comparison to those without AD‐related neuropathology.There was no significant association between increasing amyloid deposition phase A1–A3) and presence of hearing impairment  and hearing impairment was highly uncertain ; moderate tangle pathology (B2) was associated with significantly higher odds of hearing impairment , but this was not consistent to the highest stages of tangle pathology (B3), where the association was non‐significant .3.2The presence of any LB pathology was associated with significantly increased likelihood of hearing impairment . In sensitivity analyses, this effect remained, albeit attenuated and marginally significant, when restricted to cases with a high degree of LB pathology only , but was not significant if restricted to those with neocortical LB pathology only  OR was 0.96, 95% CI 0.37–2.44, Cerebral amyloid angiopathy (VCING 2) OR was 0.99, 95% CI 0.42–2.36 and WM arteriosclerosis (VCING 3) OR was 1.54, 95% CI 0.53–4.50  predicted hearing impairment in older adults , and thaThis study benefits from comprehensive neuropathological assessment, drawing from multiple sites across England and Wales, with several hundred brain tissue donors having provided ante‐mortem clinical information. There are some limitations, however. Hearing impairment was based on judgement of the researcher at the ante‐mortem assessment, incorporating self‐reported information and informant perspectives. These ratings are therefore not objective and may be inaccurate—particularly in those with loss of insight into their symptoms.Different dementia subtypes have been reported to have distinct auditory dysfunctions—LB with auditory hallucinations, AD with altered speech in noise perception and FTLD with distorted pitch and timbre perception —with WMHWhilst this sample was drawn from a broad geographical area of the United Kingdom, this is not necessarily representative of the older population overall, as looking at Table 5Whilst neuritic plaques were robustly associated with hearing impairment, overall amyloid deposition, NFTs  were not, though with consistently positive but uncertain and consequently non‐significant effects. This inconsistency between pathological measures in both this work, and the wider literature, may point to a lack of robustness in the observed associations, or reflect differences in the pathological grading systems: CERAD scores measure the density of neuritic plaques semi‐quantitatively, whereas Braak staging measures the regional spread of pathology but not the regional burden. Semi‐quantitative rating of tau burden, rather than spread, may clarify whether this association is consistent across Alzheimer's disease related pathological changes. However, some pathologies, particularly amyloid‐β and tau , play a The association between dementia and hearing loss is likely multifactorial but our findings suggest ARHL may be a factor predicting increased risk for Lewy Body dementia and Alzheimer's dementia, but not for cerebrovascular dementia. The strength of such a relationship and thus its value clinically needs further investigation including objective measures of hearing impairment. Continued efforts with objective and subjective hearing data and large, heterogeneous cohorts with both ante‐mortem and post‐mortem data are needed to further elucidate the association between ARHL and dementia, hopefully leading to improved accuracy of dementia subclassification.Jessica A. Katanga: Conceptualisation, Methodology, Software, Investigation, Writing, Review and Editing. Calum A. Hamilton: Methodology, Software, Validation, Review and Editing. Lauren Walker: Resources, Review and Editing. Johannes Attems: Resources, Review and Editing. Alan J. Thomas: Conceptualisation, Review and Editing, Funding Acquisition, Project Administration, Supervision.This research was funded by NIHR Newcastle Biomedical Research Centre (BRC) and BDR, which is jointly funded by Alzheimer's Research UK and the Alzheimer's Society.Alan Thomas is Director of the Brains for Dementia Research programme. All other authors have no competing interests.Ethical approval for this study was given by NHS Health Research Authority North East—Newcastle & North Tyneside 1 Research Ethics Committee (18/NE/0124).


Mytilus galloprovincialis have been shown to be sensitive to environmental concentrations of a number of emerging contaminants, including EDs. In this work, the effects of TCS were first evaluated in the 48 h larval assay in a wide concentration range . TCS significantly affected normal development of D-veligers . At selected concentrations, the mechanism of action of TCS was investigated. TCS modulated transcription of different genes involved in shell mineralization, endocrine signaling, ceramide metabolism, and biotransformation, depending on larval stage (24 and 48 h post-fertilization-hpf) and concentration (1 and 10 μg/L). At 48 hpf and 10 μg/L TCS, calcein staining revealed alterations in CaCO3 deposition, and polarized light microscopy showed the absence of shell birefringence due to the mineralized phase. Observations by scanning electron microscopy highlighted a variety of defects in shell formation from concentrations as low as 0.1 μg/L. The results indicate that TCS, at environmental exposure levels, can act as a developmental disruptor in early mussel larvae mainly by interfering with the processes of biomineralization.The broadly utilized biocide triclosan (TCS) is continuously discharged in water compartments worldwide, where it is detected at concentrations of ng-µg/L. Given its lipophilicity and bioaccumulation, TCS is considered potentially harmful to human and environmental health and also as a potential endocrine disruptor (ED) in different species. In aquatic organisms, TCS can induce a variety of effects: however, little information is available on its possible impact on invertebrate development. Early larval stages of the marine bivalve The online version contains supplementary material available at 10.1007/s11356-023-29854-2. Due to its incomplete removal by conventional wastewater treatment, TCS is continuously discharged in aquatic compartments worldwide, where it is present at concentrations of ng-µg/L. Given its strong lipophilicity and bioaccumulation, TCS is potentially harmful to human and environmental health .Triclosan  is an antimicrobial agent present in a variety of personal, household, and healthcare products, as well as in plastic leachates (50 ≤ 1 mg/L) (https://echa.europa.eu/substance-information/-/substanceinfo/100.020.167). TCS has been reported to be accumulated and to induce multiple effects in aquatic organisms  and tetrabromobisphenol A (TBBPA) , were first evaluated by the 48-h larval assay. At selected concentrations (1 and 10 μg/L), transcriptional profiles of different groups of genes involved in multiple processes  were assessed across early development (from eggs to 24 and 48-h post-fertilization). Shell formation at 48 hpf was also analyzed by calcein fluorescence, polarized light microscopy (PLM), and scanning electron microscopy (SEM).In this work, the possible mechanisms of action of TCS on early larval development of M. galloprovincialis Lam.), obtained from an aquaculture farm in the Ligurian Sea  between November 2021 and March 2022, were acclimatized in static tanks containing aerated artificial sea water (ASW)  ASTM , pH 7.9–SW) ASTM . FertiliThe 48-h larval assay ASTM  adapted Light microscopy images of D-veligers at 48 hpf in control larvae and larvae exposed to 10 and 100 μg/L TCS were analyzed for shell length  and height  using ImageJ software as previously described . Three wells for each condition were pooled in order to obtain approximately 6000 larvae/replicate. The larval suspension was centrifuged at 800 × g, for 10 min at 4 °C and the pellets lysed in 1-mL TRI Reagent . All the subsequent analyses  were performed following Balbi et al. , 2018. P2+-dependent fluorophore calcein  was added to fertilized eggs . At 48 hpf, larvae were washed three times in ASW to remove the excess dye, fixed in 4% paraformaldehyde (PFA) in ASW, and immediately imaged with a Leica TCS SP8 Confocal Microscope  to visualize the calcified shell in green.Shell calcification of control larvae and larvae exposed to TCS (10 μg/L) at 48 hpf was evaluated by calcein staining as previously described  at 48 hpf were collected on 0.22-μm filters, washed four times with deionized water to remove excess salts, and dried at 60 °C for 30 min. Observations were carried out on glass slides by a polarized light microscope  as previously described , was calculated by PRISM 5 software . LOEC (lowest effect concentration) was evaluated by the Mann–Whitney U test.Data from the 48-h larval assay, expressed as mean ± SD of 6 experiments carried out in 3 replicate wells, were analyzed by ANOVA plus Dunnet’s post hoc test. The ECp < 0.05, Mann–Whitney U test).Data on gene transcription, obtained from 4 independent RNA samples, are expressed as mean ± SD. Statistical differences were evaluated with respect to controls (p < 0.01). Further, small decreases in the percentage of normal D-larvae were progressively observed in a wide concentration range , with malformed larvae representing the dominant phenotype. A sharper decline was observed at 250 μg/L (− 65%); in these conditions, only immature larvae (mainly pre-veligers and some trochophore) were detected, indicating developmental delay. Highest concentrations of TCS (from 750 μg/L) completely prevented larval development. A resulting EC50 of 236.1 μg/L (95% C.I. 139–498.2) was obtained.The results of the 48-h assay Fig.  show thaShell size was evaluated in D-larvae of control samples and in samples exposed to TCS 10 and 100 μg/L, and the results are shown in Fig. The level of RNA transcripts for genes involved in different biological processes: shell biogenesis, neuroendocrine signaling, antioxidant/biotransformation processes, sphingolipid (ceramide) metabolism, and apoptosis/proliferation, was evaluated by qPCR Tab. . Data onThe effects of TCS (1 and 10 µg/L) on gene transcription at 24 and 48 hpf are reported in Fig. mRNA levels of genes involved in shell organic matrix deposition  and calcification   and upregulation of the xenobiotic transporter ABCB .Expression of genes involved in ceramide biosynthesis , metabolism (ceramide glucosyltransferase), and breakdown (acid ceramidase) were evaluated .Fluorescent calcein staining was utilized to visualize CaCO3 mineralization  on shell mineralization at 48 hpf were investigated by PLM as previously described , D-shells with normal hinges but with asymmetric valvae were detected Fig.  A and D,The results indicate that TCS can act as a potential developmental disruptor in early mussel larvae at environmental concentrations. Moreover, these represent the first data on the possible mechanisms of action of TCS in developing larvae of a marine bivalve.50 < 1 mg/L and a PNEC in marine water of 0.169 µg/L (https://echa.europa.eu/registration-dossier/-/registered-dossier/12675/6/1). Although TCS has been banned from some products and replaced by other additives/biocides, according to the analysis of future scenarios for its global river export, TCS concentrations in coastal waters could double by 2050, exceeding PNECs in particular in certain geographic areas, due to fast population growth, increasing urbanization, and sewerage systems with poor wastewater treatment  were found in coastal environments . The results show that the effects of TCS on transcription of different genes were dependent on both the developmental stage and the exposure concentration. Although the observed changes were small, TCS exposure resulted in significant upregulation of a number of key genes in critical pathways of mussel early larval development from 24 hpf, a stage where the blueprint for shell calcification is established and tissue differentiation begins  , depending on the larval stage and concentration, and of Runx at 48 hpf. Runx is a gene belonging to a family of heteromeric transcription factors, involved in developmental cell differentiation, hemopoiesis, neurogenesis, immune response and biomineralization also in bivalves  previously observed in mussel larvae grown under experimental ocean acidification . A similar effect was previously observed in larvae exposed to nanoplastics  had a straight hinge , they showed subtler malformations (in particular shell thinning and cracks at lower concentrations) that were not detectable by light microscopy. Since the dehydration protocol of sample preparation for SEM analysis was specifically developed in order to avoid any damage to normal D-veligers shells that are almost fully calcified , can underestimate the impact of contaminants on the key process of shell biogenesis at lower concentrations. Gene expression analyses obviously represent more sensitive indicators of toxicity, at the same time characterizing the molecular targets of contaminants, as shown in larvae of 3 biominerals of different marine invertebrates, including bivalves, the ACC phase is considered as a transient precursor of the crystallization pathway, which could be temporarily stabilized by organic macromolecules or trace elements, i.e., Mg2+  pathways are involved in regulation of bivalve shell biogenesis by activating the expression of key genes essential for initial organic matrix deposition, i.e., tyrosinase  for TCS in early mussel development.Overall, the results provide a first insight on the mechanisms of action of TCS in early larval stages of Increasing knowledge on the impact and mechanisms of action of TCS in marine organisms is of environmental significance also when considering that TCS is one of the main emerging contaminant associated with ocean microplastic pollution Below is the link to the electronic supplementary material.


Background: We evaluated the incidence of postoperative acute kidney injury (AKI) and complications when remimazolam (RMMZ) or sevoflurane (SEVO) were used in elderly patients undergoing total knee arthroplasty. Methods: Seventy-eight participants aged ≥65 were randomly allocated to either the RMMZ or SEVO group. The primary outcome was the incidence of AKI on postoperative day (POD) 2. The secondary outcomes included intraoperative heart rate (HR), blood pressure (BP), total drug administered, emergence time, postoperative complications on POD 2, and hospital length of stay (HLOS). Results: The incidence of AKI was comparable between the RMMZ and SEVO groups. The doses of intraoperative remifentanil, vasodilators, and additional sedatives were significantly higher in the RMMZ group than in the SEVO group. Overall intraoperative HR and BP tended to remain higher in the RMMZ group. The emergence time in the operating room was significantly faster in the RMMZ group; however, the time required for an Aldrete score ≥ 9 was comparable between the RMMZ and SEVO groups. Postoperative complications and HLOS were comparable between the RMMZ and SEVO groups. Conclusion: RMMZ may be recommended for patients who are expected to decrease in intraoperative vital signs. However, stable hemodynamics with RMMZ were not sufficient to influence the prevention of AKI. Various incidence rates of postoperative acute kidney injury (AKI) have been reported depending on the type of surgery and drugs administered ,2,3. WheTotal knee arthroplasty (TKA) is mainly performed in patients who experience pain and deterioration in quality of life because of knee cartilage wear or rheumatoid arthritis. Most patients are elderly, and the number of patients undergoing TKA increases with increasing life expectancy . Lower lRemimazolam (RMMZ) is a relatively recently approved, intravenously infused, very short-acting benzodiazepine ,11,12. SHowever, studies on the prevention of postoperative AKI using the hemodynamic stability of RMMZ have not yet been conducted. We hypothesized that the use of RMMZ, which can promote hemodynamic stability during TKA, would reduce the incidence of postoperative AKI compared to the administration of sevoflurane (SEVO), which is an inhalation anesthetic agent used for conventional anesthesia.This study evaluated the incidence of postoperative AKI after RMMZ or SEVO during TKA in elderly patients in an assessor-blinded parallel-group randomized controlled study. Ethical approval was obtained from the Institutional Review Board (IRB) of Kyung Hee University Hospital (KHUH 2022-08-066) on 16 September 2022. The trial was registered with the Clinical Research Information Service (CRIS)  and conducted in compliance with the Declaration of Helsinki. The study protocol is available from CRIS. Written informed consent was obtained from all study participants, and the study report complied with the Consolidated Standards of Reporting Trials checklist.2 were excluded. Recruitment began in September 2022 and was terminated in January 2023.Elderly individuals older than 65 yrs who planned to undergo elective TKA were included in the trial. Preoperative hemodialysis due to renal failure, allergy to any study drugs, revision TKA, second operation on the opposite side of the knee in one hospitalization, simultaneous TKA, American Society of Anesthesiologists (ASA) class ≥ IV, and body mass index >35 kg/mThe primary outcome was the incidence of AKI on postoperative day (POD) 2. AKI was evaluated using the Kidney Disease: Improving Global Outcomes criteria and was defined as an alteration of serum creatinine (Cr) level ≥ 0.3 mg/dL until POD 2 .Secondary outcomes included intraoperative blood pressure (BP), heart rate (HR), total intraoperative drugs, amount of fluid infused, estimated blood loss (EBL), and emergence time. The time from the cessation of anesthetic drugs until an Aldrete score ≥9 was reached , and theThe correlation between liver function test (LFT) and recovery time was evaluated in the RMMZ group as a subgroup analysis.On the morning of surgery, the participants were randomly allocated to the RMMZ or SEVO groups using sealed opaque envelopes. With random block sizes and a 1:1 allocation, a computer-generated random allocation sequence was produced using Microsoft Excel 2019. Because of the considerable differences in the technique of study drug administration, the anesthesia providers were not blinded to group allocation; however, the patients and outcome assessors were blinded.2 saturation were measured, and palonosetron (0.075 mg intravenous (IV)) and glycopyrrolate (0.005 mg/kg IV) were administered before anesthesia induction.After entering the operating room (OR), the patients’ baseline HR, BP, and peripheral OIn the RMMZ group, 1 mg/mL RMMZ (ByfavoTM) was prepared, and 0.1 mg/kg IV was administered for anesthesia induction. An additional 2 mg IV was administered, if necessary. If loss of consciousness was confirmed, a neuromuscular blocker was given at 0.8 mg/kg IV rocuronium. When neuromuscular block was confirmed, 0.5 µg/kg IV bolus of remifentanil was administered, and tracheal intubation was performed. Anesthesia was maintained at 1–2 mg/kg/h IV RMMZ and adjusted according to the target range of the bispectral index (BIS), which was 30–60. In the SEVO group, 1.5 mg/kg IV propofol was administered for anesthesia induction. An additional 20 mg IV was administered, if necessary. 0.8 mg/kg IV rocuronium and 0.5 µg/kg IV remifentanil were administered before tracheal intubation as the same protocol with the RMMZ group. SEVO was adjusted with reference to the BIS level during anesthesia maintenance.In both groups, 0.03 mg/kg IV midazolam was administered if the BIS level did not reach the target. Intraoperatively, remifentanil was adjusted to the range of 0.05–0.2 µg/kg/min IV and was maintained at the 20% range of the initial HR and BP in both groups. If the HR and BP were unable to be maintained by remifentanil alone, a beta blocker , a vasodilator , or a vasoconstrictor  was administered. The rate of intraoperative fluid administration was set at 3–4 mL/kg/h IV. Remifentanil administration was discontinued at the time of skin suturing. Within POD 2, IV, patient-controlled analgesia based on fentanyl (12.5 µg/kg IV) was administered in both groups. RMMZ and SEVO were discontinued at the time of splint application. Sugammadex was administered at 2 mg/kg IV to reverse neuromuscular blockade; in the case of the RMMZ group, 0.2 mg IV flumazenil was administered as a reversal agent of RMMZ.The incidence of AKI was assessed until POD 2 on the basis of the medical records.In the OR, HR and BP were measured at baseline, both before and after endotracheal intubation, at the beginning of incision, 30 min and 1 h after incision, at lower extremity tourniquet deflation, and in the post-anesthetic care unit (PACU) phase. The total intraoperative amounts of RMMZ, remifentanil, fluid, other infused medications, and EBL were recorded. SEVO was recorded as the mean vol%, which was adjusted during surgery. The emergence time from RMMZ or SEVO stop to eye opening, endotracheal tube extubation, exit from the OR, and time to reach Aldrete score ≥ 9 was measured. The incidence of postoperative hospital complications within POD 2 and postoperative HLOS wase recorded by reviewing the medical records.According to preliminary research conducted at our institution in patients who underwent TKA, the incidence rates of AKI were approximately 11% and 39% in the propofol- and remifentanil-based total intravenous anesthesia (TIVA) and inhalational groups, respectively. The number of participants in each group was calculated to be 35 based on the G-power analysis performed using pilot study data . The total number of patients was 78, with 39 patients in each group, considering a 10% dropout rate.p-Values < 0.05 were considered statistically significant.Data were expressed as numbers (%) or medians (interquartile ranges). Fisher’s exact test or the chi-square test was used to analyze categorical variables. Normality of the distribution of continuous variables was evaluated using the Shapiro–Wilk test. Comparisons between continuous variables with a normal distribution were computed using independent variable t-tests, whereas comparisons between non-normal variables were performed using Wilcoxon rank-sum tests. Spearman’s rank correlation analysis was performed to determine the correlation between the two non-normal continuous variables. Statistical analyses were conducted using the commercial statistical software SPSS , and two-tailed A total number of 174 patients were screened; 96 were excluded, and 78 were randomly assigned. Thirty-nine participants were equally allocated to the RMMZ and SEVO groups without any loss to follow-up. Finally, 39 participants from each group were analyzed . Demograp = 1.000)  in the RMMZ group and four patients  in the SEVO group on POD 2, with a comparable incidence between the RMMZ and SEVO groups (= 1.000) .p = 0.001). The patents received inotropic more frequently in the SEVO group (66.7% (26/39)) than in the RMMZ group (15.4% (6/39)) (p < 0.001), and the number of patients receiving nicardipine as vasodilator (84.6% (33/39) vs. 20.5% (8/39), p < 0.001) and midazolam as additional sedatives (20.5% (8/39) vs. 0% (0/39), p = 0.009) was definitely higher in the RMMZ group than in the SEVO group  μg/kg/min IV) than in the SEVO group (0.08 (0.05–0.11) μg/kg/min IV) (VO group .p = 0.021), 30 min  and 1 h after incision , and after tourniquet deflation  (p = 0.034) and after tracheal intubation  and 30 min  and 1 h after incision   . The mea< 0.001) .Emergence time in the OR was definitely faster in the RMMZ group than in the SEVO group, and the recovery time required to reach an Aldrete score of nine or higher was comparable between the two groups. Postoperative Cr levels were comparable between the two groups. The increase in postoperative Cr levels compared to pre-operative levels was also comparable between the RMMZ and SEVO groups. Furthermore, the postoperative HLOS was comparable between both the groups .p = 0.806), PONV (15 (38.5%) in the RMMZ group vs. 20 (51.3%) in the SEVO group, p = 0.362), PPC (6 (15.4%) in the RMMZ group vs. 5 (12.8%) in the SEVO group, p = 1.000), or delirium (5 (12.8%) in the RMMZ group vs. 2 (5.1%) in the SEVO group, p = 0.428) as postoperative complications within POD 2, these were comparable between the RMMZ and SEVO groups (In terms of POUR (26 (66.7%) in the RMMZ group vs. 28 (71.8%) in the SEVO group, O groups .r = 0.14, p = 0.403; Total Bilirubin, r = 0.07, p = 0.668; Aspartate Aminotransferase, r = 0.17, p = 0.300; and Alanine Aminotransferase, r = −0.22, p = 0.172) revealed  and opioids (remifentanil) were administered more often in the RMMZ group than in the SEVO group. The emergence time in the OR was shorter in the RMMZ group than that in the SEVO group.Previous studies have shown that hemodynamics are more stable when RMMZ is administered than when conventional anesthetics, such as propofol or inhalational agents, are administered ,16,17. TThe emergence time in the OR was faster in the RMMZ group than that in the SEVO group. Choi et al.  comparedThe incidence of postoperative complications was comparable between the RMMZ and SEVO groups. However, the incidence of POUR was high in both groups. In a meta-analysis by Chang et al. , the incStöhr et al.  reportedp = 0.57), and SEVO anesthesia was not related with postoperative AKI . Similar to previous studies, the incidence of AKI in the present study was comparable between the RMMZ (12.8%) and SEVO (10.3%) groups (p = 1.000). The higher incidence of AKI compared to previous studies is considered to be because the present study was conducted with elderly patients older than 65 years.Another study drug, sevoflurane, reacted with some carbon dioxide absorbents to decompose into Compound A . In studThis study had some limitations. First, because of the considerable differences between the administration methods of RMMZ and SEVO, double-blinding could not be achieved. However, an outcome assessor which was blinded (by the Y.N.A.) was used to minimize bias in the postoperative outcome evaluation.Second, the intraoperative RMMZ was titrated against BIS. Given that the BIS is not an anesthetic depth monitoring system designed based on the RMMZ, it may not properly reflect the depth of anesthesia induced by the RMMZ. Consequently, additional sedatives were administered more frequently. However, most previous studies related to RMMZ adjusted the dose based on the BIS during surgery ,40. If RThird, the participants were limited to elderly patients undergoing TKA, and most were relatively healthy  and female . However, the strength of this trial was the administration of RMMZ, which showed hemodynamic stability in elderly patients who were expected to have decreased BP during surgery. Additionally, when only TKA was included, the surgical position, operative time, operative difficulty, and blood loss were relatively consistent. In previous studies, most of the patients underwent TKA were female patients ,42. A stRMMZ may be recommended for patients who are anticipated to experience a decrease in intraoperative BP. However, stable hemodynamics with RMMZ are not sufficient to prevent AKI. Further large-scale, double-blind, randomized controlled trials of RMMZ should be performed.


The therapeutic administration of subcutaneous immunoglobulin (SCIg) offers various advantages over intravenous immunoglobulin (IVIg). This narrative review examines and compares SCIg versus IVIg in chronic inflammatory demyelinating polyneuropathy (CIDP). SCIg is as effective as IVIg but is better tolerated and easier to administer, as intravenous access is not required. Furthermore, SCIg administration is more convenient and cost-effective than IVIg, enabling flexible treatment scheduling at home and improving patients’ overall quality of life. The availability of highly concentrated immunoglobulin G (IgG) subcutaneous solutions, such as IgPro20, a 20% IgG solution stabilized with L-proline, allows for the administration of larger volumes in a single session, while the parallel development of new technological devices enables the delivery of higher doses over a shorter time. Based on the results of the PATH study, SCIg has become a well-established therapy in CIDP. In addition to discussing the advantages of SCIg, this review summarizes the evolution of SCIg by discussing all the relevant clinical studies which have considered its use in the treatment of CIDP. Chronic inflammatory demyelinating polyneuropathy (CIDP), an acquired peripheral sensory–motor neuropathy with an assumed autoimmune-mediated pathogenesis , is variCurrently, treatment with immunoglobulins G (IgG) is recommended as first-line therapy by clinical guidelines for chronic dysimmune neuropathies, such as CIDP and multifocal motor neuropathy (MMN) , and is In this review, some of the main aspects of SCIg treatment in CIDP will be described, as well as the differences in this treatment compared with IVIg.Through searches in MEDLINE, PubMed, EMBASE, BIOSOS, Web of Science, and Cochrane library on 31 March 2023, 185 studies were identified . Fifty-one studies were included.We acknowledge that a weak point of this narrative review is that due to its structure, it did not allow us to emphasize the levels of evidence supporting the therapies discussed.A meta-analysis that included 138 patients overall from eight studies of SCIg versus IVIg in the treatment of CIDP concluded that the risk of moderate or systemic adverse events (AEs) with SCIg was 28% lower than with IVIg . This meThe less frequent occurrence of moderate or systemic AEs may be accounted for by a difference in the pharmacokinetics of larger-volume intermittent IVIg boluses compared with smaller and more frequently administered SCIg infusions. In fact, bolus infusion with IVIg produces a spike in the concentration of serum immunoglobulin G (IgG), which drops sharply by 30–40% over 48–72 h due to the passage of IgG from the intravascular compartment to the extracellular space. IgG levels then slowly decrease following the first-order kinetics of IgG degradation . On the Wearing-off and treatment-related fluctuations in patient strength and functional capability are likely due to a progressive decline in IgG concentrations towards the end of an IVIg dosing cycle ,18. A 20SCIg administration does not require venous access, nor is there a need for premedication with corticosteroids and antihistamines. These factors reflect, along with the typical pharmacokinetic properties of SCIg, the reduced incidence and severity of SCIg-induced systemic AEs . In addiWith SCIg administration, there is not always a need for the patient to be hospitalized, to attend a medical examination, or be visited by a nurse, thus lowering the long-term healthcare costs . In a reThe first account of the therapeutic usage of SCIg dates back to 1952, when Bruton successfully treated a child with what is now known as X-linked agammaglobulinemia (XLA) and recurrent pneumococcal infections by SC administration of human IgG at 3.2 g/month . In 1980The first reference to SCIg therapy in CIDP was a case report published in 2006 by Köller and colleagues , in whicThe next account of SCIg use in CIDP was a 2008 report of two patients treated with SCIg after 5 and 13 years of previous IVIg therapy . Both paIn 2011, Cocito and colleagues  publishep < 0.05 vs. baseline) compared with an expected decline  in those who received placebo (p < 0.01 SCIg vs. placebo). Other key functional measures followed a similar pattern in relation to placebo. SCIg treatment was well-tolerated, with only six patients reporting mild AEs at the injection site. No systemic AEs were recorded, and 70% of the patients preferred SCIg over IVIg maintenance therapy, reporting a more stable condition, increased autonomy, and fewer AEs. The authors concluded that, due to its safety and effectiveness, SCIg treatment is a feasible alternative to IVIg for patients with CIDP [p = 0.033), with nonsignificant interim improvements observed after 3, 6, and 12 months ; the MRC score increased significantly by 1.7% (p = 0.007), whereas other key functional parameters remained unchanged [In 2013, the first small, double-blind, placebo-controlled, parallel-group, randomized controlled trial (RCT) evaluated the efficacy of switching from IVIg to SCIg maintenance therapy in 30 adult patients with CIDP . After 1ith CIDP . While tThe findings regarding the cost-effectiveness of SCIg versus IVIg were consistent with an Italian study by Lazzaro and colleagues , which aTo date, very few studies have focused on the various aspects of patient well-being, such as QoL and patient satisfaction, which may be the result of a combination of factors, including the efficacy of Ig therapy, occurrence of AEs, the setting of IgG administration, and discomfort.p = 0.018), whereas the MRC score was unchanged, indicating that patients in the SCIg group maintained muscle strength. Scores on the LQI-I subscale (indicating treatment interference in the activities of daily living), LQI-II subscale (indicating problems related to the administration of therapies), and LQI-III subscale (indicating the patient’s perception of the therapeutic setting) significantly improved among patients with CIDP  [A nationwide Italian multicenter prospective observational study  reportedctively) . This stctively) .In a 2-year retrospective follow-up of their 2014 study, Cocito and colleagues  evaluatep = 0.0008 vs. baseline) to a similar degree (p = 0.80). Overall, the improvements from baseline in combined isokinetic muscle strength (cIKS) were similar , but the time profiles were different, with effects of IVIg on muscle strength peaking earlier than those of SCIg. On the other hand, significant improvements in disability were only observed during SCIg treatment. Data also suggested that IgG plasma concentrations and variation in cIKS were related [In 2017, the first study to address the effects of SCIg in treatment-naïve CIDP patients was published by Markvardsen and colleagues . In this related . The stuThe efficacy of SCIg treatment for CIDP in maintaining muscle strength for up to 1 year, as well as longer term, and in improving disability and QoL has been previously established by several studies ,32,33,39®) for maintenance therapy, examining the rate of relapse or withdrawal from the study (efficacy endpoints). IVIg-dependent patients (n = 172) were stabilized on IVIg and then randomized to SCIg IgPro20, at either 0.2 g/kg/week (low dose) or 0.4 g/kg/week (high dose), or placebo for 24 weeks or until relapse or study withdrawal. The proportion of patients who suffered relapses or were withdrawn from the study was significantly greater in the placebo group (63%) compared with the low-dose (39%) or high-dose (33%) SCIg groups (p = 0.0007) [The first large-scale RCT testing the safety and efficacy of SCIg in patients with CIDP was the PATH study . The tri 0.0007) .SCIg was also well-tolerated; the rates of local and systemic AEs were low. In addition, health-related QoL outcomes were better for both SCIg groups compared with the placebo group. The patients’ preference for weekly SCIg compared with monthly IVIg was explained in terms of increased independence and fewer AEs .A subsequent analysis has evaluated changes in patient-reported outcomes in patients who took part in the PATH study from baseline to last postdose observation, including QoL, treatment satisfaction, and work productivity . This stn = 7/72) with high-dose SCIg and 48% (n = 35/73) with low-dose SCIg [An open-label, prospective, 48-week extension of the PATH study was conducted to assess the long-term safety (primary objective) and efficacy (secondary objective) of SCIg IgPro20 maintenance therapy in patients with CIDP. In this study, the relapse rate was 10% (ose SCIg . Of the ose SCIg . At the ose SCIg . The mosose SCIg .p < 0.005), supporting the feasibility of SCIg as an alternative to IVIg in the long-term treatment of CIDP [Despite the increasing number of case reports and clinical trials on the efficacy of SCIg, there remains a lack of clinical guidelines regarding the recommended timing of initiating SCIg therapy in patients with CIDP. A first attempt to address this issue was made by Cirillo and colleagues , who eva of CIDP . The ear of CIDP .As has emerged from the first years of their development, recently, different studies have substantially confirmed the efficacy, safety, and improvement in QoL with SCIg in CIDP therapy ,43,44,45SCIg administration offers advantages over IVIg therapy and appears to be preferred by many patients with CIDP for several reasons. SCIg is mostly associated with transient mild-to-moderate local reactions and fewer nonserious and serious systemic AEs than IVIg. SCIg is associated with reduced severity in end-of-dosing wear-off and results in increasing serum IgG concentrations, which reach nearly constant steady-state levels, with no “peaks-and-troughs” that are typical of IVIg administration. As the subcutaneous route of administration does not require venous access, SCIg can be self-administered at home, which increases flexibility, patient QoL, and cost-effectiveness.The currently available literature provides robust evidence that SCIg is a safe and effective alternative to IVIg for the maintenance treatment of CIDP, and it also suggests that it is an effective therapeutic option in treatment-naïve CIDP patients.Another important aspect is the lack of response to both IVIg and SCIg, which has been shown in 35% of the patients ,47,48,49The analysis of the polymorphism of the genes that codify for FcRn , togethe


A perilymphatic fistula (PLF) presents with abnormal traffic in the otic capsule, causing cochlear and vestibular symptoms. However, the mechanisms underlying symptom recurrence remain controversial. Herein, we report the case of a 27-year-old female who complained of hearing disturbance in her right ear and recurrent vertigo after sudden onset of hearing loss with vertigo. The caloric test revealed unilateral weakness in the right ear, and the video head impulse test (vHIT) showed decreased vestibulo-ocular reflex (VOR) gain. Contrast-enhanced magnetic resonance imaging (MRI) using hybrid of reversed image of positive endolymph signal and negative image of perilymph signal (HYDROPS) indicated a collapsed endolymphatic space. As the vestibular symptoms did not improve, an exploratory tympanotomy was performed on the right ear. Although perilymph leakage was not noted in the oval or round windows, both windows were sealed with connective tissue. The patient's vestibular symptoms rapidly improved after surgery, and postoperative contrast-enhanced MRI showed improvement in the collapsed endolymphatic space. Although the caloric test revealed unilateral weakness, the VOR gain on the vHIT improved to normal on the right side. Thus, these findings indicated that recurrent symptoms caused by PLF are associated with a collapsed endolymphatic space. We speculate that the collapsed endolymphatic space was due to a ruptured Reissner's membrane. We hypothesized that sealing the fistula would promote normalization of perilymph pressure. The ruptured Reissner's membrane may have been gradually repaired as vestibular symptoms improved. This case adds to the existing literature on the occurrence of the “double-membrane break syndrome”. Collapse of the endolymph due to a ruptured Reissner's membrane may be the cause of PLF symptoms. A perilymphatic fistula (PLF) presents with abnormal traffic in the otic capsule, causing cochlear and vestibular symptoms. PLFs can be classified as those with and without identifiable causes. PLFs are more likely to be diagnosed after middle or inner ear surgery, such as stapes surgery, or trauma. However, it is often difficult to identify the cause of PLFs in the absence of prior surgery or trauma. In Japan, PLFs are classified into four categories according to the cause and diagnosed based on clinical symptoms, microscopic or endoscopic examination of the fistula between the middle and inner ears, or detection of a perilymph-specific protein in the middle ear  1, 2). , 2. 1, 2A 27-year-old female complained of hearing disturbance in her right ear and recurrent vertigo after sudden onset of hearing loss with vertigo. She had no history of trauma or headaches. At the age of 15 years, she began to experience vertigo preceded by right ear blockage without any trigger. Vertigo was induced by blowing the nose. At the age of 19 years, her symptoms worsened further, and the frequency of vertigo increased; therefore, she visited a local Ear, Nose and Throat (ENT) clinic, but no hearing loss was noted and no apparent abnormality was found. At the age of 26 years, she suddenly developed hearing loss in her right ear and severe vertigo, which she had never experienced before, and visited another ENT hospital. The mean pure-tone air conduction threshold at 500 Hz, 1,000 Hz, and 2,000 Hz was 70.0 dB. An A-B gap was present at low frequencies . The spoOne year later, she returned to the hospital with hearing loss and severe vertigo, and her right hearing had deteriorated and scaled out . The patSince vertigo was induced by blowing the nose, this case was classified as Category 3 according to the Japanese PLF categorization, and the positive CTP result confirmed the diagnosis  1, 2). , 2. 1, 2PLFs generally present with an acute onset of auditory symptoms, vestibular symptoms, or both. Sometimes, vestibular symptoms occur with fluctuating or progressive hearing loss, and as in this case, they are differentiated from MD. Therefore, in previous reports, MD and PLF were closely related, and PLF is thought to be complicated by endolymphatic hydrops, similar to MD , 7–9. CeMerchant and Schuknecht first described a histopathological entity called vestibular atelectasis, which shows the collapse of the ampulla and utricle walls . EliezerThe patient's symptoms improved postoperatively. Even if the traffic between the perilymph space and middle ear space were surgically blocked, the rupture of Reissner's membrane would have remained. We hypothesized that the rupture of Reissner's membrane would have spontaneously repaired after surgery and that the endolymphatic collapse would have improved on imaging. Rupture and spontaneous repair of Reissner's membrane was considered the mechanism of vertigo attacks and their recovery in MD. However, this has been debated in recent years because it is not accompanied by significant hearing loss during vertigo attacks , 21. In The patient had vestibular disorders, as determined in both the preoperative caloric test and the vHIT. Although both tests are functional tests of semicircular canals, they differ in stimulation frequency; the caloric test uses low-frequency stimulation, whereas the vHIT uses high-frequency stimulation , 23. MerThe mechanisms by which PLFs cause vestibular symptoms and hearing loss remain unclear. However, in the present case, endolymph collapse on the affected side was noted on cochlear contrast-enhanced MRI. Endolymph collapse due to rupture of the Reissner's membrane may be the cause of these symptoms.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.YI: Writing—original draft, Writing—review and editing. TS: Writing—review and editing. YS: Writing—review and editing. FM: Writing—review and editing. IK: Writing—review and editing.


Through a cross-sectional community study of 2044 children aged 2 years, we (1) examine the impact of hearing loss on early spoken expressive vocabulary outcomes and (2) investigate how early intervention-related factors impact expressive vocabulary outcomes in children with hearing loss predominantly identified through universal newborn hearing screening. We used validated parent/caregiver-reported checklists from two longitudinal cohorts  representing the same population in Victoria, Australia. The impact of hearing loss and amplification-related factors on vocabulary was estimated using g-computation and multivariable linear regression. Children with versus without hearing loss had poorer expressive vocabulary scores, with mean scores for bilateral loss 0.5 (mild loss) to 0.9 (profound loss) standard deviations lower and for unilateral loss marginally (0.1 to 0.3 standard deviations) lower. For children with hearing loss, early intervention and amplification by 3 months, rather than by 6 months or older, resulted in higher expressive vocabulary scores. Children with hearing loss demonstrated delayed spoken expressive vocabulary despite whole-state systems of early detection and intervention. Our findings align with calls to achieve a 1-2-3 month timeline for early hearing detection and intervention benchmarks for screening, identification, and intervention. Universal newborn hearing screening (UNHS) effectively reduces the median age of congenital hearing loss detection ,2. This There are relatively few reports of the spoken language outcomes of young DHH children. Early intervention (EI)-based studies show mixed results, either demonstrating children can achieve age-appropriate speech/language outcomes by three years of age  or age-aWhile some catch-up is possible , poorer Comparing two community cohorts of 2-year-old children with and without hearing loss derived from the same Australian state, this study aimed to (1) describe the impact on spoken expressive vocabulary of all degrees of unilateral and bilateral hearing loss and (2) describe intervention-related factors  for DHH children with unilateral and bilateral losses and quantify their impact on expressive vocabulary for DHH children with bilateral hearing loss.This was a cross-sectional study of spoken expressive vocabulary in 2-year-old children from two longitudinal cohorts: DHH children from the Victorian Childhood Hearing Longitudinal Databank (VicCHILD) , and chiVicCHILD is a population-level data repository for over 1100 children with any degree or type of permanent hearing loss. All children identified with hearing loss through Victoria’s UNHS program  are invited to participate, as are children who attend the Royal Children’s Hospital Caring for Hearing In Children Clinic for congenital or late-onset hearing loss. Most VicCHILD participants are under one year of age at enrollment. All participants also have access to government-supported hearing amplification and EI programs. Data are collected longitudinally with repeated measures as the child grows. Further information on VicCHILD’s methodology is detailed elsewhere . This stELVS has documented the speech and language development of a community sample of children without known permanent hearing loss, developmental delays, or serious disabilities when recruited in 2003-4 at ages 8–10 months . Over 19The primary outcome was parent-/caregiver-reported spoken expressive vocabulary at around 2 years, collected in both cohorts using closely related measures. ELVS used the 680-word vocabulary checklist in the MacArthur Bates Communicative Development Inventory (MCDI) Words and Sentences test , whereasThe expressive vocabulary outcome was derived from standardized SSLM scores for both cohorts. For the ELVS cohort, the SSLM raw score was calculated for the 100 items in the MCDI common to the SSLM. For any combination of words, such as “sofa/couch” being a single item on the SSLM but two items on the MCDI, a single score was assigned in the SSLM raw score calculation if at least one of the words was selected on the MCDI. Based on this process, MCDI scores were converted to SSLM raw score equivalents, then to standardized scores based on age (in months) and sex.The exposure for aim 1 was hearing loss, defined as no hearing loss or a combination of the degree of loss (mild 21–40 dB)/moderate (41–60 dB)/severe (61–90 dB)/profound (>91 dB)) and presence in one/both ears . Degree of loss, calculated using three or four frequency averages, was obtained from UNHS records or parent/caregiver-supplied audiology results, classified using national decibel ranges for the affected ear  or better hearing ear  [–40 dB/moFor aim 2, intervention-related factors were considered as separate exposures to explore the impact of intervening on single characteristics individually. Within the bilateral hearing loss cohort, exposures were hearing amplification status at survey completion (amplified vs. unamplified), frequency of hearing device use (never/rarely (no device or use <4 h/day), sometimes/often (4–8 h/day) or always (>8 h/day) derived from parent/caregiver-estimated hours of daily use at time of assessment), and age first enrolled into an EI program . Age at first hearing amplification fitting  was an exposure for children ever fitted with hearing amplification.Directed acyclic graphs were developed to model assumptions about the causal structures see . For botAll analyses were completed in statistical software R version 4.0.2  and condFor aim 1, the samples of individuals with and without hearing loss were combined. We used a causal modeling approach to estimate the impact of hearing loss on expressive vocabulary at age 2 years, outlined as follows: Linear regression models were fitted to the data, modeling the outcome conditional on exposure, with three different models considered. Model 1 was an unadjusted model. Model 2 included demographic confounders as covariates, with Model 3 additionally including birth-related factors as covariates. The latter two models included interaction terms where appropriate  and 1742 children from the ELVS cohort who were considered to not have permanent hearing loss . The meap < 0.01) to 13.5 points (0.9 standard deviations) lower for profound bilateral loss . For unilateral hearing losses, the impact was less substantial, with adjusted mean scores ranging between 1.5 and 4.4 points lower  (Estimates from Model 3 are presented in ctively) .p = 0.18)  .p < 0.01 and 4.3 points, 95% CI −1.7 to 10.3, p = 0.16 for ages 3.1 to 6 months and >6 months, respectively; Reflective of a well-functioning UNHS environment, the median age at diagnosis was 1.0 month for children with any hearing loss. Most children received hearing amplification early  were enrolled in EI services early (median age 6 months) and were enrolled with a service at survey completion . ChildreDespite Victoria’s sophisticated early identification and intervention systems reaching essentially all children, the spoken expressive vocabulary of 2-year-old DHH children lagged behind those without hearing loss. Spoken expressive vocabulary of children with bilateral losses was increasingly impacted as the degree of hearing loss increased, ranging from 0.5 to 0.9 standard deviations below expected levels after adjustment for potential demographic and birth-related confounders. Children with unilateral losses had an expressive vocabulary closer to  children without hearing loss, without a clear relationship between outcome and hearing loss severity.Importantly, we demonstrated enrollment in EI by 3 months of age resulted in higher spoken expressive vocabulary scores. A similar pattern towards higher expressive vocabulary scores was also observed in the presence of earlier amplification. This may provide support for the narrower 1-2-3 month alternative timeline to the 1-3-6 EHDI indicators . HoweverOur 96% UNHS-identified community cohort represents the common early diagnosis pathway occurring in countries with well-resourced EHDI systems. By including children with any degree of hearing loss in either ear and those with unamplified hearing losses, this enables a more generalizable estimate of expressive vocabulary performance than previous studies of early intervention cohorts . DespitOur statistical approach attempted to minimize potential confounding biases. When interpreting the results, we acknowledge the trade-off between sparse data in confounder substrata (under Model 3) and the potential for additional unmeasured confounding bias (under Model 2). Therefore, results are presented under all models to allow the reader to interpret the estimates while acknowledging these potential limitations. Unmeasured residual confounding remains possible, such as nonverbal IQ and differences between our hearing and hearing loss groups with respect to the inclusion of children with developmental delays. Limited by sample size, we analyzed exposures separately for aim 2. This meant we were unable to consider the potential combined effects of these exposures.Our study was limited to examining spoken vocabulary as a measure of expressive language in DHH children, acknowledging that sign language is an important form of communication for DHH children. Among our VicCHILD participant children, less than 3% were reported to use Australian sign language (Auslan) as the predominant mode of communication. Moreover, there are no standardized or validated tools to measure sign language outcomes in preschool-aged children.Children with hearing loss were drawn from our population-level data repository, with 60% of participant parents/caregivers reporting their child had no additional special health need or medical diagnosis. This is in keeping with other studies reporting that around 40% of DHH children have concomitant medical comorbidities; however, our study did not collect adequate information about medical comorbidities to determine whether this could be a factor influencing language outcomes.For aim 2, we assumed the impact of intervention-related factors on expressive vocabulary would be different between individuals with unilateral or bilateral loss and therefore presented the estimated impact for bilateral losses only. A secondary analysis was conducted to estimate the impact for individuals with any permanent hearing loss—unilateral or bilateral. This secondary analysis indicated a similar relationship to that observed for bilateral hearing loss only, with attenuated effect sizes. However, this analysis assumed a constant causal effect across children with both lateralities of hearing loss, which we believe may not be reflective of the true behavior, and therefore have presented bilateral loss only within the main paper.Our study design surveyed hearing amplification use at a single timepoint, which may miss capturing the variance in and accumulative effect of hearing amplification use over time . All chiWhile born into the same geographic population, expressive vocabulary assessment occurred around a decade earlier for participants without known hearing loss compared to our DHH cohort. However, we believe our language performance comparisons remain valid since we do not expect typically developing children’s language outcomes to have changed greatly across time.Our findings support and extend findings from other studies by including children with unilateral loss and not limiting eligibility to those enrolled in EI programs. Like other existing studies of older children, we have demonstrated that children with even a mild degree of hearing loss have an expressive vocabulary below what is expected for their peers without hearing loss ,28. As aWe found no clear association between frequency of hearing amplification use and mean expressive vocabulary at age 2 years. The U-shaped performance curve where high vocabulary scores were found both for children reported to wear hearing amplification “never/rarely” and “always” warrants exploration. High hearing amplification use in children with high vocabulary scores may reflect the positive impact earlier detection through UNHS has on language outcomes  and the There is some evidence that children without hearing loss with larger spoken expressive vocabularies at age 2 will, at age 5, show better performance in academic and behavioral outcomes compared to those with smaller spoken expressive vocabularies . Early iThis study provides population-level evidence of delayed spoken expressive vocabulary in DHH children at age 2 years, even with early detection through UNHS. We confirmed that the earlier the enrolment in EI programs and access to hearing amplification, the better the spoken expressive vocabulary outcomes. Specifically, our data supports the 1-2-3-month goal to screen, identify, and enter intervention rather than the original 1-3-6 EHDI benchmarks. While the extent of gains that could still be made is unknown, it is clear that interventions are not yet optimized for DHH children, as their early spoken expressive vocabulary outcomes are still poorer than their hearing peers. Moving forward, we must aim to more precisely understand the factors that impact language development in DHH children so that intervention can be targeted at those who need it most.


Hearing and vision impairment are highly prevalent in ageing individuals and are significant public health concerns given their meaningful impacts on individuals and society. Yet, many cases of both visual and hearing impairment remain unidentified and thus, unaddressed. This article describes the rationale and process of monitoring for visual and hearing impairment in older adults, by summarising guidance and resources available from the World Health Organisation (WHO) that were developed based upon the best current available evidence. It is recommended that vision screening be offered at least annually to adults aged over 50 years and hearing screening be offered every 5 years to adults aged 50–64 years, and every 1–3 years to adults aged 65 years or older. Both hearing and vision screening can be conducted in community, home or clinical settings by trained health workers with simple equipment. More specifically, vision screening can be conducted with a simple eye chart. Hearing screening can be conducted without specialised equipment by using pure tones set to a fixed level, an automated mobile- or web-based digits-in-noise test, or the whispered voice test. Hearing screening can also be conducted in audiology clinics using pure-tone air conduction threshold testing. There exists WHO guidance to support the monitoring of hearing and vision impairment, which, when warranted, can facilitate referral for comprehensive assessment and prompt appropriate, person-centred interventions to mitigate the negative consequences of hearing and vision impairment. The World Health Organisation has guidance to support the monitoring of hearing and vision impairment.Hearing and vision screening can be conducted in community, home or clinical settings.Hearing and vision screening can be performed by trained health workers with simple equipment.Monitoring for hearing and vision impairment can prompt appropriate, person-centred interventions.The human body interacts with the external environment with the use of its five special senses: hearing, vision, smell, touch and taste . The losGlobally, it is estimated over 2.2 billion people have a vision impairment or blindness, whilst over 1.5 billion live with hearing impairment, the majority of whom are over 60 years of age , 4. The When hearing and vision impairments remain unaddressed, they pose a significant challenge for the quality of life of those affected . HearingFor many people (over 800 million) with refractive errors, vision impairment could simply be addressed with an appropriate pair of spectacles, and for others corrected through cataract surgery, and over 400 million of those with hearing loss could benefit through use of a hearing aid , 4. DespChallenges in managing hearing and vision impairment are further aggravated by the lack of systematic monitoring for vision and hearing capacities in older adults , 4. As aIn consideration of the above-mentioned facts, the World Health Organisation (WHO) ‘Integrated care for older people: guidelines on community-level interventions to manage declines in intrinsic capacity’ published in 2017 recommended the integration of systematic and routine vision and hearing screening followed by provision of appropriate care and rehabilitation for older adults as being essential to suitably manage the declines in physical and mental capacities . MoreoveWHO publications including the World report on vision, Package of eye care interventions, World report on hearing, Hearing screening: considerations for implementation, and the soon-to-be published WHO Sensory function survey methodology, provide guidance on how hearing and vision assessment can be routinely undertaken , 20, 21.This guidance is based on the best available evidence collated by WHO. Importantly, it demonstrates how both hearing and vision screening can be conducted with simple equipment in clinical, community or home settings by trained health workers. Wherever feasible, hearing and vision screening should be aligned with other health checks offered to older adults and screening should be embedded in health systems. The steps for hearing and vision screening are summarised below.These services should be offered at least once a year to adults over the age of 50 years . Eye exaAll people are requested to share their perceived vision function status and ongoing diseases or treatment they are aware of. In addition, all people undergo a distance and near vision testing. This is performed with distance and near optotypes, wearing spectacles if usually worn by the person. Vision apps (such as WHOEyes App) could also be used. All vision testing shall be performed with adequate lighting and correct distance by trained screeners.Any fails should be referred for refractive assessment and care. In the case of reported diseases or treatment, or if reporting having undergone eye examination ˃5 years before (or never), individuals should be referred to undergo comprehensive eye examination by a trained eye professional.It is recommended that screening be offered to all adults above the age of 50 years and may be conducted at 5-yearly intervals until the age of 64 years. From 65 years of age, the frequency of screening should be increased to every 1–3 years. Hearing screening can be conducted by trained health workers and nurses, community health workers, non-hearing care clinicians or ear and hearing care clinicians, and with one of the four following simple tests , 21. (i)Those who fail a hearing screening should be referred to a clinician for diagnostic assessment, which can be done by pure-tone audiometry . IndividFor individuals diagnosed with vision or hearing impairment, it is essential that the impairment is addressed as early as possible and in an appropriate manner to mitigate any adverse impacts. Thus, intervention strategies must be planned and available at the time of screening. These intervention strategies must be person-centred and take into account the individual’s needs and preferences, in addition to the available resources , 21. IntScreening likely supports the early identification of and intervention for hearing and vision impairment. Both hearing and vision screening can be conducted in clinical, community or home settings by trained health workers with simple equipment. The WHO has published guidance that outlines the process of monitoring for hearing and vision impairment. When warranted, this monitoring can facilitate prompt, integrated, person-centred interventions that mitigate the negative consequences of hearing and vision impairment.


Despite significant advances in the development of therapeutics for hearing loss, drug delivery to the middle and inner ear remains a challenge. As conventional oral or intravascular administration are ineffective due to poor bioavailability and impermeability of the blood-labyrinth-barrier, localized delivery is becoming a preferable approach for certain drugs. Even then, localized delivery to the ear precludes continual drug delivery due to the invasive and potentially traumatic procedures required to access the middle and inner ear. To address this, the preclinical development of controlled release therapeutics and drug delivery devices have greatly advanced, with some now showing promise clinically. This review will discuss the existing challenges in drug development for treating the most prevalent and damaging hearing disorders, in particular otitis media, perforation of the tympanic membrane, cholesteatoma and sensorineural hearing loss. We will then address novel developments in drug delivery that address these including novel controlled release therapeutics such as hydrogel and nanotechnology and finally, novel device delivery approaches such as microfluidic systems and cochlear prosthesis-mediated delivery. The aim of this review is to investigate how drugs can reach the middle and inner ear more efficiently and how recent innovations could be applied in aiding drug delivery in certain pathologic contexts. Hearing loss is one of the most common sensory disabilities, with the World Health Organization estimating over 1.5 billion people worldwide to currently experience some form of hearing impairment . The earOtitis media (OM), perforation of the tympanic membrane (TM), and cholesteatoma are the most commonly reported middle ear diseases in clinical practice. Common signs and symptoms such as pain, fever, sudden hearing loss, and the sensation of fullness in the ear may help identify middle ear diseases, but additional approaches such as otoscopy and magnetic resonance imaging (MRI) are often required to confirm the diagnosis .OM represents a spectrum of middle ear inflammatory diseases which can be classified into acute otitis media (AOM), otitis media with effusion , and chronic suppurative otitis media (CSOM), which is one of the most severe middle ear diseases. The common symptoms for AOM and OME include earache, hearing loss, swelling and bulging of the TM, and the accumulation of fluid behind the TM. Meanwhile, CSOM is characterized by chronic inflammation and recurrent purulent discharge through a perforated TM .OM is one of the leading causes of permanent hearing loss in children and a significant disease burden in developing countries and several OM-prone populations such as Australian Aboriginals . ChildreStreptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Pseudomonas aeruginosa are the most common cause of OM, but it can also be caused by Influenza viruses or fungal species such as Aspergillus  . Most trCholesteatoma is described as an inflammatory, non-malignant (and pearl-like) epithelial lesion in the middle ear cavity that can lead to conductive hearing loss, erosion of the ossicles, and other intracranial complications. Congenital cholesteatoma is rare and contributes to 1%–5% of all cholesteatoma cases; and is often detected within the first decade of life . The devde novo in the developing cochlea. In the following subsections, we summarize the etiology of the more characterized common or severe forms of SNHL: hereditary, noise-induced, age-related, drug-induced and idiopathic.The most common type of hearing impairment is sensorineural hearing loss (SNHL). Patients with SNHL perceive sound as muted and distorted when compared to other forms of hearing loss, and it is caused by the degeneration or malfunction of cochlear hair cells or spiral ganglion nerves of the inner ear. This can be caused by a wide variety of environmental insults such as excessive noise, which is the second largest cause of SNHL, the administration of ototoxic drugs, exposure to ototoxic chemicals including certain solvents and metals, intrauterine infections including toxoplasmosis, cytomegalovirus and human immunodeficiency virus, birth asphyxia and hyperbilirubinemia. Genetics also play a role in more sporadic, yet highly severe forms of SNHL where aspects of cochlear development or structure are crippled by mutations to certain genes. These mutations can be inherited or, less commonly, arise Hereditary SNHL is caused by the inheritance of one or more gene mutations from biological parents that carry defective alleles, and affects about 1 per 1,000 newborns with profound deafness . MutatioNoise-induced hearing loss (NIHL) is caused by progressive over-exposure to noise. NIHL affects all ages, however there is an increasing prevalence of NIHL occurring in younger populations from recreational noise exposure, for example from listening to music using headphones for prolonged periods, with over 50% of those aged 12–35 being estimated to risk developing NIHL . OccupatAge-related hearing loss (ARHL), or presbycusis, affects the elderly as they gradually lose hearing in both ears and over 65% of adults over 60 years of age have been shown to be affected . ARHL usDrug-induced hearing loss occurs when patients take drugs that have ototoxic side effects. Aminoglycoside and macrolide antibiotics in particular, such as gentamicin and azithromycin, are commonly used in the treatment of Meniere’s disease and in developing countries for other diseases, however they are highly ototoxic . AminoglSudden sensorineural hearing loss (SSNHL) is characterized by the presentation of patients with at least 30 dB hearing loss occurring within 72 h. The incidence in the United States was reported to be 5 to 20 per 100,000 people with the vast majority of cases being unilateral and having an unknown etiology, being termed idiopathic . BilaterS. pneunomiae and H. influenzae has become standard practice in some countries  to repair damage caused by the lesion and surgical procedure . UnfortuP. aeruginosa in patients with chronic OM. Overall, the treatment did not cause any severe side effects, significantly lowered the bacteria count (CFU per gram) and improved the clinical scores of patients. In a later clinical trial, bacteriophage therapy was conducted in burns patients infected with P. aeruginosa , a type of proteinous appendage on the surface of most bacterial species, which plays a critical role in mechanosensing, motility, and the formation of biofilm . Novotnypathogen . Anti-Tfarrhalis . More imarrhalis . Other parrhalis . Dornasearrhalis .® , which is a hyaluronic acid-derived implantable device, and acellular dermal allografts such as Alloderm   . Some ofIreland) .Otherwise, adjuvant therapies using topical application of biomolecules are becoming popular in addition to myringoplasty to enhance the healing of perforations. The most commonly used biomolecules are growth factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) . The effMultiple clinical trials have been conducted to study the effects of bFGF on both acute and chronic TM perforations. For acute TM perforations, topical drops administration is the most commonly used approach and is associated with improved healing outcomes when compared to untreated controls . For chrPlatelet-rich-plasma (PRP), a type of blood product that is rich in platelets and bioactive molecules, has been shown to be a promising alternative treatment option for tissue repair and regeneration . PRP hasclinicaltrials.gov).Overall, adjuvant therapy using biomolecules with or without myringoplasty remains an attractive avenue for the management of TM perforations with research expanded beyond the traditional growth factors . More reAuditory rehabilitation with hearing devices or cochlear implants remains the primary treatment approach for SNHL. These technologies can significantly aid in communication, yet they are still unable to mimic the quality of natural hearing and, more importantly, they do not treat the underlying cause of the hearing loss .Hearing aid technology has advanced greatly over the past decade, with innovations allowing customization of every device to fit the unique hearing needs of each patient. These devices are designed to amplify sounds and restore hearing, however no currently available devices can provide sound quality comparable to that of a healthy cochlea. Some hearing aids are capable of selectively reducing background noise while maintaining access to all distinct speech sounds, but this typically requires the user to select the voice they wish to focus on and are usually ineffective in group settings. Moreover, hearing aids still rely on functional hair cells for sound transduction .In contrast, cochlear implants have proven to be a successful therapeutic approach for patients, even for those with abnormal hair cells and severe hearing impairment. There is clear evidence showing rapid development in oral communication and auditory skills in infants and children with SNHL with cochlear implants . MoreoveATOH1 gene expression, crucial for progenitor cells residing in the organ of Corti to be directed to differentiate into a non-sensory or sensory lineage . However, most recently reported novel otoprotective, regenerative and gene replacement treatments remain too early in their stage of development to be applied clinically.There is currently a wide spectrum of drug types undergoing clinical trials for different types of SNHL, which has been recently comprehensively summarized by  lineage . CurrentFor cisplatin-induced hearing loss, sodium thiosulfate has recently been approved by the US Food and Drug Administration as an otoprotective drug. As mentioned, cisplatin is a highly ototoxic drug, with children and adolescents undergoing cisplatin treatment being particularly vulnerable to cisplatin-induced hearing loss . Sodium in vitro   . While aor CSOM) , it remaor CSOM) .Similarly, the cochlea is among the most difficult organs to deliver drugs to by conventional systemic routes. It is encased by the petrous bone, which is the densest bone in the human body, and is only accessible to the circulation via the BLB. As with the treatment of OM, drugs administered systemically generally accumulate poorly in the inner ear and can exert unwanted effects elsewhere due to the aforementioned barriers . TherefoTo counteract these physiological challenges, there has recently been considerable progress in the use of biomaterials such as hydrogels and nanotechnology. Formulations involving these biomaterials are aimed at enhancing drug bioavailability and providing controlled and sustained release. Sustained release can be triggered either upon temperature change, phase change, implantation, pH changes or administration of a secondary agent . The folin situ gelling hydrogel. The hydrogel is administered to the TM or round window niche via intratympanic injection, which solidifies upon contact with the RWM  is highly biocompatible and has been extensively studied in the laboratory as a substrate for three-dimensional mammalian cell culture due to its inert nature, tunability, and higher batch-to-batch reproducibility over other commonly used substrates . In an iAdditional classes of hydrogel include poloxamers, with a recent approach using the commercially available Poloxamer 407 to deliver a small molecule inhibitor of the apoptosome, LPT99. This approach was shown to preserve cell viability and auditory function in cisplatin-treated rats . Finally® is an FDA-approved ciprofloxacin solution suspended in a thermosensitive Poloxamer 407 gel and has been indicated primarily for the treatment of pediatric otitis externa and OME associated with tympanostomy tube placement  as it has been shown to reduce the occurrence of OM after a single intratympanic injection  are composed of solid lipids, emulsifiers and water, and are of the most recently investigated for use in hearing loss. SLNs offer many advantages over other nanoparticle types. These include controlled drug release, stability at room temperature, higher payload, low toxicity and the ability to be functionalized and sterilized  to selectively target the keratinocytes. ed light .While nanoparticles address controlled release of drugs in the inner ear, ultimately they must themselves be delivered to the inner ear. We have addressed a subset of nanoparticles that have demonstrated ability to cross the RWM, however there are many other classes of nanoparticle that have shown therapeutic potential for the treatment of hearing loss. These are usually larger nanoparticles with larger payloads or those that can be externally directed once implanted.Nanoparticles can be engineered with inherently magnetic properties. Superparamagnetic iron oxide nanoparticles are already used in the clinic, with many applications in imaging, such as MRI . While iAs previously discussed, limitations on drugs and nanoparticles administered on the RWM include size, charge, lipophilicity and membrane thickness. However, as nanoparticles can allow for controlled release of drugs once injected, invasive surgeries such as intracochlear injection, would not be repeatedly required once the nanoparticle is delivered. Intracochlear injection would additionally allow the delivery of larger drugs, including large nanoparticles, microparticles and therapeutic peptides.An example of intracochlear injection for large therapeutic delivery involves the administration of mesoporous silica supraparticles (MS-SP) containing neurotrophins. These MS-SPs are comprised of MS nanoparticles which self-assemble into larger SPs capable of delivering larger payloads, with pore sizes of 15–30 nm for neurotrophins . IntracoThe delivery of nanoparticles can additionally be enhanced through hydrogel-mediated release. As discussed previously, drugs contained in hydrogels that are implanted on the RWM reach the inner ear by passive diffusion through the membrane. Nano-encapsulation could provide an extra layer of controlled release and ensure these drugs are not compromised after RWM diffusion. For example, PEG-based nanoparticles containing a JNK inhibitor were delivered using a chitosan/glycero-2-phosphate (CGP) hydrogel implanted through intratympanic injection. These nanoparticles were functionalized by adding a peptide targeting prestin, a protein exclusively expressed by outer hair cells, and was shown to provide protection against NIHL . A previSome creative methods of introducing transient pores in the RWM have been designed for the delivery of nanoparticles into the inner ear. A “micro-shotgun” was developed to transport iron oxide and chitosan-based nanoparticles through the RWM. Briefly, this was constructed by loading nanoparticles and sodium carbonate/citric acid “fuel” into a microtube which was guided using a magnetic field and iron oxide nanoparticles in the microtube. The addition of water to the loaded tube causes a reaction generating a large amount of carbon dioxide, which launches the nanoparticle. Pores in the guinea pig RWM created by the launch closed 24 h after with no injury to the stria vascularis, organ of Corti or spiral ganglion neurons observed . AnotherNanoparticle-based treatment is an emerging area with a multitude of new preclinical studies being reported. Nanoparticles address many challenges in therapeutic delivery to the inner ear, with some formulations having the ability to traverse the RWM and effectively distribute along the cochlea. However, key areas need be addressed, including drug release kinetics and clearance, with many studies cited in this review focusing on penetration into the inner ear without the nanoparticle necessarily carrying a therapeutic payload. There are additionally some cell-protective mechanisms by which nanoparticles can be prevented from reaching their therapeutic target, most notably endosomal escape . Furtherex vivo/in vivo phage display screening, where bacteriophages are incubated with cells from target tissue, generating a library of potential homing peptides on the phage surface. These peptides are generally small, usually up to 20–30 amino acids in length, which allows greater permeation across membranes than larger targeting moieties such as antibodies.Homing peptides are widely used to deliver therapeutic payloads to tumors, diseased blood vessels and to treat neurological disorders. These peptides use “molecular zip codes” or cell/extracellular matrix recognition motifs to selectively identify cell surface markers and extracellular matrix, which permit accumulation of the peptide in not only specific tissues, but specific cells . Homing ex vivo study used TM from rats with induced OM as the substrate for peptide identification, which produced candidate peptides which were able to transport the phage across the TM in vivo , with infuse-withdraw capabilities. This functioned through the infusion-withdrawal of perilymph so as to not disturb intracochlear pressure and was used to deliver the glutamate receptor antagonist DNQX . The groin vivo evidence in animal models and humans of a fibro-inflammatory response to implants (Cochleostomy is a highly invasive process, which itself may risk affecting hearing. This procedure is usually employed to install cochlear implants and there is growing implants . The resimplants . Coatingimplants .In vivo results from animal studies from this group are highly anticipated.As discussed in previous sections however, certain drugs, especially dexamethasone and other glucocorticoids, risk being cleared prior to achieving sufficient bioavailability . A studyWe have reviewed existing clinical problems and recent innovations in drug delivery to the middle and inner ear. While drug delivery to the middle and inner ear remains a significant clinical problem, great advances have been made recently. As the anatomical barriers to the middle and inner ears preclude straightforward local delivery, it will likely require a combinatorial approach of the techniques mentioned to ensure effectiveness of these novel technologies. For example, intratympanic hydrogel administration of many drugs, including corticosteroids by themselves, is insufficient due to rapid clearance from the cochlea . HoweverAn additional challenge for the field is how the development of drug delivery systems keep up with the development of novel treatment types. Many gene therapies for example, are relatively unstable molecules and must be kept in a medium whereby they remain viable once they reach the inner ear. Conventional gene therapies, for example the delivery of whole genes, may present a problem based on molecular size. This is common and reasonably expected for those replacing the large multidomain proteins of the cochlear stereocilia bundles, and already challenges the limited capacity of the more conventional gene delivery system of adeno-associated viruses . This prin vitro RWM models would additionally be useful for large scale assessment of drug penetration. These types of studies would ensure the maintenance of drug safety and efficacy as other promising delivery systems are developed.The emergence of biomaterial-based delivery systems, particularly hydrogels, in mid-late stage clinical trials demonstrates the potential for these novel systems to become mainstream options for local middle and inner ear drug delivery. Future studies should continue to address drug release and pharmacokinetics of encapsulated drugs in animal models of hearing loss in terms of tissue penetration and clearance. Moreover, the development of reliable


Intralabyrinthine schwannomas (ILS) are rare benign tumours arising from the peripheral branches of the cochlear or vestibular nerves in the membranous labyrinth, intracochlear schwannomas being the most frequent ones. When hearing is no longer feasible on the affected side, surgical removal along with simultaneous cochlear implantation can be proposed to the patient. We hereby present a systematic review of the literature on the topic, as well as two original cases from our centre . Cochlear implantation in intracochlear schwannomas is feasible, with overall satisfactory hearing outcomes in accordance with the evidence found in the literature. Vestibular schwannomas are benign tumours of the schwan cells of the eighth cranial nerve: the overall incidence in the general population ranges between 1.7 and 4.2 cases per 100,000  dPlontke et al.’s (2017) case series  describePlontke at al. (2020)  report tTotten et al. (2021)  brought −3000 Hz .Our series of intralabyrinthine schwannoma involves 10 cases: eight coming from our previous published work by Zanoletti et al.  and two The first case involves a 33-year-old female patient with NF2 .In 2009, the patient underwent stereotactic radiotherapy for right eight cranial nerve schwannoma. In 2014, the patient underwent successful hearing preservation surgery via retrosigmoid approach for a left eight cranial nerve schwannoma. Hearing was preserved in the right ear for the first six years, but after 2017, it progressively diminished, ending in deafness in 2019. While right hearing was diminishing, a tumour recurrence occurred in the left side . Post-raThe patient underwent right subtotal petrosectomy and EAC  cul-de-sac closure for intravestibular-intracochlear schwannoma removal with simultaneous cochlear implant branded Medel, MI1200 with Flex 28 electrode. The choice of a flexible electrode was made because the objective of our surgery was a complete removal of the tumour, and after this step, the introduction of a soft array would have been possible. The tumour was inside the vestibule and in the basal turn of the cochlea, and it was completely removed before placing CI. As predicted, complete insertion of the electrode was attained, with overall good impedances. A cul-de-sac closure of the EAC was performed as planned in the subtotal petrosectomy.One month after cochlear implant activation, the hearing outcome was 52.5 Pure Tone Average (PTA) with replicable responses at 40After three months, the hearing threshold was identifiable at 45In 2021, the patient underwent surgery on the left growing recurrent schwannoma, with a translabyrinthine approach and simultaneous placement of a cochlear implant branded Medel, MI1200, with electrode array type Flex 28 mm; during surgery there was an incomplete insertion of the electrode, with two basal electrodes which remained out of the round window. Although intraoperatively good impedances were reported on all the inserted electrodes, during follow-ups, the left side CI did not provide the same benefit as the right CI, and never elicited any useful response.At the last follow-up visit, the hearing threshold with the right IC was 350 dB nHL . The speOn the left ear there is no auditory gain, except for an improvement of tinnitus since CI placement.The second case concerns a 65-year-old man with an onset of left sensorineural hearing loss and tinnitus from 2018. At the beginning, occupational exposure to noise was considered as the aetiology of his hearing loss, as it was a symmetrical loss. The patient was invited to use hearing aids on the left side, with scarce benefits. He also underwent computed tomography (CT) and Magnetic Resonance Imaging (MRI) scans in 2020, but the radiologist only reported a possible cochlear inflammation.In the following years, a worsening of his left hearing was progressively observed, so the placement of a left cochlear implant (CI) was recommended to him; a device branded AB, type HiRes Ultra 3D, with slim electrode was chosen. Preoperative pure-tone audiometry shows bilateral sensorineural hearing loss, which is worse on the left as there is only mild hearing loss on the right .During surgery in September 2022, the surgeon complained that the array could not be fully inserted and, after a small anterior drilling of the round window, a mass occupying the basal gyrus of the cochlea was found. Therefore, a biopsy of the neoformation and impermanent closure of the cochleostomy was carried out; the CI was temporarily housed in the postero-superior region of the temporal bone, envisaging a future positioning.Histologically, the biopsy sample of the neoformation turned out to be a schwannoma.In October 2022, the patient returned to the operating room for the exeresis of the left intracochlear neurinoma via subtotal petrosectomy; the drill out of the first 3–4 mm of the basal turn of the cochlea was necessary to achieve the complete removal of the neoplasia. The cochlear implant electrode was moved from its temporary site and correctly placed in the scala tympani; postoperative clinical course was uneventful. In this case, we used a soft array to avoid having to throw away an already open and fully functional cochlear implant. In addition, once the neurinoma was removed, the placement of the array had no problems.A few days later, at first postoperative evaluation, the CI was activated; pure-tone audiometry performed with CI was 50At the last visit, the hearing threshold with the left CI was 300 dB nHL .Intralabyrinthine schwannomas (ILS) are rare benign tumours arising from the peripheral branches of the cochlear or vestibular nerve, and are located in the membranous labyrinth. Although their classification depends on their anatomical location, in the literature there are several. Some authors classify ILS in seven subtypes: intravestibular, intracochlear, intravestibulocochlear, transmodiolar, transmacular, transotic and tympanolabyrinthine ,24. SalzThis review was focused on cochlear implant (CI) positioning in intracochlear ILS, which aside from being the most frequent, is also the most surgically challenging because of tumour position . The plaDifferent strategies were proposed in relation to surgical techniques for ILS excision. The “standard” cochleostomy approach as performed in our patients, is, in our opinion, the most feasible approach, but the surgeon must be aware that the drilling of the lateral wall of the cochlea makes it more difficult to keep the IC in its correct position, with consequences on its performance. Another approach is a “double cochleostomy” with “pull-through” or “push-through” of the tumour, as described by Plontke et al.  One limiAs for ILS’s symptoms, fluctuating, progressive or sudden hearing loss is often the early symptom at the onset. The latter is typical for intracochlear and intravestibular ILS. The mechanisms causing hearing loss are most probably related to the direct compression of the cochlear nerve, damage to the organ of Corti, and damage to the cochlear vascularisation, which ends with a reduction of the number of hair cells and spiral ganglion neurons . In addiILS are currently diagnosed with Magnetic Resonance Imaging (MRI), which is able to detect and locate ILS as little as 2mm, greatly reducing the intraoperative event of ILS, which may still happen in smaller tumours as an unexpected finding in cochlear implant surgery. Their radiological appearance is of well-delimited lesions with an intermediate signal on T1-weighted imaging, while on T2-weighted imaging, an effacement of the normal intracochlear fluid can be noted; the intense and homogeneous contrast uptake in gadolinium-enhanced T1 sequences allows us to differentiate the lesion from labyrinthine haemorrhage, infectious labyrinthitis and labyrinthine ossification .Treatment involves a wait-and-see attitude and surgical removal. MRI accuracy allows detection of a potential growth over time, which may lead to increasing obstruction of the cochlea, resulting in problems in CI effectiveness . SurgeryCI can be positioned either simultaneously or in a second stage surgery . Staged Regarding the preferred surgical approach, when a simultaneous tumour removal and CI positioning is planned, some authors suggest to adopt surgical refinements in the attempt to preserve a functioning cochlea, like an infero-lateral cochleostomy to open the basal turn without disrupting the round window, or partial drilling with partial opening of the cochlea turns to protect the modiolus area and the basal membrane. ,13 On thThe treatment choice depends on the tumour size, the growth pattern, the preoperative ipsilateral and contralateral hearing, the possible coexistence of other symptoms, as well as general considerations like a patient’s age and general performance status . StereotThe limitation of this study involves first of all the great heterogeneity of the considered data of each study, as shown in Intracochlear schwannomas are rare benign tumours arising from the peripheral branches of the cochlear or vestibular nerves in the membranous labyrinth. Despite early symptoms and the possibility of early Magnetic Resonance Imaging (MRI) diagnosis, no treatment can preserve hearing. Surgery comes with complete deafness, as does the wait-and-scan attitude, even if the latter has more unpredictable hearing loss, which occurs over a long period of time. Cochlear Implant (CI) has been proposed as a rehabilitative tool both when the tumour is removed or left in site, simultaneously to tumour excision or in a second staged surgery. This review aimed to investigate the topic to explore the efficacy of CI rehabilitation, the methods of measurements in single side-deafness rehabilitation, the criteria to choose CI placement with or without tumour removal, the surgical refinements which are necessary to prevent cochlea damage and the problem of MRI surveillance for recurrence when CI is in situ. Both in the literature and our personal experience hereby reported, the hearing outcomes are promising, although the heterogeneous data and the low level of evidence did not contribute to assessing any consistent conclusions.