Endoscopic treatment in pediatric patients with recurrent and H-type tracheoesophageal fistulas - A systematic review and meta-analysis.

OBJECTIVES: Endoscopic treatments for managing recurrent tracheoesophageal fistula (rTEF) and H-type TEF are being utilized lately; however, the preferred technique is yet to be determined. We aimed to systematically review existing publications on endoscopic treatment of rTEF and H-type TEF to analyze their success and complication rates. METHODS: PRISMA guidelines were followed. MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials were comprehensively searched in accordance to a priori developed protocol, from 1975 until 2020. English, Spanish and German papers were included. Studies were independently screened and analyzed by two reviewers. RESULTS: 84 full texts were assessed for eligibility out of 581 screened studies, of these, 39 studies with 127 patients were eligible for inclusion (115 rTEF and 12 H-type TEF). All included studies were cases reports or case series. Overall success rate was 45% with sealant injection, 87% with de-epithelialization and 80% with sealant injection and de-epithelialization combined. The mean number of required treatments for success was 1.9 (range 1-6). Mixed effect model meta-analysis of case series with n > 1 showed that sealant injection had a significantly lower success rate of 50% (95% CI 1-99%, I2 72%) compared to de-epithelialization 90% (95% CI 72-99%, I2 27%), p = 0.007 and the combination of both techniques 87% (95% CI 68-99%, I2 11%), p = 0.02. Nine patients (7%) had transient respiratory distress. No mortalities reported. CONCLUSION: Endoscopic treatment for rTEF and H-type fistula is a minimally invasive technique with favorable outcome and considerably less morbidity compared to open surgery, suggesting it as a safe and effective first line treatment option. Repeated endoscopic treatment attempts can be expected to obtain complete closure. De-epithelization techniques with or without combined tissue adhesive injection had significantly better results than sealant injection techniques alone.

Patient reported outcome measures in unilateral aural atresia treated using a transcutaneous bone conduction implant (The Cochlear Baha Attract®).

OBJECTIVES: Unilateral aural atresia (UAA) is a congenital condition that is associated with maximal conductive hearing loss. The primary objective of this study was to assess the long-term compliance, complications, and quality of life of pediatric patients with UAA who had transcutaneous bone conduction hearing implants (TCBI). METHODS: Retrospective consecutive case series at a single centre between 2014 and 2018. Inclusion criteria consisted of UAA patients between 5 to 17 years-old receiving the Cochlear Baha Attract ® device. Demographic and audiologic data was extracted from charts. A prospective telephone survey was done, with patients and their families completing the Glasgow Children's Benefit Inventory (GCBI). Basic descriptive statistics, paired t-tests, and a univariate analysis were completed. RESULTS: Data was successfully collected from all 9 eligible children who received the Cochlear Baha Attract ® device for UAA (100%). The mean follow-up duration was 33 months after TBCI (9-60 months). The mean daily use was 7.7 h/day. Pure tone average and mean speech in noise scores were both significantly improved when comparing the unaided condition to the aided condition with TCBI (p < 0.001). The majority (89%) of patients had an improvement in GCBI; the median GCBI score was +14.6, indicating overall positive benefit. A linear regression showed no demographic variables were significant for mean daily use or GCBI scores. CONCLUSION: This preliminary study showed that patients with a TCBI for UAA had high long-term compliance and daily usage rates. TCBI improved the quality of life for the majority of patients and significantly improved hearing measures.

Single-use device endoscopy for the diagnosis of acute bacterial rhinosinusitis in primary care: A pilot and feasibility study.

OBJECTIVE: Antibiotics are largely overprescribed for acute rhinosinusitis in primary care, mainly due to the lack of diagnostic tests to confirm or rule out bacterial infection. The study objective was to assess the on-site applicability and safety of the newly developed JGG endoscope® for the diagnosis of acute bacterial rhinosinusitis in primary care. DESIGN: Five Swiss primary care centres and one university-affiliated ENT unit participated in this single-arm pilot study. PARTICIPANTS: Adults with acute suspected bacterial rhinosinusitis. The newly developed JGG endoscope® , which is attached to a pocket otoscope, was used to inspect after local anaesthesia the nasal cavity and middle meatus and to gain material for bacterial culture from paranasal sinuses draining ostium. MAIN OUTCOME MEASURES: Applicability and safety. RESULTS: The visualisation of the middle meatus was successful in 16 of 21 patients (13 in both sides and three in one side), and unclear or unsuccessful in five patients. Sample collection from the middle meatus was successful in 10 patients (six on both and four on one side) and unclear or unsuccessful in the remaining patients. Only one culture-confirmed bacterial rhinosinusitis and 11 PCR-confirmed viral infections were identified from collected samples. After a 2-week follow-up, no serious adverse events were observed. CONCLUSIONS: The on-site use of the JGG endoscope® in daily primary care routine is feasible and safe and was well accepted by the trial physicians and patients (assessed with structured questionnaires). The JGG endoscope® may support general practitioners to differentiate between bacterial and viral rhinosinusitis.

Strategies for restarting Pediatric Otolaryngology outpatient clinics after a pandemic-related shutdown such as from COVID-19.

The novel coronavirus 19 SARS-CoV2 caused a change in the practice of Otolaryngology around the globe. The high viral load in the nasal cavity, nasopharynx and airway subjects Otolaryngologists to a high risk of catching the virus during aerosol generating procedures. After the first outbreak wave has subsided, many teams are now discussing how our 'new normal' practice will look. We share our guidelines on restarting elective clinical work in order to create a safe environment for patients and staff in a Pediatric Otolaryngology outpatient clinic.

Induction of mitophagy in the HEI-OC1 auditory cell line and activation of the Atg12/LC3 pathway in the organ of Corti.

Autophagy is a highly evolutionary conserved quality control defense mechanism within cells, which has also been implicated in cell death processes. In the mammalian inner ear, autophagy has been shown to play a role during early morphogenesis as well as in adult cochlear hair cells exposed to ototoxic insults. Mitophagy, a selective autophagic cell process targeting mitochondria, hasn't been studied in the inner ear so far. On this work, we searched for molecular indicators of mitophagy within House Ear Institute-Organ of Corti-1 (HEI-OC1) cells as well as in the organ of Corti (OC). We first tested for the expression of Pink1/Park2 mRNA in 5-day-old C57BL/6 mice's cochleae using RT-PCR. We focused on the induction of mitophagy in HEI-OC1 cells as well as in the OC and investigated a possible mitophagic potential of the aminoglycoside agent gentamicin. The induction of mitophagy in HEI-OC1 cells was detected by objectivizing the translocation of fluorescence-tagged LC3 to mitochondria using confocal microscopy after a 6-h incubation with a well-described mitochondrial uncoupler and mitophagy-inducing agent: carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Incubation with gentamicin generated no mitochondrial translocation of LC3. Protein levels of COXIV, Atg5/12 and LC3 were evaluated by an immunoblot analysis after a 24-h CCCP treatment as well as gentamicin. We demonstrated mitophagy after CCCP exposure in HEI-OC1 cells by showing a downregulation of COXIV. A downregulation of COXIV could also be visualized in the OC after CCCP. A significant oxygen consumption rate (OCR) changed in cells treated with CCCP as well as significant morphological changes of mitochondria by electron microscopy (EM) strengthen this assumption. Gentamicin exposure generated no impact on OCR or mitochondrial morphological changes by EM. Finally, we demonstrated changes in the expression of Atg12 and LC3 proteins in both the OC and HEI-OC1 cells after CCCP exposure but not after gentamicin. Our data indicate that gentamicin had no impact in the activation of mitophagy-neither in the HEI-OC1 cell line nor in the OC. Therefore, we speculate that mitophagic-independent mechanisms may underly aminoglycoside ototoxicity.

Effects of peroxisome proliferator activated receptors (PPAR)-γ and -α agonists on cochlear protection from oxidative stress.

Various insults cause ototoxicity in mammals by increasing oxidative stress leading to apoptosis of auditory hair cells (HCs). The thiazolidinediones (TZDs; e.g., pioglitazone) and fibrate (e.g., fenofibrate) drugs are used for the treatment of diabetes and dyslipidemia. These agents target the peroxisome proliferator-activated receptors, PPARγ and PPARα, which are transcription factors that influence glucose and lipid metabolism, inflammation, and organ protection. In this study, we explored the effects of pioglitazone and other PPAR agonists to prevent gentamicin-induced oxidative stress and apoptosis in mouse organ of Corti (OC) explants. Western blots showed high levels of PPARγ and PPARα proteins in mouse OC lysates. Immunofluorescence assays indicated that PPARγ and PPARα proteins are present in auditory HCs and other cell types in the mouse cochlea. Gentamicin treatment induced production of reactive oxygen species (ROS), lipid peroxidation, caspase activation, PARP-1 cleavage, and HC apoptosis in cultured OCs. Pioglitazone mediated its anti-apoptotic effects by opposing the increase in ROS induced by gentamicin, which inhibited the subsequent formation of 4-hydroxy-2-nonenal (4-HNE) and activation of pro-apoptotic mediators. Pioglitazone mediated its effects by upregulating genes that control ROS production and detoxification pathways leading to restoration of the reduced:oxidized glutathione ratio. Structurally diverse PPAR agonists were protective of HCs. Pioglitazone (PPARγ-specific), tesaglitazar (PPARγ/α-specific), and fenofibric acid (PPARα-specific) all provided >90% protection from gentamicin toxicity by regulation of overlapping subsets of genes controlling ROS detoxification. This study revealed that PPARs play important roles in the cochlea, and that PPAR-targeting drugs possess therapeutic potential as treatment for hearing loss.

Simvastatin Results in a Dose-Dependent Toxic Effect on Spiral Ganglion Neurons in an In Vitro Organotypic Culture Assay.

Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme necessary for the production of mevalonate. They are widely used as cholesterol-lowering drugs. However, conflicting data about the effect of statins on neuronal cells has been published. To explore the effect of simvastatin on spiral ganglion neurons (SGNs), SG explants of 5-day-old rats were treated with increasing concentrations of simvastatin. In addition, SG explants were treated with mevalonate and with the combination of simvastatin and mevalonate. SGN number, length of the neurites, area of nonneuronal supporting cells, and neuronal survival were analyzed. Simvastatin treatment results in a significant dose-dependent decrease of SG neurite number, length of neurites, area of supporting cells, and SG neuronal survival compared to control. Interestingly, treatment with mevalonate in addition to simvastatin increased SG neuronal survival compared to simvastatin treatment only. However, treatment with mevalonate in addition to simvastatin did not influence SG neurite number, length of neurites, and area of supporting cells compared to simvastatin treatment only. Our results suggest a neurotoxic effect of simvastatin on SGNs in vitro. Neurotoxicity seems to be at least partially mediated by the mevalonate pathway. Therefore, caution is warranted to use simvastatin as a potential otoprotective drug.

Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro.

Metformin is a commonly used antidiabetic drug. It has been shown that this drug activates the AMP-activated protein kinase, which inhibits downstream the mammalian target of rapamycin. In addition, several studies indicate that metformin reduces intracellular reactive oxygen species. Our data, using an in vitro rat model, indicate that metformin is able to protect auditory hair cells (HCs) from gentamicin-induced apoptotic cell death. Moreover, metformin has no toxic effect on spiral ganglion neuronal survival or outgrowth in vitro. These results suggest a protective effect of metformin on auditory HC survival in gentamicin-induced HC loss in vitro.

Inhibition of mTOR by Rapamycin Results in Auditory Hair Cell Damage and Decreased Spiral Ganglion Neuron Outgrowth and Neurite Formation In Vitro.

Rapamycin is an antifungal agent with immunosuppressive properties. Rapamycin inhibits the mammalian target of rapamycin (mTOR) by blocking the mTOR complex 1 (mTORC1). mTOR is an atypical serine/threonine protein kinase, which controls cell growth, cell proliferation, and cell metabolism. However, less is known about the mTOR pathway in the inner ear. First, we evaluated whether or not the two mTOR complexes (mTORC1 and mTORC2, resp.) are present in the mammalian cochlea. Next, tissue explants of 5-day-old rats were treated with increasing concentrations of rapamycin to explore the effects of rapamycin on auditory hair cells and spiral ganglion neurons. Auditory hair cell survival, spiral ganglion neuron number, length of neurites, and neuronal survival were analyzed in vitro. Our data indicates that both mTOR complexes are expressed in the mammalian cochlea. We observed that inhibition of mTOR by rapamycin results in a dose dependent damage of auditory hair cells. Moreover, spiral ganglion neurite number and length of neurites were significantly decreased in all concentrations used compared to control in a dose dependent manner. Our data indicate that the mTOR may play a role in the survival of hair cells and modulates spiral ganglion neuronal outgrowth and neurite formation.

Role of somatostatin receptor-2 in gentamicin-induced auditory hair cell loss in the Mammalian inner ear.

Hair cells and spiral ganglion neurons of the mammalian auditory system do not regenerate, and their loss leads to irreversible hearing loss. Aminoglycosides induce auditory hair cell death in vitro, and evidence suggests that phosphatidylinositol-3-kinase/Akt signaling opposes gentamicin toxicity via its downstream target, the protein kinase Akt. We previously demonstrated that somatostatin-a peptide with hormone/neurotransmitter properties-can protect hair cells from gentamicin-induced hair cell death in vitro, and that somatostatin receptors are expressed in the mammalian inner ear. However, it remains unknown how this protective effect is mediated. In the present study, we show a highly significant protective effect of octreotide (a drug that mimics and is more potent than somatostatin) on gentamicin-induced hair cell death, and increased Akt phosphorylation in octreotide-treated organ of Corti explants in vitro. Moreover, we demonstrate that somatostatin receptor-1 knockout mice overexpress somatostatin receptor-2 in the organ of Corti, and are less susceptible to gentamicin-induced hair cell loss than wild-type or somatostatin-1/somatostatin-2 double-knockout mice. Finally, we show that octreotide affects auditory hair cells, enhances spiral ganglion neurite number, and decreases spiral ganglion neurite length.