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Jennifer Wong, Elliot Backer, Joseph C Keenan, Huseyin Erhan Dincer, Roy Joseph Cho Interventional Pulmonology Division, Department of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN, USACorrespondence: Roy Joseph Cho Tel +1 612-626-2637Email choxx548@umn.eduPurpose: Balloon-expandable stents are commonly used for the treatment of tracheobronchial strictures. We routinely perform targeted overdilation of these stents 1– 2mm on initial deployment to prevent stent migration or allow foreshortening to target airway caliber; however, specific data on the effect of targeted overdilation is unknown.Patients and Methods: We used three iCAST stents (6× 22mm, 7× 22mm, and 10× 38mm) to perform the study. We had two sets of each size to average our results. Targeted overdilation was accomplished with Merit Elation balloons.Results: The 6 × 22 and 7 × 22 stent OD increased from 6 to 11.4mm and 7 to 11.6mm. The 10 × 38 stent demonstrated minimal OD change with overdilation (OD change of 10.4 to 12.2mm). All stents demonstrated significant foreshortening with overdilation (20.2 to 5.65mm, 19.4 to 6mm, and 30.9 to 10.2mm for 6 × 22, 7 × 22, and 10 × 38, respectively). The breakpoint was seen at near twice the stated stent OD (13.5mm, 15mm, and 15mm with 6 × 22, 7 × 22 and 10 × 38, respectively).Conclusion: We have demonstrated that iCAST stents can increase their OD with subsequent foreshortening during targeted overdilation. This data can help facilitate decisions when selecting a particular iCAST stent for a specific airway application. Additionally, we have highlighted that balloon inflation diameter does not correspond to the actual stent OD during deployment. We believe that this data offers practical information for end-users of this stent type and additional data will be needed to corroborate our findings.Keywords: airway stenosis, tracheobronchial disease, interventional pulmonary, airway stent, balloon expandable stent, airway balloon dilation

Traditionally, the cochlea has been considered as an immunological privileged site, as the blood-labyrinth barrier provides isolation from the systemic immune system. However, the presence of immune cells in the cochlea has been recently reported, suggesting that immune-mediated processes can play a crucial role within the auditory system. In this context, both protective and detrimental T-cell functions have been linked to normal hearing and hearing loss, respectively, thereby emphasizing the dual role of T cells in cochlear health. Current knowledge also suggests that a balanced presence and activity of T cells is crucial for tissue homeostasis in the cochlea, avoiding pathologies such as age-related hearing loss and autoimmune inner ear diseases. Although cochlea-resident T cells are scarce under physiological conditions, the number of T cells appear to rise in response to acoustic trauma revealing the active recruitment of peripheral immune cells through cochlear blood vessels. In order to evaluate the induction of a peripheral inflammatory response upon noise trauma, we exposed mice to excessive noise (115 dB) for two hours. Hearing levels were determined 72 h and 1 week after noise-exposure, which revealed a substantial increase in hearing thresholds in all mice. To evaluate if the auditory stimulation would trigger a peripheral immune response we isolated splenocytes and analyzed cytokine production in different immune subsets by high parametric flow cytometry. The analyses revealed increased activation of both CD4+ and CD8+ T cells, illustrated by significant increases in the expression of INF-γ, TNF and CD44. These data suggest a peripheral component in the elevated inflammatory response following acoustic trauma. Future research will be performed to explore the link between noise-induced hearing loss, peripheral inflammation and more specifically antigen-specificity of the observed increase in activated CD4+ and CD8+ T-cell populations. [ABSTRACT FROM AUTHOR]

The c.151C>T (p.P51S) mutation in COCH is highly prevalent in the Dutch/Belgian population and causes DFNA9 (hearing loss and vestibular dysfunction) in > 1500 individuals. The initial symptoms manifest between the 3rd and 5th decade of life, which leaves ample time for therapeutic intervention. The clear non-haploinsufficiency disease mechanism indicates that blocking or reducing the p.P51S mutant cochlin protein levels may alleviate or prevent the DFNA9 phenotypes. Considering the broad expression of COCH by the fibrocytes of the inner ear, we designed "gapmer" antisense oligonucleotides (ASO) to specifically induce RNase H1-mediated degradation of COCH transcripts containing the c.151C>T mutation. We established several model systems to investigate the molecular efficacy of ASOs targeting the c. 151C>T mutation or low-frequency mutant allele-specific SNPs. Using overexpression models, we identified several ASOs that efficiently induce the degradation of mutant COCH transcripts. By introducing chemical modification to the oligonucleotide bases, we can alter the affinity and selectivity for the mutation transcript. We identified several ASOs with a strong preference for the mutant transcript in overexpression models. To investigate allele-specificity under physiological expression levels, we exposed patient-derived otic progenitor cells (iPCS-OPCs) to different ASOs for 8 days. In parallel, we developed a genetically humanized mouse model for DFNA9 in which human sequence-specific therapeutic strategies can be evaluated. Phenotypic follow-up of mice of all genotypes indicate that the genetic humanization has no adverse effects, and removal of the Cdh23ahl allele is mandatory to observe the late-onset auditory phenotype: the first signs of high-frequency hearing loss emerged at 12 months of age. Studies in iPSC-OPCs indicated that the ASOs identified in overexpression studies also effectively reduce mutant COCH transcript levels in patient-derived cells with physiological expression levels. Unfortunately, variation between replicate wells of OPC differentiation is relatively high, making it difficult to draw conclusions on allele-specificity. We selected a candidate ASO, directed against a rare mutant allele-spe-cific intronic SNP, for subsequent studies in our humanized mouse model. First intracochlear injections will be conducted in May 2024, after which we can collect the first in vivo data on gapmer ASO uptake and efficacy in fibrocytes of the mammalian inner ear. [ABSTRACT FROM AUTHOR]

The formation mechanism of non-recessed Au–free Ohmic contacts on the AlGaN/GaN heterostructures is investigated for various Ti/Al atomic ratios (Al–rich versus Ti–rich) and annealing temperatures ranging from 500 to 950 °C. It is shown that Ti/Al atomic ratio is the key parameter defining the optimum annealing temperature for Ohmic contact formation. Ti–rich contacts processed at high temperature result in low contact resistance ∼0.7 Ω mm, better to those obtained at low temperature or with Al–rich metal stacks. The variation of the contact resistance with Ti/Al atomic ratio and annealing temperature is correlated with the intermetallic phase changes and interfacial reaction. Depending on the Ti/Al atomic ratio, two distinct mechanisms can be distinguished. For a small quantity of Ti (e.g., Al–rich contacts), Ohmic contact formation is done through a weak interfacial reaction which is nonexistent at high temperature due to the degradation of the metal morphology. However, for a quantity of Ti higher than 25 at. % (e.g., Ti–rich contacts), the agglomeration is delayed by 200 °C as compared to Al–rich contacts, and optimal contacts are formed at high temperature through a strong interfacial reaction. [ABSTRACT FROM AUTHOR]