Identifying Disadvantaged Groups for Cochlear Implantation: Demographics from a Large Cochlear Implant Program.

OBJECTIVE: To identify demographic predictors of patients undergoing cochlear implantation evaluation and surgery. METHODS: Consecutive adult patients between 2009 and 2018 who underwent cochlear implantation evaluation at a university cochlear implantation program were retrospectively identified to determine (1) cochlear implantation qualification rate and (2) pursuit of surgery rate with respect to age, gender, race, primary spoken language, marital status, insurance type, and distance to the cochlear implantation center. RESULTS: A total of 823 cochlear implantation evaluations were analyzed. Overall, 76.3% of patients qualified for cochlear implantation and 61.5% of these patients pursued surgery. Age was the only independent predictor for cochlear implantation qualification, such that, for each year younger, the odds of qualifying for cochlear implantation increased by 2.5% (OR 0.98; 95% CI: 0.96-0.99). Age, race, marital status, and insurance type were each independent predictors of the decision to pursue surgery. The odds of pursuing surgery increased by 2.8% for each year younger (OR 1.03; 95% CI: 1.01-1.05). Compared to White patients, non-Whites were half as likely to pursue surgery (OR 0.47; 95% CI: 0.25-0.88). Single (OR 0.49; 95% CI: 0.26-0.94) and widowed patients (OR 0.46; 95% CI: 0.23-0.95) were about half as likely to pursue surgery as compared to married patients. Patients with military insurance were 13 times more likely to pursue surgery as compared to patients with Medicare (OR 13.0; 95% CI: 1.67-101.4). CONCLUSION: Younger age is an independent predictor for a higher cochlear implantation qualification rate, suggesting the possibility for delayed candidacy referral. Rate of surgical pursuit in qualified cochlear implantation candidates is lower for racial minorities, single and widowed patients, and older patients.

Cochlear Implantation in Patients With Neurofibromatosis Type 2.

OBJECTIVE: To describe cochlear implantation (CI) outcomes in patients with neurofibromatosis type 2 (NF2). STUDY DESIGN: Retrospective case series. SETTING: A multidisciplinary NF2 clinic at a university hospital. PATIENTS/INTERVENTIONS: Patients with NF2 who underwent CI. MAIN OUTCOME MEASURES: Pre- and postimplantation audiometric data, including pure-tone average (PTA) and AzBio Sentence scores. RESULTS: Eight patients with NF2 underwent CI. The mean age at implantation was 28.6 years (range: 17-63 yr) and six were female. The average length of deafness before CI was 3.5 years (range: 0.3-10 yr). Two patients underwent previous microsurgical resection via middle fossa craniotomy and one patient was treated with stereotactic radiotherapy before CI. Two tumors were growing at the time of CI, five tumors were not growing for an average period of 3.8 years (range: 1-6 yr), and one tumor had undergone previous gross total resection. Mean preoperative unaided PTA was 103.1 dB (range: 81.3-115 dB) and all preoperative AzBio scores were 0% in the ear to be implanted. These improved to a mean postoperative PTA of 30.9 dB (range: 12.5-43.8 dB) and mean postoperative AzBio score of 20% (range: 0-82%) with an average follow-up length of 16.6 months (range: 1.4-27.6 mo). Data logging demonstrated that six patients were daily CI users and two were nonusers, one of whom had normal hearing in the contralateral ear. CONCLUSIONS: CI is an effective option for rehabilitating hearing loss in patients with NF2; however, patients with normal contralateral hearing or poor follow-up do not perform as well.

In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension.

PURPOSE: Pulmonary arterial hypertension (PAH) results from occlusion or vasoconstriction of pulmonary vessels, leading to progressive right ventricular failure. Dasatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myelogenous leukemia, has been associated with PAH. In contrast, the BCR-ABL1 TKI imatinib has demonstrated anti-vasoproliferative properties and has been investigated as a potential treatment for PAH. Here we describe studies evaluating the effects of dasatinib and imatinib on cardiovascular and pulmonary functions to understand the reported differential consequences of the two TKIs in a clinical setting. METHODS: The direct effects of dasatinib and imatinib were explored in vivo to investigate possible mechanisms of dasatinib-induced PAH. In addition, effects of dasatinib and imatinib on PAH-related mediators were evaluated in vitro. RESULTS: In rats, both TKIs increased plasma nitric oxide (NO), did not induce PAH-related structural or molecular changes in PA or lungs, and did not alter hemodynamic lung function compared with positive controls. Similarly, in the pulmonary artery endothelial cells and smooth muscle cells co-culture model, imatinib and dasatinib increased NO and decreased endothelin-1 protein and mRNA. CONCLUSIONS: The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.

Effects of BMS-986094, a Guanosine Nucleotide Analogue, on Mitochondrial DNA Synthesis and Function.

BMS-986094, the prodrug of a guanosine nucleotide analogue (2'-C-methylguanosine), was withdrawn from clinical trials due to serious safety issues. Nonclinical investigative studies were conducted as a follow up to evaluate the potential for BMS-986094-related mitochondrial-toxicity. In vitro, BMS-986094 was applied to human hepatoma cells (HepG2 and Huh-7) or cardiomyocytes (hiPSCM) up to 19 days to assess mitochondrial DNA content and specific gene expression. There were no mitochondrial DNA changes at concentrations ≤10 µM. Transcriptional effects, such as reductions in Huh-7 MT-ND1 and MT-ND5 mRNA content and hiPSCM MT-ND1, MT-COXII, and POLRMT protein expression levels, occurred only at cytotoxic concentrations (≥10 µM) suggesting these transcriptional effects were a consequence of the observed toxicity. Additionally, BMS-986094 has a selective weak affinity for inhibition of RNA polymerases as opposed to DNA polymerases. In vivo, BMS-986094 was given orally to cynomolgus monkeys for 3 weeks or 1 month at doses of 15 or 30 mg/kg/day. Samples of heart and kidney were collected for assessment of mitochondrial respiration, mitochondrial DNA content, and levels of high energy substrates. Although pronounced cardiac and renal toxicities were observed in some monkeys at 30 mg/kg/day treated for 3-4 weeks, there were no changes in mitochondrial DNA content or ATP/GTP levels. Collectively, these data suggest that BMS-986094 is not a direct mitochondrial toxicant.

MicroRNA as biomarkers of mitochondrial toxicity.

Mitochondrial toxicity can be difficult to detect as most cells can tolerate reduced activity as long as minimal capacity for function is maintained. However, once minimal capacity is lost, apoptosis or necrosis occurs quickly. Identification of more sensitive, early markers of mitochondrial toxicity was the objective of this work. Rotenone, a mitochondrial complex I inhibitor, and 3-nitropropionic acid (3-NP), a mitochondrial complex II inhibitor, were administered daily to male Sprague-Dawley rats at subcutaneous doses of 0.1 or 0.3mg/kg/day and intraperitoneal doses of 5 or 10mg/kg/day, respectively, for 1week. Samples of kidney, skeletal muscle (quadriceps femoris), and serum were collected for analysis of mitochondrial DNA (mtDNA) copy number and microRNA (miRNA) expression patterns. MtDNA was significantly decreased with administration of rotenone at 0.3mg/kg/day and 3-NP at 5 and 10mg/kg/day in the quadriceps femoris and with 3-NP at 10mg/kg/day in the kidney. Additionally, rotenone and 3-NP treatment produced changes to miRNA expression that were similar in direction (i.e. upregulation, downregulation) to those previously linked to mitochondrial functions, such as mitochondrial damage and biogenesis (miR-122, miR-202-3p); regulation of ATP synthesis, abolished oxidative phosphorylation, and loss of membrane potential due to increased reactive oxygen species (ROS) production (miR-338-5p, miR-546, miR-34c); and mitochondrial DNA damage and depletion (miR-546). These results suggest that miRNAs may be sensitive biomarkers for early detection of mitochondrial toxicity.

D-α-tocopheryl polyethylene glycol 1000 succinate-containing vehicles provide no detectable chemoprotection from oxidative damage.

The objective of this study was to evaluate potential protective effects of vehicles containing d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), which may impact nonclinical safety assessments of oxidative processes. This was achieved by evaluating plasma, liver and adrenal gland concentrations of d-α-tocopheryl succinate (TS) and d-α-tocopherol as well as oxidative status of plasma following oral dosing of TPGS-containing vehicles, intraperitoneal (IP) dosing of TS or ex vivo treatment of blood with H2O2. Male and female rats were dosed orally with formulations containing 5% or 40% TPGS (70 or 550 mg kg(-1) day(-1) TS, respectively) for 1 week. A control group was dosed orally with polyethylene glycol-400 (PEG-400; no vitamin E) and positive control animals received a single 100 mg kg(-1) day(-1) IP injection of TS. Whole blood from untreated animals was treated ex vivo with 5 or 50 mm H(2)O(2), with or without TS (0.5, 5, 50 or 500 µm) or ascorbate (1 mm), for 1 h. Oral TPGS treatments did not affect d-α-tocopherol concentrations in plasma or adrenal glands and caused only transient increases in liver. Concentrations of TS in plasma, liver and adrenal glands were undetectable in control animals, but increased in all other groups. Oral administration of TPGS did not reduce plasma lipid peroxidation in vivo. Substantially greater TS concentrations used ex vivo (100× greater than in vivo) were also unable to reduce lipid peroxidation in H2O2 -treated whole blood. These results provide evidence that administration of oral TPGS vehicles is unlikely to impact nonclinical safety assessments of pharmaceuticals.