Temperature-controlled radiofrequency device treatment of septal swell bodies for nasal airway obstruction: An open-label, single arm multicenter study.

BACKGROUND: Nasal airway obstruction (NAO) is a highly prevalent disorder. Septal swell body (SSB) hypertrophy is an often overlooked contributor to NAO. SSB treatment may relieve symptoms of NAO. The objective of this study was to assess the clinical use of a temperature-controlled radiofrequency (TCRF) device to treat SSBs to improve symptoms in adults with NAO. METHODS: In this prospective, multicenter, open-label, single arm study, patients with severe or extreme NAO related to SSB hypertrophy received bilateral TCRF treatment in the SSB area. The primary endpoint was improvement in Nasal Obstruction Symptom Evaluation (NOSE) Scale scores from baseline to 3 months postprocedure. A subset of study patients underwent computed tomography (CT) imaging to evaluate posttreatment changes in SSB size. RESULTS: Mean NOSE Scale scores significantly improved from 73.5 (SD 14.2) at baseline to 27.9 (SD 17.2) at 3 months postprocedure, a reduction of -45.3 (SD 21.4, 95% confidence interval [CI]: -50.4 to -40.1; p < 0.0001); the responder rate was 95.7% (95% CI: 0.88 to 0.99; p < 0.0001). CT evaluation at 3 months showed statistically significant reductions in the SSB with the greatest reduction in the middle thickness (mean change -3.4 [SD 1.8] mL, 95% CI: -4.0 to -2.8; p < 0.0001). Minimal adverse events with any relationship to the device or procedure were reported; none were serious in nature and no septal perforations occurred. CONCLUSIONS: This study demonstrates that TCRF treatment of SSB hypertrophy is well tolerated and effective at reducing both SSB size and symptoms of NAO at 3 months posttreatment.

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

OBJECTIVES: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. STUDY DESIGNS: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. SETTING: Three private otolaryngology practices in the US. PATIENTS: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. INTERVENTIONS: Intratympanic FX-322. MAIN OUTCOME MEASURES: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. RESULTS: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). CONCLUSIONS: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Prospective, multicenter evaluation of balloon sinus dilation for treatment of pediatric chronic rhinosinusitis.

BACKGROUND: Although balloon sinus dilation is a treatment option for adults with chronic rhinosinusitis (CRS), there have been few studies performed in pediatric patients. METHODS: This study was designed as a prospective, multicenter, single-arm investigation. Children (2 to 21 years old) with CRS who had failed medical management were treated with balloon sinus dilation and followed to 6 months postprocedure. RESULTS: Fifty children were treated at 4 centers; 33 participants were 2 to 12 years old (mean ± standard deviation age: 6.6 ± 2.2 years) and 17 participants were >12 to 21 years (mean age: 15.7 ± 2.5 years). A total of 157 sinus dilations were attempted (98 maxillary, 30 frontal, and 29 sphenoid sinuses) and all were successful with no complications. Significant improvement in the Sinus and Nasal Quality of Life Survey (SN-5) was seen for all children between baseline and 6 months (4.6 ± 1.2 vs 1.7 ± 0.8; p < 0.0001) and 92% improved by a minimal clinically important difference (MCID) of 1.0 or more. Those children aged 2 to 12 years with standalone balloon dilation also showed significant SN-5 improvements between baseline and follow-up (4.5 ± 1.0 vs 1.9 ± 0.8; p < 0.0001). Multivariate regression analysis showed no differences or associations of SN-5 improvement at 6 months with the presence of allergy, asthma, or concomitant procedures. For adolescents, overall 22-item Sino-Nasal Outcome Test (SNOT-22) mean scores were also significantly improved at 6 months (42.2 ± 19.2 vs 10.4 ± 9.7; p < 0.0001). CONCLUSION: Balloon sinus dilation is safe and appears effective for children with CRS aged 2 years and older.

Genomic landscapes of Chinese hamster ovary cell lines as revealed by the Cricetulus griseus draft genome.

Chinese hamster ovary (CHO) cells, first isolated in 1957, are the preferred production host for many therapeutic proteins. Although genetic heterogeneity among CHO cell lines has been well documented, a systematic, nucleotide-resolution characterization of their genotypic differences has been stymied by the lack of a unifying genomic resource for CHO cells. Here we report a 2.4-Gb draft genome sequence of a female Chinese hamster, Cricetulus griseus, harboring 24,044 genes. We also resequenced and analyzed the genomes of six CHO cell lines from the CHO-K1, DG44 and CHO-S lineages. This analysis identified hamster genes missing in different CHO cell lines, and detected >3.7 million single-nucleotide polymorphisms (SNPs), 551,240 indels and 7,063 copy number variations. Many mutations are located in genes with functions relevant to bioprocessing, such as apoptosis. The details of this genetic diversity highlight the value of the hamster genome as the reference upon which CHO cells can be studied and engineered for protein production.

Mutational bias for body size in rhabditid nematodes.

Mutational bias is a potentially important agent of evolution, but it is difficult to disentangle the effects of mutation from those of natural selection. Mutation-accumulation experiments, in which mutations are allowed to accumulate at very small population size, thus minimizing the efficiency of natural selection, are the best way to separate the effects of mutation from those of selection. Body size varies greatly among species of nematode in the family rhabditidae; mutational biases are both a potential cause and a consequence of that variation. We report data on the cumulative effects of mutations that affect body size in three species of rhabditid nematode that vary fivefold in adult size. Results are very consistent with previous studies of mutations underlying fitness in the same strains: two strains of Caenorhabditis briggsae decline in body size about twice as fast as two strains of C. elegans, with a concomitant higher point estimate of the genomic mutation rate; the confamilial Oscheius myriophila is intermediate. There is an overall mutational bias, such that mutations reduce size on average, but the bias appears consistent between species. The genetic correlation between mutations that affect size and those underlying fitness is large and positive, on average.