The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Reducing interaction in simultaneous paired stimulation with CI.

In this study simultaneous paired stimulation of electrodes in cochlear implants is investigated by psychophysical experiments in 8 post-lingually deaf subjects (and one extra subject who only participated in part of the experiments). Simultaneous and sequential monopolar stimulation modes are used as references and are compared to channel interaction compensation, partial tripolar stimulation and a novel sequential stimulation strategy named phased array compensation. Psychophysical experiments are performed to investigate both the loudness integration during paired stimulation at the main electrodes as well as the interaction with the electrode contact located halfway between the stimulating pair. The study shows that simultaneous monopolar stimulation has more loudness integration on the main electrodes and more interaction in between the electrodes than sequential stimulation. Channel interaction compensation works to reduce the loudness integration at the main electrodes, but does not reduce the interaction in between the electrodes caused by paired stimulation. Partial tripolar stimulation uses much more current to reach the needed loudness, but shows the same interaction in between the electrodes as sequential monopolar stimulation. In phased array compensation we have used the individual impedance matrix of each subject to calculate the current needed on each electrode to exactly match the stimulation voltage along the array to that of sequential stimulation. The results show that the interaction in between the electrodes is the same as monopolar stimulation. The strategy uses less current than partial tripolar stimulation, but more than monopolar stimulation. In conclusion, the paper shows that paired stimulation is possible if the interaction is compensated.

Relevance of physical fitness levels and exercise-related beliefs for self-reported and experimental pain in fibromyalgia: an explorative study.

BACKGROUND: It has been suggested that low physical fitness is a contributor to pain in fibromyalgia and that exercise-related beliefs play a role in the persistence of this association. Yet the association between physical fitness and pain is hardly explored in detail. OBJECTIVES: The aim of this exploratory study in patients with fibromyalgia was to investigate the association of physical fitness levels with self-reported and experimental pain as well as with pain catastrophizing and activity-avoidance beliefs. METHODS: Physical fitness of 18 patients with fibromyalgia was examined using maximal ergocycling and the 6-minute walking test (6MWT). Pain intensity was assessed using self-report scales and quantitative sensory testing. RESULTS: A reduced walking distance on the 6MWT was correlated with more severe self-reported pain on the Fibromyalgia Impact Questionnaire (r = -0.52, P < 0.05). Recovery of heart rate after ergocycling was correlated with cold pain thresholds (r = 0.70, P < 0.01), pressure pain thresholds (r = -0.70, P < 0.01), and heat wind-up (r = 0.66, P < 0.05). Activity-avoidance beliefs correlated with a lower peak VO2 on the cycle test (r = -0.52, P < 0.05), a shorter distance on the 6MWT (r = -0.56, P < 0.05), and more severe self-reported pain (r = 0.61, P < 0.05), reflecting that patients with activity-avoidance beliefs were less physically fit and experienced more severe pain. CONCLUSIONS: The results demonstrate some associations between physical fitness and pain in fibromyalgia and point to the importance of activity avoidance. Although the causal directionality of the associations needs substantiation in clinical research, the findings support the notion that low fitness and activity-avoidance beliefs should be targeted while treating pain in fibromyalgia.