Objective Voltage‐gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain‐expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN‐related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone. Methods We analyzed genotype‐phenotype correlations in large SCN‐patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders. Results Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy‐associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain‐of‐function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed. Significance Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.
Cochlear hair cells are critical for the conversion of acoustic into electrical signals and their dysfunction is a primary cause of acquired hearing impairments, which worsen with aging. Piezoelectric materials can reproduce the acoustic-electrical transduction properties of the cochlea and represent promising candidates for future cochlear prostheses. The majority of piezoelectric hearing devices so far developed are based on thin films, which have not managed to simultaneously provide the desired flexibility, high sensitivity, wide frequency selectivity, and biocompatibility. To overcome these issues, we hypothesized that fibrous membranes made up of polymeric piezoelectric biocompatible nanofibers could be employed to mimic the function of the basilar membrane, by selectively vibrating in response to different frequencies of sound and transmitting the resulting electrical impulses to the vestibulocochlear nerve. In this study, poly(vinylidene fluoride-trifluoroethylene) piezoelectric nanofiber-based acoustic circular sensors were designed and fabricated using the electrospinning technique. The performance of the sensors was investigated with particular focus on the identification of the resonance frequencies and acoustic-electrical conversion in fibrous membrane with different size and fiber orientation. The voltage output (1–17 mV) varied in the range of low resonance frequency (100–400 Hz) depending on the diameter of the macroscale sensors and alignment of the fibers. The devices developed can be regarded as a proof-of-concept demonstrating the possibility of using piezoelectric fibers to convert acoustic waves into electrical signals, through possible synergistic effects of piezoelectricity and triboelectricity. The study has paved the way for the development of self-powered nanofibrous implantable auditory sensors.
Objective Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy, leading to reduced health‐related quality of life (HRQOL). Prospective outcome data on HRQOL are sparse, and this study investigated long‐term predictors of HRQOL in DS. Methods One hundred thirteen families of SCN1A‐positive patients with DS, who were recruited as part of our 2010 study were contacted at 10‐year follow‐up, of which 68 (60%) responded. The mortality was 5.8%. Detailed clinical and demographic information was available for each patient. HRQOL was evaluated with two epilepsy‐specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL); a generic HRQOL instrument, the Pediatric Quality of Life Inventory (PedsQL); and a behavioral screening tool, the Strength and Difficulties Questionnaire (SDQ). Results Twenty‐eight patients were 10–15 years of age (0–5 years at baseline) and 40 were ≥16 years of age (≥6 years at baseline). Patients 0‐ to 5–years‐old at baseline showed a significant decline in mean scores on the PedsQL total score (p = .004), physical score (p < .001), cognitive score (p = .011), social score (p = .003), and eating score (p = .030) at follow‐up. On multivariate regression, lower baseline and follow‐up HRQOL for the whole cohort were associated with worse epilepsy severity and a high SDQ total score (R2 = 33% and 18%, respectively). In the younger patient group, younger age at first seizure and increased severity of epilepsy were associated with a lower baseline HRQOL (R2 = 35%). In the older age group, worse epilepsy severity (F = 6.40, p = .016, R2 = 14%) and the use of sodium‐channel blockers were independently associated with a lower HRQOL at 10‐year follow‐up (F = 4.13, p = .05, R2 = 8%). Significance This 10‐year, prospective follow‐up study highlights the significant HRQOL‐associated cognitive, social, and physical decline particularly affecting younger patients with DS. Sodium channel blocker use appears to negatively impact long‐term HRQOL, highlighting the importance of early diagnosis and disease‐specific management in DS.
Understanding and controlling the vibration of piezoelectric components induced by oscillating external stimuli is essential to develop smart sensing and energy harvesting devices that convert mechanical energy into electricity. Piezoelectric polymers based on Poly(vinylidenefluoride) (PVDF) thin films are amongst the most widely studied materials for flexible sensors and harvesters. Despite the large amount of research on these materials, their electromechanical response under acoustic sound stimuli has not yet been studied in detail. In this work, a thorough investigation on the mechanical vibrations and electrical response of PVDF circular plates of different diameters in response to multiple sound wave frequencies (100Hz-10kHz) has been carried out to gain further understanding of the resonance behaviour and acousto-electric conversion mechanisms of vibrating PVDF thin films. The work is based on experimental data generated using an integrated piezo-acoustic laser vibrometry system and on a theoretical framework based on the continuum theory of thin plates. The developed model enables the prediction of the resonance frequencies in dependence of the plates' diameter, and suggests that the electrical voltage generated during vibrations is not solely originating from the piezoelectric properties of the films, but might be affected by additional factors, including the triboelectric effect. The results of this study are expected to have a strong impact on the investigation of piezoelectric vibrating plates and on the development of different types of transducers and energy harvesting devices.
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