Hair cell transduction efficiency of single- and dual-AAV serotypes in adult murine cochleae

Gene delivery is a key component for the treatment of genetic hearing loss. To date, a myriad of adeno-associated virus (AAV) serotypes and surgical approaches have been employed to deliver transgenes to cochlear hair cells, but the efficacy of dual transduction remains unclear. Herein, we investigated cellular tropism of single injections of AAV serotype 1 (AAV1), AAV2, AAV8, AAV9, and Anc80L65, and quantitated dual-vector co-transduction rates following co-injection of AAV2 and AAV9 vectors in adult murine cochlea. We used the combined round window membrane and canal fenestration (RWM+CF) injection technique for vector delivery. Single AAV2 injections were most robust and transduced 96.7% ± 1.1% of inner hair cells (IHCs) and 83.9% ± 2.0% of outer hair cells (OHCs) throughout the cochlea without causing hearing impairment or hair cell loss. Dual AAV2 injection co-transduced 96.9% ± 1.7% of IHCs and 65.6% ± 8.95% of OHCs. Together, RWM+CF-injected single or dual AAV2 provides the highest auditory hair cell transduction efficiency of the AAV serotypes we studied. These findings broaden the application of cochlear gene therapy targeting hair cells

Parental Attitudes toward Genetic Testing for Pediatric Deafness

Recent molecular genetic advances have resulted in genetic testing becoming an option for deaf individuals and their families. However, there is little information about the interest in such testing. To investigate this issue, parents with normal hearing who have one or more deaf children were surveyed about their attitudes toward diagnostic, carrier, and prenatal genetic testing for deafness. This population was chosen because it represents the majority of individuals who are encountered in clinical practice, given that 90%–95% of deaf individuals are born to persons with normal hearing. Of 328 surveys distributed, 96 were completed and returned. Of the respondents, 96% recorded a positive attitude toward genetic testing for deafness, including prenatal testing, although none would use this information to terminate an affected pregnancy. All respondents had a poor understanding of genetics, with 98% both incorrectly estimating the recurrence risk of deafness and misunderstanding the concept of inheritance. Notably, these findings were similar in the group who had had genetic testing for their children and in the group who had not, suggesting either that the parents who received genetic testing did not receive genetic counseling or that the counseling was not effective. On the basis of these results, it was concluded that this population is interested in the use of genetic testing and that testing should not be done without first providing formal genetic counseling. Appropriate counseling can help parents to understand the risks, benefits, and limitations of genetic testing

Col11a2 Deletion Reveals the Molecular Basis for Tectorial Membrane Mechanical Anisotropy

The tectorial membrane (TM) has a significantly larger stiffness in the radial direction than other directions, a prominent mechanical anisotropy that is believed to be critical for the proper functioning of the cochlea. To determine the molecular basis of this anisotropy, we measured material properties of TMs from mice with a targeted deletion of Col11a2, which encodes for collagen XI. In light micrographs, the density of TM radial collagen fibers was lower in Col11a2 –/– mice than wild-types. Tone-evoked distortion product otoacoustic emission and auditory brainstem response measurements in Col11a2 –/– mice were reduced by 30–50 dB independent of frequency as compared with wild-types, showing that the sensitivity loss is cochlear in origin. Stress-strain measurements made using osmotic pressure revealed no significant dependence of TM bulk compressibility on the presence of collagen XI. Charge measurements made by placing the TM as an electrical conduit between two baths revealed no change in the density of charge affixed to the TM matrix in Col11a2 –/– mice. Measurements of mechanical shear impedance revealed a 5.5 ± 0.8 dB decrease in radial shear impedance and a 3.3 ± 0.3 dB decrease in longitudinal shear impedance resulting from the Col11a2 deletion. The ratio of radial to longitudinal shear impedance fell from 1.8 ± 0.7 for TMs from wild-type mice to 1.0 ± 0.1 for those from Col11a2 –/– mice. These results show that the organization of collagen into radial fibrils is responsible for the mechanical anisotropy of the TM. This anisotropy can be attributed to increased mechanical coupling provided by the collagen fibrils. Mechanisms by which changes in TM material properties may contribute to the threshold elevation in Col11a2 –/– mice are discussed.National Institutes of Health (U.S.) (Grant R01-DC00238

The role of discharge variability in determining alluvial stratigraphy

We illustrate the potential for using physics-based modeling to link alluvial stratigraphy to large river morphology and dynamics. Model simulations, validated using ground penetrating radar data from the Río Paraná, Argentina, demonstrate a strong relationship between bar-scale set thickness and channel depth, which applies across a wide range of river patterns and bar types. We show that hydrologic regime, indexed by discharge variability and flood duration, exerts a first-order influence on morphodynamics and hence bar set thickness, and that planform morphology alone may be a misleading variable for interpreting deposits. Indeed, our results illustrate that rivers evolving under contrasting hydrologic regimes may have very similar morphology, yet be characterized by marked differences in stratigraphy. This realization represents an important limitation on the application of established theory that links river topography to alluvial deposits, and highlights the need to obtain field evidence of discharge variability when developing paleoenvironmental reconstructions. Model simulations demonstrate the potential for deriving such evidence using metrics of paleocurrent variance

International Pediatric Otolaryngology Group (IPOG) consensus recommendations: Hearing loss in the pediatric patient

Objective To provide recommendations for the workup of hearing loss in the pediatric patient. Methods Expert opinion by the members of the International Pediatric Otolaryngology Group. Results Consensus recommendations include initial screening and diagnosis as well as the workup of sensorineural, conductive and mixed hearing loss in children. The consensus statement discusses the role of genetic testing and imaging and provides algorithms to guide the workup of children with hearing loss. Conclusion The workup of children with hearing loss can be guided by the recommendations provided herein

International Pediatric ORL Group (IPOG) laryngomalacia consensus recommendations

Objective To provide recommendations for the comprehensive management of young infants who present with signs or symptoms concerning for laryngomalacia. Methods Expert opinion by the members of the International Pediatric Otolaryngology Group (IPOG). Results Consensus recommendations include initial care and triage recommendations for health care providers who commonly evaluate young infants with noisy breathing. The consensus statement also provides comprehensive care recommendations for otolaryngologists who manage young infants with laryngomalacia including: evaluation and treatment considerations for commonly debated issues in laryngomalacia, initial work-up of infants presenting with inspiratory stridor, treatment recommendations based on disease severity, management of the infant with feeding difficulties, post-surgical treatment management recommendations, and suggestions for acid suppression therapy. Conclusion Laryngomalacia care consensus recommendations are aimed at improving patient-centered care in infants with laryngomalacia

Solar Neutrino Constraints on the BBN Production of Li

Using the recent WMAP determination of the baryon-to-photon ratio, 10^{10} \eta = 6.14 to within a few percent, big bang nucleosynthesis (BBN) calculations can make relatively accurate predictions of the abundances of the light element isotopes which can be tested against observational abundance determinations. At this value of \eta, the Li7 abundance is predicted to be significantly higher than that observed in low metallicity halo dwarf stars. Among the possible resolutions to this discrepancy are 1) Li7 depletion in the atmosphere of stars; 2) systematic errors originating from the choice of stellar parameters - most notably the surface temperature; and 3) systematic errors in the nuclear cross sections used in the nucleosynthesis calculations. Here, we explore the last possibility, and focus on possible systematic errors in the He3(\alpha,\gamma)Be7 reaction, which is the only important Li7 production channel in BBN. The absolute value of the cross section for this key reaction is known relatively poorly both experimentally and theoretically. The agreement between the standard solar model and solar neutrino data thus provides additional constraints on variations in the cross section (S_{34}). Using the standard solar model of Bahcall, and recent solar neutrino data, we can exclude systematic S_{34} variations of the magnitude needed to resolve the BBN Li7 problem at > 95% CL. Additional laboratory data on He3(\alpha,\gamma)Be7 will sharpen our understanding of both BBN and solar neutrinos, particularly if care is taken in determining the absolute cross section and its uncertainties. Nevertheless, it already seems that this ``nuclear fix'' to the Li7 BBN problem is unlikely; other possible solutions are briefly discussed.Comment: 21 pages, 3 ps figure

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.

BACKGROUND: The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. METHODS: In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ≥50% during follow-up. RESULTS: Carotid stenosis longer than 0.65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2.79 (1.17-6.65), P = 0.02] and carotid endarterectomy [2.43 (1.03-5.73), P = 0.04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1.68 (1.12-2.53), P = 0.01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0.003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. CONCLUSIONS: Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials

Spectrum of GJB2 (Cx26) gene mutations in Iranian Azeri patients with nonsyndromic autosomal recessive hearing loss

Objective: Hereditary hearing impairment is a genetically heterogeneous disorder. In spite of this,mutations in the GJB2 gene, encoding connexin 26 (Cx26), are a major cause of nonsyndromic recessivehearing loss in many countries and are largely dependent on ethnic groups. The purpose of our study wasto characterize the type and prevalence of GJB2 mutations among Azeri population of Iran.Methods: Fifty families presenting autosomal recessive nonsyndromic hearing loss from Ardabilprovince of Iran were studied for mutations in GJB2 gene. All DNA samples were screened for c.35delGmutation by ARMS PCR. Samples from patients who were normal for c.35delG were analyzed for theother variations in GJB2 by direct sequencing. In the absence of mutation detection, GJB6 was screenedfor the del(GJB6-D13S1830) and del(GJB6-D13S1854).Result: Thirteen families demonstrated alteration in the Cx26 (26%). The 35delG mutation was the mostcommon one, accounting for 69.2% (9 out of 13 families). All the detected families were homozygous forthis mutation. Two families were homozygous for delE120 and 299–300delAT mutations. We alsoidentified a novel mutation: c.463–464 delTA in 2 families resulting in a frame shift mutation.Conclusion: Our results suggest that c.35delG mutation in the GJB2 gene is the most important cause ofGJB2 related deafness in Iranian Azeri population

Trajectories of Big Five Personality Traits: A Coordinated Analysis of 16 Longitudinal Samples

This study assessed change in self‐reported Big Five personality traits. We conducted a coordinated integrative data analysis using data from 16 longitudinal samples, comprising a total sample of over 60 000 participants. We coordinated models across multiple datasets and fit identical multi‐level growth models to assess and compare the extent of trait change over time. Quadratic change was assessed in a subset of samples with four or more measurement occasions. Across studies, the linear trajectory models revealed declines in conscientiousness, extraversion, and openness. Non‐linear models suggested late‐life increases in neuroticism. Meta‐analytic summaries indicated that the fixed effects of personality change are somewhat heterogeneous and that the variability in trait change is partially explained by sample age, country of origin, and personality measurement method. We also found mixed evidence for predictors of change, specifically for sex and baseline age. This study demonstrates the importance of coordinated conceptual replications for accelerating the accumulation of robust and reliable findings in the lifespan developmental psychological sciences. © 2020 European Association of Personality PsychologyPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/156004/1/per2259.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156004/2/per2259-sup-0001-Data_S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156004/3/per2259-sup-0002-Open_Practices_Disclosure_Form.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156004/4/per2259_am.pd