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While digital tools, such as the Internet, smartphones, and social media, are an important part of modern society, little is known about the specific role they play in the healthcare management of individuals and caregivers affected by rare disease. Collectively, rare diseases directly affect up to 10% of the global population, suggesting that a significant number of individuals might benefit from the use of digital tools. The purpose of this qualitative interview-based study was to explore: (a) the ways in which digital tools help the rare disease community; (b) the healthcare gaps not addressed by current digital tools; and (c) recommended digital tool features. Individuals and caregivers affected by rare disease who were comfortable using a smartphone and at least 18 years old were eligible to participate. We recruited from rare disease organizations using purposive sampling in order to achieve a diverse and information rich sample. Interviews took place over Zoom and reflexive thematic analysis was utilized to conceptualize themes. Eight semistructured interviews took place with four individuals and four caregivers. Three themes were conceptualized which elucidated key aspects of how digital tools were utilized in disease management: (1) digital tools should lessen the burden of managing a rare disease condition; (2) digital tools should foster community building and promote trust; and (3) digital tools should provide trusted and personalized information to understand the condition and what the future may hold. These results suggest that digital tools play a central role in the lives of individuals with rare disease and their caregivers. Digital tools that centralize trustworthy information, and that bring the relevant community together to interact and promote trust are needed. Genetic counselors can consider these ideal attributes of digital tools when providing resources to individuals and caretakers of rare disease., (© 2024 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

For proper reconstruction of scalp and forehead defects following Mohs micrographic surgery (MMS), knowledge of the unique anatomy and aesthetic importance of these structures is necessary to restore function and appearance. However, the inflexibility, convexity, and hair-bearing nature of the scalp and forehead can make reconstruction challenging. Detailed planning and precise management are essential to achieve adequate reconstructive results. Defect size, location, prior radiation history, and symmetry of hairlines should be taken into consideration during planning, and the simplest reconstructive technique should be utilized whenever feasible. This review will discuss the reconstructive options available for acquired defects of the scalp and forehead., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

A new high energy proton radiography facility PRIOR-II (Proton Microscope for FAIR) has been designed, constructed, and successfully commissioned at the GSI Helmholtzzentrum für Schwerionenforschung (Darmstadt, Germany) pushing the technical boundaries of charged particle radiography with normal conducting magnets to the limits. The setup is foreseen to become a new and powerful user facility for carrying out fundamental science experiments in the fields of plasma and shock wave physics, material science, and medical physics. It will help address several unsolved scientific challenges, which require high-speed and precise non-invasive diagnostic methods capable of probing matter with up to 100 g/cm2 areal density. PRIOR-II is specifically designed to utilize the full timing capabilities of the SIS-18 synchrotron at GSI for ultra-fast dynamic experiments with up to 4 GeV protons and will also be fielded at the future FAIR facility, where higher proton energies and beam intensities will be available. This will enable experiment geometries with even higher areal densities, more flexible experiment timing, and further enhanced spatial resolution., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Objective: To perform the cross-cultural adaptation and validation of the Dyspnea Index (DI) in Brazilian Portuguese (BP)., Methods: This validation study followed the Consensus-based Standards for the Selection of Health Measurement Instruments recommendations. The translation was conducted in five stages: translation, synthesis, back translation, committee review, and pretest performance. The validation comprised the following steps: (a) construct validity, (b) criterion validity, (c) internal consistency, and (d) reproducibility. The study included 86 adults with dyspnea complaints in the dyspnea group (DG) and 46 adults without dyspnea complaints in the control group (CG), matched for age and gender. All participants completed the DI, the Vocal Handicap Index-10, and the Laryngeal Hypersensitivity Questionnaire. The DG completed the DI a second time., Results: The item "the change in weather affects my breathing problem" did not reach agreement in the DI translation and required adjustments in the synthesis stage. In the pretest stage, all items had a lower proportion of "not applicable" responses, with P < 0.001. Construct validity confirmed a 10-item, one-factor structure. Internal consistency achieved a Cronbach's alpha of 0.941 and reproducibility yielded an intraclass correlation coefficient of 0.765. For criterion validity, the DI significantly distinguished the DG from the CG with higher scores (U = 434.5; P < 0.001) and showed parallel correlations with perceived vocal handicap (r = 0.232; P = 0.032) and laryngeal sensations (r = 0.400; P = 0.001)., Conclusion: The DI was cross-culturally adapted and validated in BP as the Índice de Dispneia. It has a 10-item, one-factor structure and is considered valid and reliable for self-administration in BP speakers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Relative to other regions of the body, the ear has a high risk of developing cutaneous malignancies that often necessitate Mohs micrographic surgery (MMS) for removal. This procedure can create defects that are immediately noticeable if left untreated. Reconstructive techniques are often needed to restore the appearance of the affected ear and its symmetrical relationship to the contralateral ear. However, achieving optimal aesthetic results can be challenging due to the subtle intricacies of the external ear. Therefore, careful planning and execution should be implemented prior to managing the acquired defect. Additionally, depending on the size and location of the defect, various options aligning with the reconstructive ladder can provide desired outcomes. The purpose of this article was to highlight and discuss the different techniques used in ear reconstruction following MMS., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Protons from the Los Alamos Neutron Science Center have been used for pulsed radiography in dynamic experiments for the past 25 years. Pulses of protons are imaged on a scintillator, and the light from these images is captured by fast gated cameras. The need for fast, bright scintillators has led to some compromises in image quality due to tiling the scintillators and backgrounds with totally internally reflected light. We show how large-grain scintillator screens, made using a thin plastic binder, solve these problems., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Intraoperative use of vasopressors in free flap surgeries is controversially debated. The predominant concern is that pedicle blood supply will decrease leading to post-operative complications. This study examined the role of intraoperative vasopressors, specifically norepinephrine, in free flap partial necrosis based on the patients' comorbidities. We retrospectively analyzed 192 patients who received free flap treatment between 2006 and 2021 and were stratified based on vascular comorbidities. We assessed the role of intraoperative vasopressors using multivariate analysis. Patients who were administered vasopressors did not have a significantly higher risk of partial flap necrosis compared to patients who were not administered vasopressors (OR: 1.439, 95% CI: 0.618-3.348, p =0.399). Upon stratifying by vascular comorbidities, we found that patients with two or more vascular comorbidities who were administered vasopressors had a significantly higher risk of developing flap necrosis (OR: 3.882, 95% CI: 1.266-14.752, p =0.046), indicating that vasopressor use in patients with multiple vascular comorbidities is a risk factor for partial flap necrosis. To minimize the risk of flap marginal necrosis in patients with vascular comorbidities, we recommend limited use of vasopressors or minimizing the flap area to preserve vascularization., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s).)

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts., Competing Interests: Declaration of competing interest Adeline Vanderver and Laura Adang have received research support from IONIS pharmaceuticals, Takeda, Sanofi, Eli Lilly, Boehringer Ingelheim, Affinia and Orchard Therapeutics. In addition, Dr. Vanderver has received research support from Illumina, Sana, Passage Bio, Homology and PMD foundation. Dr. Adang from Biogen, MSD Foundation, Don't Forget Morgan, Legacy of Angels and Orphan Disease Center. Dr. Vanderver and Dr. Adang hold the license for the AGS Severity Scale and Dr. Vanderver the patent of ASO in TUBB4A. Dr. Vanderver participates on the advisory board of ELA and United Leukodystrophy Foundation. Dr. Adang is the scientific advisor for CureMLD, MLD Foundation, Don't Forget Morgan, Yaya Foundation and MLDi. Dr. Vanderver is a site Principal Investigator (PI) for Takeda Pharmaceutical's clinical trial for Metachromatic Leukodystrophy NCT03771898 and is an advisor to Passagebio. Dr. Adang also serves as an advisor to Biogen. Dr. Vanderver, Dr. Adang, Dr. Fatemi, Dr. Eichler, Dr. Bonkowsky, Dr. Fraser, Dr. Keller, Dr. Emrick and Dr. Van Haren are recipients of NIH funding through the NINDS (National Institute of Neurological Disorders and Stroke) and/or NCATS (National Center for Advancing Translational Sciences). Dr. Eichler is a recipient of grants through Kennedy Krieger Institute Inc. and Children's Hospital Corporation dba Boston Children's Hospital, and has <1% equity in Swan Bio, and royalties from AAV9 license for AMN. Dr. Eichler receives consulting fees from Leal Therapeutics, Swan Bio, Ionis, Minoryx, UptoDate, Origen, Takeda Therapeutics and Third Rock Ventures. Dr. Eichler is the founder and consultant of Swan Bio, is the ALD connect chair, and serves on the chair on the advisory board of European Leukodystrophy Association, board member at United Leukodystrophy Foundation, and as a scientific advisor for National Tay Sachs and Allied Diseases Association. Dr. Fatemi is a PI for Viking Therapeutics and Minoryx Therapeutics and receives research support from CureLBSL, Brian's Hope Foundation, SwanBio, Autobahn Therapeutics, Poxel Therapeutics, Vertex Pharmaceuticals, and Maryland Stem Cell Research Fund. Also, Dr. Fatemi was former Data and Safety Monitoring Board (DSMB) member for BlueBird Bio, and serves as the ALD Connect Board member. Dr. Fatemi co-invented a patent currently licensed to Ashvattha. All other authors have no conflicts of interest. Dr. Bonkowsky receives research support through grant from European Leukodystrophy Association, and consults for Ionis, Sanofi, Autobahn, Denali, Passage Bio, Bluebird, Calico. He also serves on the ALD connect board. Dr. Keller is the site PI for Ionis Pharmaceuticals Alexander Disease trial and Biomarin Pharmaceuticals Brineura extension study. Dr. Keller consults for Veristat and serves on United Leukodystrophy Foundation and Leukodystrophy Care Network Certified Center. Dr. Emrick serves on the advisory board for Ionis pharmaceuticals. Dr. Van Haren receives research support from United Leukodystrophy Foundation and Stanford MCHRI. He consults for Bluebird Bio, Poxel, Autobahn Therapeutics and Viking, and has participated in the Calico Board. He also serves in the leadership capacity at ALD connect, United Leukodystrophy Foundation and Global Leukodystrophy Alliance. All other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Objective: A limitation of traditional semi-occluded vocal tract exercises (SOVTE) is the single sustained vowel task that precludes co-articulated singing. This study investigated immediate effects of a variably occluded face mask (VOFM) on vocal effort, acoustic, and aerodynamic measures in sung low and high pitches of healthy singers., Design: Single-group, pre-post intervention study., Methods: The outlet ports of disposable anesthesia facemasks were fitted with plastic caps with two drilled openings sizes (9.6 mm, 6.4 mm). Twenty-three singers with no voice complaints provided baseline vocal effort, acoustic, and aerodynamic measures in high and low pitches. Participants trained in four conditions: two VOFM sizes (9.6 mm, 6.4 mm) in combination with the 20th and 80th percentile of the singer's pitch range. Participants were trained on three phonatory tasks: repeated consonant/vowel syllables, sung sentence, and sustained vowel. Vocal effort before and after training was compared using a visual-analog scale, while standardized mean differences captured acoustic and aerodynamic changes before and after training., Results: Participants reported decreased vocal effort after VOFM training at all occlusion and pitch combinations. On average, consistent beneficial effect sizes were found in cepstral peak prominence (CPP) and cepstral spectral index of dysphonia (CSID) for all 4 occlusion-pitch combinations, and vocal intensity and mean estimated subglottal pressure increased for all 4 occlusion-pitch training combinations. Changes in mean phonatory airflow and resistance were less consistent., Discussion: There was an immediate effect of decreased vocal effort in singing after VOFM training. Acoustic and aerodynamic effects were variable and modest. Future studies should explore changes in these outcomes after VOFM in singing voice therapy., Competing Interests: DECLARATION OF COMPETING INTERESTS Dr. S. N. Awan licenses the algorithms that form the basis of the Analysis of Dysphonia in Speech & Voice (ADSV) program to Pentax Medical/KayPentax (Montvale, NJ)., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

We present an inversion method capable of robustly unfolding MeV x-ray spectra from filter stack spectrometer (FSS) data without requiring an a priori specification of a spectral shape or arbitrary termination of the algorithm. Our inversion method is based upon the perturbative minimization (PM) algorithm, which has previously been shown to be capable of unfolding x-ray transmission data, albeit for a limited regime in which the x-ray mass attenuation coefficient of the filter material increases monotonically with x-ray energy. Our inversion method improves upon the PM algorithm through regular smoothing of the candidate spectrum and by adding stochasticity to the search. With these additions, the inversion method does not require a physics model for an initial guess, fitting, or user-selected termination of the search. Instead, the only assumption made by the inversion method is that the x-ray spectrum should be near a smooth curve. Testing with synthetic data shows that the inversion method can successfully recover the primary large-scale features of MeV x-ray spectra, including the number of x-rays in energy bins of several-MeV widths to within 10%. Fine-scale features, however, are more difficult to recover accurately. Examples of unfolding experimental FSS data obtained at the Texas Petawatt Laser Facility and the OMEGA EP laser facility are also presented., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Objective: The potential for negative sequalae in psychosocial well-being presents clinical importance to the assessment of voice disorders. Despite the impairment voice disorders cause in the psychosocial domain, the clinical assessment of these disorders relies heavily on visual perceptual judgments of the larynx, audio-perceptual, as well as acoustic and aerodynamic measures. While these measures aid in accurate diagnosis and are necessary for standard of care, they present little insight into the patient experience of having a voice disorder., Design: Retrospective between-subject, non-experimental design., Methods: Data from 335 patients from the University of Pittsburgh Voice Center were collected from scores of the Voice Handicap Index-10 (VHI-10) and two recent questionnaires, the Voice Present Perceived Control scale (VPPC), and the Vocal Congruency Scale (VCS). Examining how these voice-specific scales related to three mental health screeners for stress (Perceived Stress Scale-4), anxiety (Generalized Anxiety Disorder-7) and depression (Patient Health Questionnaire-9) were also examined. Patient diagnoses included primary muscle tension dysphonia (pMTD), unilateral vocal fold paralysis (UVFP), vocal fold atrophy, and mid membranous vocal fold lesions., Results: There were significant differences in scores from the voice-specific scales between diagnostic groups with UVFP being the highest (worst) in VHI-10 and UVFP being the lowest (worst) in VCS compared to healthy controls. There was no significant difference in VPPC scores between diagnostic groups. Results showed statistically significant inverse relationships between the VHI-10 and the VPPC and between the VHI-10 and VCS for all diagnostic groups. A significant direct relationship was found between the VPPC and the VCS for patients diagnosed with MTD, UVFP and Lesions. In sum, patients with UVFP presented with the most frequent and sometimes strongest relationships between voice and mental health measures., Discussion: This study marks an initial investigation into the nuanced patient experience of having a voice disorder. Three theoretically unrelated voice constructs: handicap, perceived control, and sense of self, were measured via self-report. Results from this study describe the patient experience correlating to these constructs with weak correlations to stress, anxiety, and depression. Findings also clearly suggest that patient experience varies among diagnostic groups, as well as varying constructs. Measures of multiple constructs of patient perception provide valuable insight into a patient's experience of their voice disorder, guidance on the direction of voice treatment, and justification for such treatments., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Presbyphonia negatively impacts quality of life in patients with age-related voice changes. A proof-of-concept study showed promise for high vocal intensity exercise to treat presbyphonia, which became the basis for a novel intervention for age-related voice changes known as Phonation Resistance Training Exercises (PhoRTE). Expiratory Muscle Strength Training (EMST) has also been proposed as an additional intervention to target and strengthen the aging respiratory system; however, EMST has undergone limited evaluation as an adjunct treatment for elderly patients undergoing voice therapy for presbyphonia. This study determined if the addition of EMST to PhoRTE voice therapy (PhoRTE + EMST) is at least as effective at voice improvement as PhoRTE alone., Study Design: Prospective, randomized, controlled, single-blinded, non-inferiority., Materials and Methods: Participants aged 55 years or older with a diagnosis of vocal fold atrophy were randomized to complete PhoRTE therapy or PhoRTE + EMST. The primary outcome was change in Voice Handicap Index-10 (VHI-10). Secondary outcomes included the Aging Voice Index, maximum expiratory pressure, and acoustic and aerodynamic measures of voice. Repeated measures linear mixed models were constructed to analyze outcomes at a significance level of α = 0.10., Results: Twenty-six participants were recruited for the study, and 24 participants were randomized to either treatment arm. Sixteen participants completed the entire study. Both treatment arms showed statistically significant and clinically meaningful improvements in VHI-10 (PhoRTE mean [M] = -8.20, P < 0.001; PhoRTE + EMST M = -9.58, P < 0.001), and PhoRTE + EMST was noninferior to PhoRTE alone (P = 0.069). Both groups experienced a statistically significant pre-post treatment decrease (improvement) in AVI scores (PhoRTE M = -18.40, P = 0.004; PhoRTE + EMST M = -16.28, P = 0.005). PhoRTE+EMST had statistically significantly greater changes in maximum expiratory pressure compared to PhoRTE alone (PhoRTE M = 8.24 cm H 2 O, PhoRTE + EMST M = 32.63 cm H 2 O; P= 0.015). Some secondary acoustic and aerodynamic outcomes displayed trends toward improvement., Conclusion: This study demonstrates that voice therapy targeting high vocal intensity exercise (eg, PhoRTE) and EMST can play a role in improving voice outcomes for patients with presbyphonia., Competing Interests: DECLARATION OF COMPETING INTEREST The authors declare the following financial interests/personal relationships which may be considered as potential competing interests – Dr. Aaron Ziegler and Dr. Edie R. Hapner are co-developers of Phonation Resistance Training Exercises (PhoRTE) and have equal ownership interest in the for-profit company PhoRTE, LLC., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this investigation was to assess clinician and patient feedback about voice therapy using a variably occluded face mask (VOFM) and to determine if voice therapy augmented via a VOFM would result in favorable changes in patient self-perceived handicap, as well as acoustic and aerodynamic measures., Methods/design: This pilot study used a prospective, pre-post single group design. Eleven patients with dysphonia due to primary muscle tension dysphonia (8) or benign vocal fold lesions (3) were recruited. Data collected included patient and clinician feedback of voice therapy using a VOFM, voice handicap index (VHI)-10, acoustic and aerodynamic measures. Data were collected before treatment (baseline) and 1-week post-therapy. Wilcoxon signed-rank tests were used to compare data pre- and post-therapy., Results: Statistically significant improvement was observed for the VHI-10 with a median delta of -7. Clinician feedback generally reported that patients liked the VOFM, using the VOFM within the first two sessions of therapy, and within less than 10 min of use. All clinicians ranked the conversation level of the hierarchy as the most effective level. Three themes emerged from the Therapy Feedback Form: the VOFM was a (1) "Facilitator for Sensation," (2) a "Physical Tool," and that there was (3) "No Program Needed" to use the VOFM in voice therapy. There was a statistically significant improvement in cepstral peak prominence (p = 0.0329) and cepstral spectral index of dysphonia (p = 0.0164) in sustained vowels., Discussion: This pilot study represents the first investigation into clinician and patient perceptions of using a VOFM. Reported measures via patient perception, as well as clinician perceptions, and some acoustic and aerodynamic measures showed that participants got better with VOFM voice therapy. Last, in general, both clinicians and patients liked utilizing a VOFM in voice therapy., (© 2022 S. Karger AG, Basel.)

Background: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study., Methods: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case., Results: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia., Conclusions: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: One of the presumed etiologies of primary muscle tension dysphonia (MTD) is a respiratory-phonatory disruption resulting in poor phonatory airflow in speech; however, few data exist on the differences between vocally healthy adults and patients diagnosed with MTD. The goal of this study was to compare aerodynamic and acoustic measures of self-perceived vocally healthy adults with patients diagnosed with MTD., Study Design: Retrospective, observational, matched cohort study., Methods: Vocally healthy adults age 19-60 years were matched on age, gender, and body mass index (BMI) to patients diagnosed with MTD. Recorded samples of the first four sentences of The Rainbow Passage were analyzed for between-group differences in the following acoustic and aerodynamic dependent measures in connected speech: mean airflow during voicing, breath number, reading passage duration, inspiratory and expiratory durations, phonation time, inspiratory and expiratory volumes, cepstral peak prominence (CPP), CPP standard deviation (CPP SD), low to high ratio (L/H ratio), L/H ratio SD, CPP Fo, CPP Fo SD, cepstral spectral index of dysphonia, and dB sound pressure level (SPL)., Results: One hundred and seventy participants were studied; 85 patients diagnosed with primary MTD and 85 vocally healthy control participants. The two groups differed significantly in mean SPL, duration of the reading passage, and inspiratory and expiratory airflow duration (P ≤ 0.003). No significant differences were observed between the groups on any other phonatory aerodynamic or acoustic measure. Mean SPL, duration of the reading passage, and inspiratory and expiratory airflow durations were lower and longer, respectively, in patients with MTD. Ranges and standard deviations were greater for all aerodynamic and acoustic measurements in patients with MTD., Conclusion: Large variability in aerodynamic and acoustic measurements were observed in patients with primary MTD with no salient differences at the group level compared to vocally healthy participants. Individual phonatory aerodynamic and acoustic profiles should be used when setting goals for patient treatment plans and to track response to treatment for patients with MTD. Taken in its entirety, connected speech from patients diagnosed with MTD essentially reflect normal acoustic and aerodynamic values., (Copyright © 2020. Published by Elsevier Inc.)

Serotonin receptor 4 (5-HT 4 R) plays an important role in regulating mood, anxiety, and cognition, and drugs that activate this receptor have fast-acting antidepressant (AD)-like effects in preclinical models. However, 5-HT 4 R is widely expressed throughout the central nervous system (CNS) and periphery, making it difficult to pinpoint the cell types and circuits underlying its effects. Therefore, we generated a Cre-dependent 5-HT 4 R knockout mouse line to dissect the function of 5-HT 4 R in specific brain regions and cell types. We show that the loss of functional 5-HT 4 R specifically from excitatory neurons of hippocampus led to robust AD-like behavioral responses and an elevation in baseline anxiety. 5-HT 4 R was necessary to maintain the proper excitability of dentate gyrus (DG) granule cells and cell type-specific molecular profiling revealed a dysregulation of genes necessary for normal neural function and plasticity in cells lacking 5-HT 4 R. These adaptations were accompanied by an increase in the number of immature neurons in ventral, but not dorsal, dentate gyrus, indicating a broad impact of 5-HT 4 R loss on the local cellular environment. This study is the first to use conditional genetic targeting to demonstrate a direct role for hippocampal 5-HT 4 R signaling in modulating mood and anxiety. Our findings also underscore the need for cell type-based approaches to elucidate the complex action of neuromodulatory systems on distinct neural circuits., (© 2021. The Author(s).)

Meta-therapy refers to the clinical dialogue via which direct and indirect voice treatments are introduced and discussed, and which helps build a useful conceptual framework for voice therapy. Meta-therapy was idiosyncratically defined in previous work. However, the current colloquial narrative of meta-therapy is not standardized or specific enough to be reliably taught, rigorously studied, or clinically delivered with high fidelity. Therefore, this article uses a standard framework (the Rehabilitation Treatment Specification System or RTSS) to further articulate and operationalize meta-therapy in vocal rehabilitation. Meta-therapy's conceptual framework generally aligns with the RTSS's treatment theory and associated concepts; e.g., the treatment component and its underlying ingredients, mechanisms of action, and target. Because the treatment theories in meta-therapy most frequently involve mechanisms of action related to information processing, they primarily map onto the RTSS's Representations treatment components. The treatment targets in meta-therapy are often focused on changes in the patient's cognitions, knowledge, beliefs, attitudes, intentions, and/or awareness regarding voice-related modifications. The ingredients in meta-therapy are frequently clinician actions conveying information with the goal of appropriately shaping the patient's mental representations, and are delivered with verbal cues, stories, analogies, etc. This manuscript provides specific examples of how meta-therapy is applied in clinical voice practice. Considerations for future investigation of meta-therapy are proposed., Competing Interests: None declared, (Thieme. All rights reserved.)

Background: Despite the impact of Parkinson disease (PD) on speech communication, there is no consensus regarding the effect of lead location on voice-related outcomes in subthalamic nucleus (STN) deep brain stimulation (DBS)., Objective: To determine the relationship of stimulation location to changes in cepstral analyses of voice following STN DBS., Methods: Speech pathology evaluations were obtained from 14 PD subjects, before and after STN DBS, including audio-perceptual voice ratings (overall severity, loudness, hoarseness changes), measured indices of dysphonia (cepstral peak prominence and cepstral spectral index of dysphonia), and phonatory aerodynamics. The contact locations used for active stimulation at the time of postoperative voice evaluations were determined and assessed in relation to voice outcomes., Results: Voice outcomes remained relatively unchanged on average. Stimulation locations in the anterior portion of the sensorimotor region of the left STN, however, were associated with improvements in voice severity scores, cepstral spectral index of dysphonia, shortness of breath, and phonatory airflow during connected speech. Posterior locations were associated with worsening of these outcomes. Variation in the medial-lateral or dorsal-ventral position on the left, and in any direction on the right, did not correlate with any voice outcome., Conclusion: Active contact placement within the anterior sensorimotor STN was associated with improved perceptual and acoustic-aerodynamic voice-related outcomes. These findings suggest an STN topography for improving airflow for speech, in turn improving how PD patients' voices sound., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A-related leukodystrophy, Peroxisomal biogenesis disorders, POLR3-related Leukodystrophy, Vanishing White Matter, and Pelizaeus-Merzbacher Disease. Despite the relative frequency of these conditions, carrier-screening laboratories regularly test only 20 of the 55 leukodystrophy-related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening., (© 2020 Wiley Periodicals, Inc.)

Objectives: Ulcerative laryngitis (UL) is challenging in terms of treatment and patient counseling, with few reports in the literature. This study describes UL patients and their clinical course including detailed voice and stroboscopic outcomes after treatment which have not been described in previous literature., Methods: Single-institution, retrospective review of 23 UL patients. Demographics, historical factors, disease course, treatment, and outcomes are presented. Treatment results were compared to prior studies., Results: Seventy four percent had inflammatory/infectious precipitating event. Average presenting Voice-Handicap-Index-10 (VHI-10) was 25 (range: 6-38) and average final VHI-10 was 9 (range: 0-26). Ninty five percent had improvement in VHI-10 (average decrease of 15). Only 50% had final VHI-10 within "normal" limits. Treatment comprised reflux medications (85%), antibiotics (22%), antifungals (39%), antivirals (52%) steroids (52%), and/or voice rest (65%). Average symptom duration before evaluation was 42 days; average follow-up was 6.8 months. Final laryngovideostroboscopy revealed no ulcers in 78%, but 65% had persistently decreased mucosal wave vibration. Average time to ulcer resolution was 2.25 months but resolution or plateau of voice symptoms occurred later, average 2.7 months. Multiple regression analyses revealed that younger age, shorter symptom duration, and antireflux treatment were significant predictors of decrease in VHI-10 (P < 0.05)., Conclusions: Most patients have good voice outcomes following resolution of UL, although vocal fold mucosal wave abnormalities may persist. This study provides the most detailed report of UL, disease course and treatment outcomes to date. Additionally, this study is also the first to suggest that earlier initiation of treatment may improve voice outcome after UL., (Copyright © 2018 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Purpose Conversation training therapy (CTT) is the 1st voice therapy approach to eliminate the traditional therapeutic hierarchy and use patient-driven conversation as the sole therapeutic stimulus. The purpose of this investigation was to determine the efficacy of CTT compared to standard-of-care voice therapy approaches for the treatment of patients with voice disorders. Method A prospective study of CTT treatment outcomes in adults with dysphonia due to primary muscle tension dysphonia or benign vocal fold lesions compared to age, gender, and diagnosis historical matched control (HMC) patients was used. The primary outcome was change in Voice Handicap Index-10 (VHI-10); secondary outcomes included acoustic, aerodynamic, and auditory-perceptual outcomes. Data were collected before treatment (baseline), at the start of each therapy session, 1 week after the final therapy session (short-term follow-up), and 3 months after the final therapy session (long-term follow-up). Results For the CTT group, statistically significant improvements were observed for VHI-10. Though statistically significant improvements were observed for the VHI-10 for the HMC group, the CTT group saw significantly greater improvement in VHI-10. Furthermore, equivalent gains were observed following only 2 sessions of CTT compared to 4-8 sessions of traditional therapy. Significant improvements in the CTT group were observed for cepstral peak prominence in a vowel, fundamental frequency, Cepstral Spectral Index of Dysphonia in a vowel and connected speech, vocal intensity, average airflow in speech in a reading passage, number of breaths and duration of reading passage, and auditory-perceptual measurement of overall voice severity. Conclusions Results support the hypothesis that training voice techniques in the context of spontaneous conversational speech improves patient perception of voice handicap and acoustic, aerodynamic, and auditory-perceptual voice outcomes both immediately following treatment and at long-term follow-up. CTT participants also demonstrated significantly larger decreases in VHI-10 compared to HMC participants who received standard-of-care, nonconversational, hierarchical-based voice therapy.

Changes in voice in aging adults impact their ability to use their voice to communicate in all situations and can lead to decreased quality of life (QOL). The primary objective of this study was to determine the validity and reliability of the Aging Voice Index (AVI)-a tool specifically designed for aging adults with voice disorders. A total of 92 older adults were asked to complete the Voice-Related Quality of Life Scale (VRQOL) and the AVI as well as provide their self-perceived voice severity rating of their voice problem and demographic information. Intraclass correlation for test-retest reliability was 0.952. The AVI was highly correlated to the VRQOL (P < 0.0001). Additionally, the AVI score was found to distinguish between self-rated voice quality (P < 0.0001) and diagnostic voice categories (P < 0.0001). No significant differences were identified for sex or race. The AVI is a valid and reliable quality of life assessment for older adults with voice disorders. The AVI will capture the quality of life impact a voice disorder has on older adults. Future studies will further explore differences in clinical diagnoses and identify clinically significant changes in pre-to post-AVI scores., (Copyright © 2018 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: This study reports on experiments designed to examine the effects of a variably occluded face mask (VOFM) on (a) estimated subglottal pressure (P sub ) in normophonic participants and (b) aerodynamic and acoustic characteristics of voice in dysphonic participants., Design: A prospective design was used for experiment 1, and a prospective, randomized cohort design was used for experiment 2., Methods: The outlet ports of disposable anesthesia face masks were fitted with plastic caps with variable diameter drilled openings (9.6, 6.4, 3.2, and 1.6 mm) to create a series of mask openings. In experiment 1, P sub was measured in normophonic participants using the face mask during syllable repetitions in unoccluded and variable diameter opening conditions. In experiment 2, aerodynamic and acoustic measures were obtained in a group of dysphonic speakers before and after syllable and speech repetition tasks using the VOFM., Results: In experiment 1, mean P Sub was observed to decrease while using the VOFM in all occlusion conditions versus nonocclusion, with a significant reduction in P sub observed between the baseline and the 6.4 mm condition. In experiment 2, standardized mean differences showed that many dysphonic participants produced reduced P sub , increased airflow, and improved acoustic measures after the use of the VOFM in at least one occlusion condition., Conclusions: Beneficial changes in both aerodynamic and acoustic characteristics of voice may be obtained in dysphonic speakers using a VOFM. By moving the place of occlusion outside of the oral cavity, therapeutic stimuli options may be extended beyond vowel and humming elicitations to syllable and speech contexts and assist with generalization of voice therapy targets to conversational speech., (Copyright © 2018 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism. FXS is also accompanied by attention problems, hyperactivity, anxiety, aggression, poor sleep, repetitive behaviors, and self-injury. Recent work supports the role of γ-aminobutyric-acid (GABA), the primary inhibitory neurotransmitter in the brain, in mediating symptoms of FXS. Deficits in GABA machinery have been observed in a mouse model of FXS, including a loss of tonic inhibition in the amygdala, which is mediated by extrasynaptic GABA A receptors. Humans with FXS also show reduced GABA A receptor availability. Here, we sought to evaluate the potential of gaboxadol (also called OV101 and THIP), a selective and potent agonist for delta-subunit-containing extrasynaptic GABA A receptors (dSEGA), as a therapeutic agent for FXS by assessing its ability to normalize aberrant behaviors in a relatively uncharacterized mouse model of FXS ( Fmr1 KO2 mice). Four behavioral domains (hyperactivity, anxiety, aggression, and repetitive behaviors) were probed using a battery of behavioral assays. The results showed that Fmr1 KO2 mice were hyperactive, had abnormal anxiety-like behavior, were more irritable and aggressive, and had an increased frequency of repetitive behaviors compared to wild-type (WT) littermates, which are all behavioral deficits reminiscent of individuals with FXS. Treatment with gaboxadol normalized all of the aberrant behaviors observed in Fmr1 KO2 mice back to WT levels, providing evidence of its potential benefit for treating FXS. We show that the potentiation of extrasynaptic GABA receptors alone, by gaboxadol, is sufficient to normalize numerous behavioral deficits in the FXS model using endpoints that are directly translatable to the clinical presentation of FXS. Taken together, these data support the future evaluation of gaboxadol in individuals with FXS, particularly with regard to symptoms of hyperactivity, anxiety, irritability, aggression, and repetitive behaviors.

Counseling after consumer-driven whole exome sequencing (WES) and whole genome sequencing (WGS) presents challenges for genetic counselors as availability of this testing increases. There are no standard practice guidelines and limited resources for genetic counselors in this area, but consumer demand for counseling and data interpretation exists and is likely to grow along with testing opportunities. In this paper, we comment upon our experiences as three independent, private practice genetic counselors who have provided counseling services for clients with WES/WGS reports and data. In our counseling experience, we have encountered three main types of client motivation for seeking testing and counseling: generally healthy individuals who are curious to learn more about their genomic data, individuals with family histories of various conditions, and/or who want to better understand specific disease risks, and individuals who are ill, undiagnosed and searching for an understanding of their ailments. Research is needed to better understand client motivations for undergoing testing and counseling, as well outcomes of counseling sessions. In addition to improvements in variant identification, classification and bioinformatics, there is a need for practice guidelines, counseling resources, service delivery models, and efforts to increase awareness and access to genetic counseling services., (© 2019 National Society of Genetic Counselors.)

Objectives/hypothesis: The Voice Handicap Index-10 (VHI-10) is commonly used to measure patients' perception of vocal handicap. Clinical consensus has previously defined clinically meaningful improvement as a decrease ≥5. This study determines the minimal clinically important difference (MCID) for VHI-10 in patients with unilateral vocal fold paralysis (UVFP) using anchor-based methodology., Study Design: Prospective cohort questionnaire analysis., Methods: Two hundred eighty-one UVFP patients completed the VHI-10 on two consecutive visits (within 3 months). At the follow-up visit, patients answered an 11-point Global Rating of Change Questionnaire (GRCQ) scored from -5 to +5. Relationship between the GRCQ and change in VHI-10 was quantified using analysis of variance, and MCID for the VHI-10 was determined using receiver operating characteristic (ROC) curve analysis., Results: Overall mean VHI-10 change was -3.71 (standard deviation [SD] = 8.89) and mean GRCQ was 1.37 (SD = 2.51). Average interval between measurements was 1.73 months (SD = 0.83). Mean changes in VHI-10 scores were -7.45, -0.53, and +4.40 for patients whose GRCQ scores indicated improvement, no change, and worsening, respectively. Differences between mean scores were statistically significant (P < .001). Area under the ROC curve was 0.80, demonstrating the classification accuracy of VHI-10 change scores. A VHI-10 change of -4 was determined to be the optimal threshold that discriminated between improvement and no improvement (sensitivity and specificity 0.62 and 0.88, respectively)., Conclusions: The MCID for improvement in VHI-10 in UVFP patients is a decrease of 4. This information improves understanding of patients' response to treatment and allows comparison between different treatments. Future research should determine MCID for VHI-10 across all voice disorders., Level of Evidence: 4. Laryngoscope, 128:1419-1424, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

The mechanical properties of brain tissue in vivo determine the response of the brain to rapid skull acceleration. These properties are thus of great interest to the developers of mathematical models of traumatic brain injury (TBI) or neurosurgical simulations. Animal models provide valuable insight that can improve TBI modeling. In this study we compare estimates of mechanical properties of the Yucatan mini-pig brain in vivo and ex vivo using magnetic resonance elastography (MRE) at multiple frequencies. MRE allows estimations of properties in soft tissue, either in vivo or ex vivo, by imaging harmonic shear wave propagation. Most direct measurements of brain mechanical properties have been performed using samples of brain tissue ex vivo. It has been observed that direct estimates of brain mechanical properties depend on the frequency and amplitude of loading, as well as the time post-mortem and condition of the sample. Using MRE in the same animals at overlapping frequencies, we observe that porcine brain tissue in vivo appears stiffer than porcine brain tissue samples ex vivo at frequencies of 100 Hz and 125 Hz, but measurements show closer agreement at lower frequencies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The mechanical properties of brain tissue, particularly those of white matter (WM), need to be characterized accurately for use in finite element (FE) models of brain biomechanics and traumatic brain injury (TBI). Magnetic resonance elastography (MRE) is a powerful tool for non-invasive estimation of the mechanical properties of soft tissues. While several studies involving direct mechanical tests of brain tissue have shown mechanical anisotropy, most MRE studies of brain tissue assume an isotropic model. In this study, an incompressible transversely isotropic (TI) material model parameterized by minimum shear modulus (μ 2 ), shear anisotropy parameter (ϕ), and tensile anisotropy parameter (ζ) is applied to analyze MRE measurements of ex vivo porcine white matter (WM) brain tissue. To characterize shear anisotropy, "slow" (pure transverse) shear waves were propagated at 100, 200 and 300Hz through sections of ex vivo brain tissue including both WM and gray matter (GM). Shear waves were found to propagate with elliptical fronts, consistent with TI material behavior. Shear wave fields were also analyzed within regions of interest (ROI) to find local shear wavelengths parallel and perpendicular to fiber orientation. FE simulations of a TI material with a range of plausible shear modulus (μ 2 ) and shear anisotropy parameters (ϕ) were run and the results were analyzed in the same fashion as the experimental case. Parameters of the FE simulations which most closely matched each experiment were taken to represent the mechanical properties of that particular sample. Using this approach, WM in the ex vivo porcine brain was found to be mildly anisotropic in shear with estimates of minimum shear modulus (actuation frequencies listed in parenthesis): μ 2 = 1.04 ± 0.12 kPa (at 100Hz), μ 2 = 1.94 ± 0.29 kPa (at 200Hz), and μ 2 = 2.88 ± 0.34 kPa (at 300Hz) and corresponding shear anisotropy factors of ϕ= 0.27 ± 0.09 (at 100Hz), ϕ= 0.29 ± 0.14 (at 200Hz) and ϕ= 0.34 ± 0.13 (at 300Hz). Future MRE studies will focus on tensile anisotropy, which will require both slow and fast shear waves for accurate estimation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives/hypothesis: At presentation, unilateral vocal fold paralysis (UVFP) patients have different treatment options, including conservative management (CM), injection laryngoplasty (IL) with a temporary agent, or permanent medialization (PM). This study evaluates long-term outcomes for UVFP patients relative to intervention., Study Design: Retrospective chart review., Methods: A retrospective chart review was performed of UVFP patients who presented to the University of California San Francisco Voice and Swallowing Center. Videolaryngostroboscopy examinations were reviewed. Maximum glottic closure was quantified with the normalized glottic gap area (NGGA). Perceptual voice analysis was performed using the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) at corresponding time points., Results: Fifty-three patients met inclusion criteria. Six underwent CM only, 20 went on to require PM, 19 underwent IL only, and eight underwent IL and subsequent PM. NGGA at presentation was similar among groups; however, the CM group was noted to have more favorable CAPE-V scores for Breathiness (P = .007) and Loudness (P = .018). All groups had similar NGGA and CAPE-V scores at last follow-up. When compared to pooled data for patients who underwent PM, the IL group was noted to have similar NGGA and CAPE-V scores at presentation. Although improvements in both groups were noted following intervention, both groups appeared similar at last follow-up with the exception of Roughness, for which the IL group retained a slightly improved outcome (13.3 vs. 18.3, P = .03)., Conclusions: At presentation, UVFP patients have similar NGGA. This finding suggests that treatment recommendations cannot be made on the size of the glottic gap alone. Furthermore, in many patients, IL results in long-term benefit with glottic closure and CAPE-V scores equivalent to that obtained with PM., Level of Evidence: 4. Laryngoscope, 128:430-436, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Breast cancer patients have the option to choose a breast reconstruction after mastectomy. A range of studies have postulated that patients' individually appraised significance of their breast is an important factor in the decision for or against breast reconstruction. This study explored the individually perceived significance of the breast among patients with and without breast reconstruction and its correlation with postoperative satisfaction., Methods: Ten patients without breast reconstruction, and ten patients with immediate breast reconstruction after mastectomy participated in the study. The perceived importance of the breast and the pre-and postoperative esthetic satisfaction of the patients were obtained using an 11-point Likert scale. Qualitative interviews explored patients' views on the meaning of their breast and their experience after surgery., Results: Patients who had decided for breast reconstruction rated the importance of their breast for femininity (p = 0.004) and attractiveness (p = 0.037) significantly higher than patients without reconstruction. The qualitative data provide evidence that the breast of a woman fulfills a variety of intrapsychic and interactional functions. Difficulties in integrating the reconstructed breast into the body image were reported. A high importance of the breast correlated significantly with a decrease in satisfaction with the breast after reconstruction (rs = -0.652, p = 0.041)., Conclusions: Patients who found their breast to be highly important were more likely to decide for a reconstruction. Mastectomy has an impact on various psychosocial variables but impairments may also occur after breast reconstruction. Patients reporting a high significance of their breast showed the greatest decrease in satisfaction with their breast after reconstruction.

Objectives: The Vocal Handicap Index-10 (VHI-10) was designed as an item reduction of the original VHI to provide a quick, reliable, and quantifiable measure of patients' own vocal handicap perception. Many translations of the VHI-10 have been produced, but methodologies of translation vary between articles and do not always mirror that of the English VHI-10. This discrepancy leads to confusion about normative values and the applicability of published data in non-English-speaking cultures. This article examines the various item reductions of the VHI-10 from the VHI and the differing methodologies of translation of the VHI-10., Study Design: This is an invited review article., Methods: Published item reductions and translations of the VHI-10 were reviewed. Normative values for each translation, where available, were calculated. The World Health Organization recommendations for the translation of instruments are reviewed., Results/conclusions: There are substantial differences between the original VHI-10 (created and published in American English) and many of the translations of the VHI-10 and other proposed item reductions, both in the actual questions used and the order of the questions. We have to conclude that for a number of the non-English VHI-10/VHI reductions, the instruments are not equivalent, meaning the results from different languages are not comparable. Our recommendation for future patient-reported instrument translations is to translate and validate the instrument according to the World Health Organization protocol while maintaining item consistency and order, allowing studies to be better focused and decrease unnecessary replication of well-performed studies, as well as allowing metadata to be combined from different countries and cultures., (Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXG-associated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life., (Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.)

Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases. Ann Neurol 2016;79:1031-1037., (© 2016 American Neurological Association.)

Mechanical anisotropy is an important property of fibrous tissues; for example, the anisotropic mechanical properties of brain white matter may play a key role in the mechanics of traumatic brain injury (TBI). The simplest anisotropic material model for small deformations of soft tissue is a nearly incompressible, transversely isotropic (ITI) material characterized by three parameters: minimum shear modulus (µ), shear anisotropy (ϕ=µ1µ-1) and tensile anisotropy (ζ=E1E2-1). These parameters can be determined using magnetic resonance elastography (MRE) to visualize shear waves, if the angle between the shear-wave propagation direction and fiber direction is known. Most MRE studies assume isotropic material models with a single shear (µ) or tensile (E) modulus. In this study, two types of shear waves, "fast" and "slow", were analyzed for a given propagation direction to estimate anisotropic parameters µ, ϕ, and ζ in two fibrous soft materials: turkey breast ex vivo and aligned fibrin gels. As expected, the speed of slow shear waves depended on the angle between fiber direction and propagation direction. Fast shear waves were observed when the deformations due to wave motion induced stretch in the fiber direction. Finally, MRE estimates of anisotropic mechanical properties in turkey breast were compared to estimates from direct mechanical tests., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives/hypothesis: Benign midmembranous vocal fold lesions (BMVFLs) are common voice disorders, but interpretation of outcomes following treatment is difficult due to the lack of a standardized nomenclature system for these lesions. Outcome results are increasingly important to third party payers. This study aimed to investigate the outcomes of patients with BMVFLs using a previously validated nomenclature, and to provide incidences and outcome results for each diagnosis., Methods: A retrospective chart review of BMVFL patients was performed. Treatment was individualized but typically involved implementation of nonsurgical therapy followed by phonomicrosurgery as needed. A previously reported BMVFL stratification system was used., Results: A total of 224 patients with BMVFLs were studied. Sixty-seven percent of all patients with a BMVFL underwent phonomicrosurgery. The most common BMVFL types were polyp and nonspecific vocal fold lesion. Pseudocyst represented 0.9% of the cohort. The Voice Handicap Index-10 (VHI-10) and acoustic data demonstrate a high degree of treatment success. The mean change in VHI-10 was greatest for cyst-subepithelial and polyp. Fibrous mass-ligamentous patients had the smallest mean change in VHI-10. Mean post-treatment VHI-10 scores of all the lesions except fibrous mass-ligamentous were within normal limits (<11)., Conclusions: This study represents the first outcomes-based report of BMVFLs using a strictly defined nomenclature system for stratification of lesions. Ligamentous fibrous mass lesions have a decreased response to treatment compared to all other lesions. This study demonstrates the ability to return most BMVFL patients to normal speaking voice capabilities following treatment., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: 1) Present phonatory aerodynamic data for healthy controls (HCs) in connected speech; 2) contrast these findings between HCs and patients with nontreated unilateral vocal fold paralysis (UVFP); 3) present pre- and post-vocal fold augmentation outcomes for patients with UVFP; 4) contrast data from patients with post-operative laryngeal augmentation to HCs., Study Design: Retrospective, single-blinded., Methods: For phase I, 20 HC participants were recruited. For phase II, 20 patients with UVFP were age- and gender-matched to the 20 HC participants used in phase I. For phase III, 20 patients with UVFP represented a pre- and posttreatment cohort. For phase IV, 20 of the HC participants from phase I and 20 of the postoperative UVFP patients from phase III were used for direct comparison. Aerodynamic measures captured from a sample of the Rainbow Passage included: number of breaths, mean phonatory airflow rate, total duration of passage, inspiratory airflow duration, and expiratory airflow duration. The VHI-10 was also obtained pre- and postoperative laryngeal augmentation., Results: All phonatory aerodynamic measures were significantly increased in patients with preoperative UVFP than the HC group. Patients with laryngeal augmentation took significantly less breaths, had less mean phonatory airflow rate during voicing, and had shorter inspiratory airflow duration than the preoperative UVFP group. None of the postoperative measures returned to HC values. Significant improvement in the Voice Handicap Index-10 scores postlaryngeal augmentation was also found., Conclusions: Methodology described in this study improves upon existing aerodynamic voice assessment by capturing characteristics germane to UVFP patient complaints and measuring change before and after laryngeal augmentation in connected speech., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

This paper describes a method to estimate mechanical properties of soft, anisotropic materials from measurements of shear waves with specific polarization and propagation directions. This method is applicable to data from magnetic resonance elastography (MRE), which is a method for measuring shear waves in live subjects or in vitro samples. Here, we simulate MRE data using finite element analysis. A nearly incompressible, transversely isotropic (ITI) material model with three parameters (shear modulus, shear anisotropy, and tensile anisotropy) is used, which is appropriate for many fibrous, biological tissues. Both slow and fast shear waves travel concurrently through such a material with speeds that depend on the propagation direction relative to fiber orientation. A three-parameter estimation approach based on directional filtering and isolation of slow and fast shear wave components (directional filter inversion, or DFI) is introduced. Wave speeds of each isolated shear wave component are estimated using local frequency estimation (LFE), and material properties are calculated using weighted least squares. Data from multiple finite element simulations are used to assess the accuracy and reliability of DFI for estimation of anisotropic material parameters., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Exhumation of the southern Tibetan plateau margin reflects interplay between surface and lithospheric dynamics within the Himalaya-Tibet orogen. We report thermochronometric data from a 1.2-km elevation transect within granitoids of the eastern Lhasa terrane, southern Tibet, which indicate rapid exhumation exceeding 1 km/Ma from 17-16 to 12-11 Ma followed by very slow exhumation to the present. We hypothesize that these changes in exhumation occurred in response to changes in the loci and rate of rock uplift and the resulting southward shift of the main topographic and drainage divides from within the Lhasa terrane to their current positions within the Himalaya. At ∼17 Ma, steep erosive drainage networks would have flowed across the Himalaya and greater amounts of moisture would have advected into the Lhasa terrane to drive large-scale erosional exhumation. As convergence thickened and widened the Himalaya, the orographic barrier to precipitation in southern Tibet terrane would have strengthened. Previously documented midcrustal duplexing around 10 Ma generated a zone of high rock uplift within the Himalaya. We use numerical simulations as a conceptual tool to highlight how a zone of high rock uplift could have defeated transverse drainage networks, resulting in substantial drainage reorganization. When combined with a strengthening orographic barrier to precipitation, this drainage reorganization would have driven the sharp reduction in exhumation rate we observe in southern Tibet.

Objectives/hypothesis: This study investigated financial and treatment implications of a speech-language pathologist (SLP) performing a voice evaluation at the initial laryngologic visit., Study Design: Retrospective chart review., Methods: Medical records from 75 consecutive adult voice therapy patients during a 3-month period were categorized into two groups: group 1 (n = 37) represented patients who underwent a medical speech evaluation (MSE) at the initial voice assessment with the laryngologist (+SLP), and group 2 (n = 38) represented patients who did not receive an MSE (-SLP). Data collected included age, gender, voice diagnosis, number of therapy sessions attended and cancelled, reason for discharge, and pre- and post-voice therapy Voice Handicap Index-10 (VHI-10) scores., Results: Patients in the +SLP group had fewer cancellations (P = 0.001), greater change in VHI-10 from pre- to post-therapy (P = .001), and were more likely to be discharged from therapy having met therapeutic goals (P = .007) than patients in the -SLP group. In addition, lost revenue over 3 months due to cancellations/no-shows was $2,260 in the +SLP group compared to $7,030 in the -SLP group (P < .001)., Conclusions: Concurrent voice evaluation by an SLP and laryngologist at initial diagnostic visit affects therapy attendance, voice therapy outcomes, and ultimately SLP and departmental billing revenue. Results may be due to more appropriate therapy referrals from SLP assessment of patients in conjunction with a laryngologist., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Residency applicants commonly complete visiting student electives (VSEs) hoping to increase their odds of matching at host institutions. Existing evidence on Match outcomes for applicants who complete VSEs is limited. As VSEs involve monetary and opportunity costs to students and administrators, data on their utility are vital for student well-being, preparedness for residency, and, ultimately, success in the Match. We investigated the utilization and impact of VSEs for all applicants. We hypothesized that completion of VSEs would increase the likelihood of matching at a host institution., Materials and Methods: A retrospective review was conducted of academic records and National Resident Matching Program outcomes for the graduates of one institution and visiting students to that institution over the course of 7 y., Results: Utilization of VSEs varied significantly among specialties. Across all specialties and in general surgery, applicants were more likely to match into host programs than others. The size of the effect of VSEs on outcomes varied by specialty. Host programs were applicants' top choice for residency in 48% of cases., Conclusions: Completion of VSEs may give surgical applicants increased control over Match outcomes. Our findings may assist future students in strategic decision making when determining whether and where to use VSEs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders., (Published by Elsevier Inc.)

Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat's digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively. HEMEC and HIMEC were stimulated with TNF-α/IL-1β with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial cell-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways. BRE inhibited TNF-α/IL-1β-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations. BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1β activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Endothelial-mesenchymal transition (EndoMT) has been recognized as a key determinant of tumor microenvironment in cancer progression and metastasis. Endothelial cells undergoing EndoMT lose their endothelial markers, acquire the mesenchymal phenotype, and become more invasive with increased migratory abilities. Early stages of esophageal adenocarcinoma (EAC) are characterized by strong microvasculature whose impact in tumor progression remains undefined. Our aim was to determine the role of EndoMT in EAC by investigating the impact of tumor cells on normal primary human esophageal microvascular endothelial cells (HEMEC). HEMEC were either cocultured with OE33 adenocarcinoma cells or treated with IL-1β and transforming growth factor-β2 (TGF-β2) for indicated periods and analyzed for EndoMT-associated changes by real-time PCR, Western blotting, immunofluorescence staining, and functional assays. Additionally, human EAC tissues were investigated for detection of EndoMT-like cells. Our results demonstrate an increased expression of mesenchymal markers [fibroblast-specific protein 1 (FSP1), collagen1α2, vimentin, α-smooth muscle actin (α-SMA), and Snail], decreased expression of endothelial markers [CD31, von Willebrand factor VIII (vWF), and VE-cadherin], and elevated migration ability in HEMEC following coculture with OE33 cells. The EndoMT-related changes were inhibited by IL-1β and TGF-β2 gene silencing in OE33 cells. Recombinant IL-1β and TGF-β2 induced EndoMT in HEMEC. Although the level of VEGF expression was elevated in EndoMT cells, the angiogenic property of these cells was diminished. In vivo, by immunostaining EndoMT-like cells were detected at the invasive front of EAC. Our findings underscore a significant role for EndoMT in EAC and provide new insights into the mechanisms and significance of EndoMT in the context of tumor progression., (Copyright © 2014 the American Physiological Society.)

Objectives: To (1) develop and validate the Dyspnea Index (DI); (2) quantify severity of symptoms in upper airway dyspnea; and (3) validate the DI as an outcome measure., Study Design: Survey development and validation., Methods: Three hundred sixty-nine participants were recruited for different phases of the study. Two hundred participants with chief complaints of dyspnea were given a 41-item questionnaire addressing common symptoms of dyspnea related to the upper airway. The questions were then reduced based on principal component analysis (PCA) and internal consistency resulting in a 10-item questionnaire. Cognitive interviews were conducted with 15 participants. Test-retest reliability and discriminant validity were measured from 51 participants. The DI was further validated by administering the index to 57 healthy controls (HC). Validation of the DI as a treatment outcome tool occurred with 46 participants' pre- and post-treatment scores., Results: PCA revealed that only a single factor was being measured in both the original 41- and 10-item questionnaires. Additional cognitive interviewing suggested that no modification was needed to the DI. Test-retest reliability was r = 0.83. Discriminant validity was r = 0.62. The Mann-Whitney test demonstrated significant differences between healthy/symptomatic participants. Scores from the HC cohort resulted in a mean of 3.12 (SEM = 0.484; SD = 3.65) for the normative values., Conclusions: The DI is an effective and efficient instrument to quantify patients' symptoms of upper airway dyspnea. It is a statistically robust index, with significant reliability and validity, and can be dependably used as a treatment outcome measure., (Copyright © 2014 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)