No Space to Sing: A Narrative Inquiry into the Experiences of Classical Singers with Primary Muscle Tension Dysphonia

This study was designed as a qualitative narrative inquiry study into the experiences of classical singers with Primary Muscle Tension Dysphonia (PMTD). PMTD is defined as Muscle Tension Dysphonia (MTD) without organic or neurological factors. In the population of professional voice users, PMTD is typically associated with occupational/behavioural causes. A review of the literature shows that occupational disorders are associated with stigma in the classical music community, that research on PMTD in the demographic of singers is sparse and often broadly defined, and that PMTD is not well-represented in the vocal pedagogy literature. Additionally, PMTD may present differently in classical singers than in other populations of singers, or in the general population. The gap in the vocal pedagogy literature, and the stigma present could contribute to students developing PMTD and could cause delayed diagnosis for singers. Further, living with undiagnosed PMTD could have a grave impact on the ability to sing and on mental health. Narrative inquiry was chosen as the most appropriate qualitative approach for an early study in this population. Eleven adult classical singers with PMTD diagnoses – in career stages from still undergoing undergraduate training to the midst of major international careers – were interviewed regarding their experiences prior to diagnosis, during treatment, and post-recovery. These interviews pursued a dual purpose: to discover emergent themes relating to PMTD in this population, and to create a space for voices to be heard that may have previously been rendered voiceless both by the disorder and the classical singing community. The many themes that emerged across participant experiences fell into mainly medical and vocal pedagogy categories. Without fail, participants were severely impacted by the disorder, often by stigma and isolation, and in a few cases by medical mismanagement. Both institutional factors, and specific voice technique elements (such as registration), in the current vocal pedagogy paradigm appeared to be causal factors in this demographic

Atypical prediction error learning is associated with prodromal symptoms in individuals at clinical high risk for psychosis

Reductions in the auditory mismatch negativity (MMN) have been well-demonstrated in schizophrenia rendering it a promising biomarker for understanding the emergence of psychosis. According to the predictive coding theory of psychosis, MMN impairments may reflect disturbances in hierarchical information processing driven by maladaptive precision-weighted prediction errors (pwPEs) and enhanced belief updating. We applied a hierarchical Bayesian model of learning to single-trial EEG data from an auditory oddball paradigm in 31 help-seeking antipsychotic-naive high-risk individuals and 23 healthy controls to understand the computational mechanisms underlying the auditory MMN. We found that low-level sensory and high-level volatility pwPE expression correlated with EEG amplitudes, coinciding with the timing of the MMN. Furthermore, we found that prodromal positive symptom severity was associated with increased expression of sensory pwPEs and higher-level belief uncertainty. Our findings provide support for the role of pwPEs in auditory MMN generation, and suggest that increased sensory pwPEs driven by changes in belief uncertainty may render the environment seemingly unpredictable. This may predispose high-risk individuals to delusion-like ideation to explain this experience. These results highlight the value of computational models for understanding the pathophysiological mechanisms of psychosis

Familial ALS-Associated Mutations Decrease the Thermal Stability of Distinctly Metallated Species of Human Copper/Zinc Superoxide Dismutase

We report the thermal stability of wild type (WT) and 14 different variants of human copper/zinc superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis (FALS). Multiple endothermic unfolding transitions were observed by differential scanning calorimetry for partially metallated SOD1 enzymes isolated from a baculovirus system. We correlated the metal ion contents of SOD1 variants with the occurrence of distinct melting transitions. Altered thermal stability upon reduction of copper with dithionite identified transitions resulting from the unfolding of copper-containing SOD1 species. We demonstrated that copper or zinc binding to a subset of “WT-like” FALS mutants (A4V, L38V, G41S, G72S, D76Y, D90A, G93A, and E133Δ) conferred a similar degree of incremental stabilization as did metal ion binding to WT SOD1. However, these mutants were all destabilized by ∼1–6 °C compared with the corresponding WT SOD1 species. Most of the “metal binding region” FALS mutants (H46R, G85R, D124V, D125H, and S134N) exhibited transitions that probably resulted from unfolding of metal-free species at ∼4–12 °C below the observed melting of the least stable WT species. We conclude that decreased conformational stability shared by all of these mutant SOD1s may contribute to SOD1 toxicity in FALS

Hyperthermia, radiation and chemotherapy: the role of heat in multidisciplinary cancer care.

The compelling biologic basis for combining hyperthermia with modern cancer therapies including radiation and chemotherapy was first appreciated nearly half a century ago. Hyperthermia complements radiation as conditions contributing to radio-resistance generally enhance sensitivity to heat and sensitizing effects occur through increased perfusion/tumor oxygenation and alteration of cellular death pathways. Chemosensitization with hyperthermia is dependent on the particular mechanism of effect for each agent with synergistic effects noted for several commonly used agents. Clinically, randomized trials have demonstrated benefit including survival with the addition of hyperthermia to radiation or chemotherapy in treatment of a wide range of malignancies. Improvements in treatment delivery techniques, streamlined logistics, and greater understanding of the relationship of thermal dosimetry to treatment outcomes continue to facilitate wider clinical implementation. Evolving applications include thermal enhancement of immunotherapy, targeted drug delivery and application of principals of thermal biology towards integration of thermal ablation into multimodality oncologic care

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution