214 research outputs found

    Common Practices of Australian Speech-Language Pathologists in the Management of Paediatric Vocal Health

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    Speech-Language Pathology Session IBConference Theme: Care of the Professional VoiceObjective: This study aimed to determine the common approaches taken by Australian speech language pathologists (SLPs) in the management of paediatric voice caseloads. Methods & Results: Forty-eight Australian SLPs with a current paediatric voice caseload completed an online questionnaire containing 38-items related to assessment, treatment and discharge procedures used in managing a paediatric voice caseload. Paediatric voice comprised between 1-100% of the respondents’ caseloads (M = 8.27%, SD = 17.71). Eight respondents (16.6%) considered themselves to be a voice specialist. Perceptual ratings of voice disorders were used more frequently than instrumental assessment tools throughout the management process. Respondents considered instrumental assessment by an Ear Nose and Throat (ENT) specialist to be important however reported barriers related to ENT service constraints (e.g., ENT availability and long waiting lists) and the associated cost to the client. A range of direct and indirect voice therapy approaches (often in combination) were employed by the respondents, usually determined by client specific factors. Respondents reported that it was more common for patients to be formally discharged (M= 42.32%; SD=41.1) than to self-discharge (M=24.71%; SD=31.78). The most commonly used outcome measures were clinician judgement, pre/post voice recording comparison, and review of results from a follow-up ENT assessment. Quality of life scales were rarely used as outcome measures. The majority of clinicians (56.25%, n = 27/48) indicated that they did not feel confident when managing children with voice disorders, and would welcome further training in the area. Conclusion: This investigation captured current practice of Australian SLPs managing paediatric voice caseloads. This data allows for comparison with management approaches in other countries. The findings highlight a need for further training in this area, particularly to enhance translation of recent research evidence into clinical practice.published_or_final_versio

    Multiple Quantum Well Structures As Optical Waveguides

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    This thesis is concerned with the design, fabrication and characterisation of semiconductor optical waveguides in which the high index guiding layer is a multiple quantum well structure (MQWS), consisting of alternate layers of high and low band gap semiconductors with the electrons and holes in the MQWS being confined to the low band gap material. This confinement in two dimensions alters greatly the electronic and optical properties of the MQWS in comparison to the bulk properties of the constituent layers. The basic concepts involved in MQW waveguides are introduced using an elementary quantum mechanical analysis of quantum wells together with a brief description of the properties of dielectric waveguides, A more detailed treatment of the electronic and optical properties of MQWS and a review of published experimental work is used to show that the fundamental absorption edge is much more abrupt than that in the corresponding bulk material with strong excitonic characteristics being evident even at room temperature. In addition, the absorption edge is seen to be anisotropic with the fundamental energy gap being larger for light polarised perpendicular to the MQW layers. This anisotropic absorption edge, together with the layered dielectric nature of MQWS, makes them birefringent with a smaller refractive index for light polarised perpendicular to the MQW layers. The quantum confinement of carriers in MQWS also enhances their electroabsorption and electro-optic properties through the quantum confined Stark effect. Standard techniques used in the design, fabrication and analysis of bulk semiconductor waveguides are developed for application to MQW waveguides. These include analytical and numerical techniques for the design of dielectric waveguides; dry etching and metallisation processes for the fabrication of devices; and a laser/optics system to analyse the waveguide devices. To verify these techniques they are first applied to the well-understood case of n/n+ GaAs waveguides and are used to successfully fabricate and analyse single-mode, passive, rib waveguides at l=1.15mum. The electro-optic coefficient is also measured in an active, planar n/n+ waveguide and found to be close to that reported by other workers. The design techniques are then applied to MOWS waveguides resulting in the design of a MQW double heterostructure (MQW-DH), p-i-n diode which was predicted to produce the required Quantum properties (strong, room temperature, excitonic behaviour), waveguide properties (single-mode propagation up to the fundamental absorption edge) and electronic properties (a high reverse bias breakdown voltage and uniform applied electric field). Most of the theoretical work and all the experimental work included is devoted to MQWS in the (Al,Ga)As, III-V semiconductor alloy system. Accordingly, the methods available for growing MQWS in this system are reviewed with Molecular Beam Epitaxy (MBE) being found the most likely method to satisfactorily reproduce the desired structure. MQW-DH were grown at two establishments and are initially studied by photoluminescence and scanning electron microscopy before their planar optical waveguide characteristics are checked using the laser system. Only one sample is found to satisfy all the design requirements, and then only partially. Detailed analysis of the properties of MQW waveguides is therefore limited to this structure. Passive MQW-DH waveguides are demonstrated to exhibit an anisotropic absorption edge as predicted, and it is shown that the design and fabrication techniques developed can be successfully used to obtain single, double and multi-mode strip loaded waveguides. Single-mode waveguides are also used to fabricate passive directional couplers with coupling lengths in good agreement with theoretically predicted values. A semi-empirical model is put forward to describe the band edge electro-absorption of MQWS. Although simple, the model is in qualitative and approximate quantitative agreement with published results. (Abstract shortened by ProQuest.)

    WTO accession, the changing competitiveness of foreign-financed firms and regional development in Guangdong of southern China

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    This paper investigates the changing competitiveness of foreign-financed manufacturing firms and its implications for regional development in Guangdong province of southern China in the run-up to World Trade Organization (WTO) accession. It is argued that transnational corporations (TNCs) and some competitive, large-scale, locally-funded firms in Guangdong will triumph after WTO accession. The crowding-out process of small and medium sized enterprises (SMEs) in Guangdong will be accelerated in the near future, as they are competing directly with TNCs, and as their competitive advantages are diminishing, due to bureaucratic red tape and the rigorous enforcement of new government policies. Due to close business linkages with local privately-funded firms, the competitiveness and vitality of foreign-financed enterprises will have profound long term effects on the economic development of Guangdong, before and after WTO accession

    Negative phenotypic and genetic associations between copulation duration and longevity in male seed beetles

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    Reproduction can be costly and is predicted to trade-off against other characters. However, while these trade-offs are well documented for females, there has been less focus on aspects of male reproduction. Furthermore, those studies that have looked at males typically only investigate phenotypic associations, with the underlying genetics often ignored. Here, we report on phenotypic and genetic trade-offs in male reproductive effort in the seed beetle, Callosobruchus maculatus. We find that the duration of a male's first copulation is negatively associated with subsequent male survival, phenotypically and genetically. Our results are consistent with life-history theory and suggest that like females, males trade-off reproductive effort against longevity

    Participant retention in follow-up studies of prematurely born children.

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    BACKGROUND: Follow-up studies of infants born prematurely are essential to understand the long-term consequences of preterm birth and the efficacy of interventions delivered in the neonatal period. Retention of participants for follow-up studies, however, is challenging, with attrition rates of up to 70%. Our aim was to examine retention rates in two follow-up studies of prematurely born children and identify participant or study characteristics that were associated with higher attrition, and to discuss retention strategies with regard to the literature. METHODS: Data from children recruited at birth to one of two studies of prematurely born infants were assessed. The two studies were the United Kingdom Oscillation Study (UKOS, a randomised study comparing two modes of neonatal ventilation in infants born less than 29 weeks of gestational age (GA)), and an observational study examining the impact of viral lower respiratory tract infections in infancy in those born less than 36 weeks of GA (virus study). The UKOS participants, but not those in the virus study, had regularly been contacted throughout the follow-up period. UKOS subjects were followed up at 11 to 14 years of age and subjects in the virus study at 5-7 years of age. At follow up in both studies, pulmonary function and respiratory morbidity were assessed. Retention rates to follow-up in the two studies and baseline characteristics of those who were and were not retained were assessed. RESULTS: Retention was significantly higher in UKOS than the virus study (61% versus 35%, p < 0.0001). Subjects lost to UKOS follow up had greater deprivation scores (p < 0.001), a greater likelihood of intrauterine tobacco exposure (p = 0.001) and were more likely to be of non-white ethnicity (p < 0.001). In the virus study, those lost to follow-up had higher birth weights (p = 0.036) and were less likely to be oxygen dependent at hospital discharge (p = 0.003) or be part of a multiple birth (p = 0.048). CONCLUSIONS: Higher retention was demonstrated when there was regular contact in the follow-up period. Both social factors and initial illness severity affected the retention into follow-up studies of prematurely born infants, though these factors were not consistent across the two studies

    The Roles of Guanine Nucleotide Binding Proteins in Health and Disease

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    G-proteins are important mediators of cellular and tissue functions and are characterised by a recognition site for Guanine Triphosphate (GTP), Guanine Diphosphate (GDP) and possess intrinsic GTPase activity. They play important roles in signal transduction responsible for cytoskeletal remodelling, cellular differentiation and vesicular transport. They are made up of three types namely, the small G-proteins, the sensors and the heterotrimeric G-proteins. The G-protein heterotrimers consist of G-alpha (G), G-beta (G)andGgamma(G()subunits.EachheterotrimericGproteinhavedifferentsubunitsandthecombinationofthesesubunitsdefinethespecificroleofeachGprotein.TheactivationofGsubunitsregulatestheactivityofeffectorenzymesandionchannelswhileG) and G-gamma (G() subunits. Each heterotrimeric G-protein have different subunits and the combination of these subunits define the specific role of each G-protein. The activation of G subunits regulates the activity of effector enzymes and ion channels while G( subunits function in the regulation of mitogen-activated protein kinase (MAP-kinase) pathway. The G-protein-mediated signal transduction is important in the regulation of a cells morphological and physiological response to external stimuli. MAPKs are involved in the phosphorylation of transcription factors that stimulate gene transcription. Gs stimulates adenylate cyclase, thereby increasing cyclic adenosine monophosphate (cAMP) leading to the phosphorylation and subsequent activation of Ca_+ channels. G proteins are involved in disease pathology through several mechanisms which interfere with the G protein activity. Other disease pathologies associated with abnormal mutations in G proteins can interfere with signal transduction pathways which may involve signal transmission that is either excessive, by augmentation of G protein function, or insufficient, via inactivation of G proteins.sch_dieBenians, A., M. Nobles, S. Hosny and A. Tinker, 2005. Regulators of G-protein signalling form a quaternary complex with the agonist, receptor, and G-protein. A novel explanation for the acceleration of signalling activation kinetics. J. Biol. Chem., 280(14): 13383-13394. Berman, D.M. and A.G. Gilman, 1998. Mammalian RGS proteins: barbarians at the gate. J Biol. Chem., 273(3): 1269-1272. Berridge, M.J., 2006. Cell Signalling Biology. Portland Press Ltd. Retrieved from: www.cellsignalling biology.org. Berridge, M.J., M.D. Bootman and H.L. Roderick, 2003. Calcium signalling: Dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell Biol., 4(7): 517-529. Blackmer, T., E.C. Larsen, M. Takahashi, T.F.J. Martin, S. Alford and H.E. Hamm, 2001. G protein ( subunit-mediated presynaptic inhibition: Regulation of exocytotic fusion downstream of Ca2+ entry. Science, 292(5515): 293-297. Blaukat, A., A. Barac, M.J. Cross, S. Offermanns and I. Dikic, 2000. G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of Galpha(q) and Galpha(i) signals. Mol Cell Biol., 20(18): 6837-6848 Burgoyne, R.D., 2007. Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling. Nat. Rev. Neurosci., 8: 182-193. Cabrera-Vera, T.M., J. Vanhauwe, T.O. Thomas, M. Medkova, A. Preininger, M.R. Mazzoni and H.E. Hamm, 2003. Insights into G protein structure, function, and regulation. Endocr Rev., 24(6): 765-781. Clapham, D.E., 1996. Intracellular signalling: More jobs for G beta gamma. Curr. Biol., 6(7): 814-816. Danner, S. and M.J. Lohse, 1996. Phosducin is a ubiquitous G-protein regulator. Proc. Natl. Acad. Sci. U.S.A., 93(19): 10145-10150. Dhanasekaran, N. and M.V. Prasad, 1998. G protein subunits and cell proliferation. Biol Signals Recept., 7(2): 109-117. Dignard, D., D. Andr and M. Whiteway, 2008. Heterotrimeric G protein subunit function in Candida albicans: both the {} and {} subunits of the pheromone response G protein are required for mating. Eukaryot Cell, 7(9): 1591-1599. Dohlman, H.G. and J. Thorner, 1997. RGS proteins and signaling by heterotrimeric G proteins. J Biol Chem., 272(7): 3871-3874. Dolphin, A.C., 1990. G protein modulation of calcium currents in neurons. Ann. Rev. Physiol., 52: 243-255. Dolphin, A.C., 1996. Facilitation of Ca2+ current in excitable cells. Trends Neurosci., 19(1): 35-43. Durchnkov, D., J. Novotn_ and P. Svoboda, 2008. The time-course of agonist-induced solubilization of trimeric G(q)/G(11) proteins resolved by twodimensional electrophoresis. Physiol Res., 57(2): 195-203. Farfel, Z., H.R. Bourne and T. Iiri, 1999. The expanding spectrum of G protein diseases.N. Engl. J. Med., 340(13): 1012-1020. Flavahan, N.A. and P.M. Vanhoutte, 1990. G-proteins and endothelial responses. Blood Vessels, 27(2-5): 218-229. Fromm, C., O.A. Coso, S. Montaner, N. Xu and J.S. Gutkind, 1997. The small GTP-binding protein Rho links G protein-coupled receptors and Galpha12 to the serum response element and to cellular transformation. Proc. Natl. Acad. Sci. USA, 94(19): 10098-10103. Hamm, H.E. and A. Gilchrist, 1996. Heterotrimeric G proteins. Curr. Opin. Cell Biol., 8(2): 189-196. Hepler, J.R. and A.G. Gilman, 1992. G proteins. Trend. Biochem. Sci., 17(10): 383-387. Howe, L.R. and C.J. Marshall, 1993. Lysophosphatidic acid stimulates mitogen-activated protein kinase activation via a G-protein-coupled pathway requiring p21ras and p74raf-1. J. Biol. Chem., 268(28): 20717-20720. Jiang, M., M.S. Gold, G. Boulay, K. Spicher, M. Peyton, P. Brabet, Y. Srinivasan, U. Rudolph, G. Ellison and L. Birnbaumer, 1998. Multiple neurological abnormalities in mice deficient in the G protein Go. Proc. Natl. Acad. Sci. USA, 95(6): 3269-3274. Kaziro, Y., H. Itoh, T. Kozasa, M. Nakafuku and T. Satoh, 1991. Structure and function of signaltransducing GTP-binding proteins. Annu. Rev. Biochem., 60: 349-400. Kitanaka, N., J. Kitanaka, F.S. Hall, T. Tatsuta, Y. Morita, M. Takemura, X.B. Wang and G.R. Uhl, 2008. Alterations in the levels of heterotrimeric G protein subunits induced by psychostimulants, opiates, barbiturates, and ethanol: Implications for drug dependence, tolerance, and withdrawal. Synapse, 62(9): 689-699. Kolch, W., G. Heidecker, G. Kochs, R. Hummel, H. Vahidi, H. Mischak, G. Finkenzeller, D. Marme and U.R. Rapp, 1993. Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature, 364(6434): 249-252. Levitzki, A., 1990. GTP-GDP exchange proteins. Science, 248(4957): 794. Lorenz, S., R. Frenzel, R. Paschke, G.E. Breitwieser and S.U. Miedlich, 2007. Functional desensitization of the extracellular calcium-sensing receptor is regulated via distinct mechanisms: Role of G proteincoupled receptor kinases, protein kinase C and {$}- arrestins. Endocrinology, 148(5): 2398-2404. Lowes, V.L., N.Y. Ip and Y.H. Wong, 2002. Integration of signals from receptor tyrosine kinases and g protein-coupled receptors. Neurosignals, 11(1): 5-19. Luttrell, L.M., Y. Daaka, G.J. Della Rocca and R.J. Lefkowitz, 1997. G protein-coupled receptors mediate two functionally distinct pathways of tyrosine phosphorylation in rat 1a fibroblasts. Shc phosphorylation and receptor endocytosis correlate with activation of ERK kinases. J. Biol. Chem., 272(50): 31648-31656. Milligan, G., D.A. Groarke, A. McLean, R. Ward, C.W. Fong, A. Cavalli and T. Drmota, 1999. Diversity in the signalling and regulation of Gprotein- coupled receptors. Biochem. Soc. Trans., 27(2): 149-154. Milligan, G., I. Mullaney and F.R. McKenzie, 1990. Specificity of interactions of receptors and effectors with GTP-binding proteins in native membranes. Biochem. Soc Symp., 56: 21-34. Morris, A.J. and C.C. Malbon, 2000. Physiological regulation of G protein-linked signalling. Physiol. Rev., 79(4): 1373-1430. Mullaney, I., 1999. Signal transduction: A practical approach. Milligan G., 5: 73-90. Muller, S. and M.J. Lohse, 1995. The role of G-protein beta gamma subunits in signal transduction. Biochem. Soc. Trans., 23(1): 141-148. Murray, A.J. and D.A. Shewan, 2008. Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration. Mol. Cell Neurosci., 38(4): 578-588. Neer, E.J., 1995. Heterotrimeric G proteins: organizers of transmembrane signals. Cell, 80(2): 249-257. Novotny, J. and P. Svoboda, 1998. The long (Gs()-L) and short (Gs()-S) variants of the stimulatory guanine nucleotide-binding protein. Do they behave in an identical way? J. Mol. Endocrinol., 20(2): 163-173. Nunn, C., H. Mao, P. Chidiac and P.R. Albert, 2006. RGS17/RGSZ2 and the RZ/A family of regulators of G-protein signaling. Semin Cell Dev. Biol., 17(3): 390-399. Ohkubo, S. and N. Nakahata, 2007. Role of lipid rafts in trimeric G protein-mediated signal transduction. Yakugaku Zasshi, 127(1): 27-40. Oldham, W.M. and H.E. Hamm, 2006. Structural basis of function in heterotrimeric G proteins. Q. Rev. Biophys., 39(2): 117-166. Schneider, T., P. Igelmund and J. Hescheler, 1997. G protein interaction with K+ and Ca2+ channels. Trend. Pharmacol. Sci., 18(1): 8-11. Schrder, S. and M.J. Lohse, 1996. Inhibition of Gprotein betagamma-subunit functions by phosducinlike protein. Proc. Natl. Acad. Sci. USA, 93(5): 2100- 2104. Siegel, G.J., B.W. Agranoff, R.W. Albers, S.K. Fisher and M.D. Uhler, 1999. Basic Neurochemistry; Molecular, Cellular and Medical Aspects. 6th Edn., Lippincott Williams and Wilkins, Philadelphia, pp: 1023-1120. Siegel, G.J., R.W. Albers, S.T. Brady and D.L. Price, 2006. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 7th Edn., Elsevier Academic Press, San Diego, pp: 339-346. Slessareva, J.E., H. Ma, K.M. Depree, L.A. Flood, H. Bae, T.M. Cabrera-Vera, H.E. Hamm and S.G. Graber 2003. Closely related G-protein-coupled receptors use multiple and distinct domains on Gprotein alpha-subunits for selective coupling. J. Biol. Chem., 278(50): 50530-50536. Sprang, S.R., 1997. G proteins, effectors and GAPs: structure and mechanism.Curr. Opin. Struct. Biol., 7(6): 849-856. Straiker, A.J., C.R. Borden and J.M. Sullivan, 2002. GProtein subunit isoforms couple differentially to receptors that mediate presynaptic inhibition at rat hippocampal synapses. J. Neurosci., 22(7): 2460-2468. Wang, L., 1999. Multi-associative neural networks and their applications to learning and retrieving complex spatio-temporal sequences. IEEE Trans. Syst. Man. Cybern B Cybern, 29(1): 73-82. Walter, L. and N. Stella, 2004. Cannabinoids and neuroinflammation. Br. J. Pharmcl., 141(5): 775-785. Walter, L., A. Franklin, A. Witting, C. Wade, Y. Xie, G. Kunos, K. Mackie and N. Stella, 2003. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. Neurosci., 23(4): 1398-1405. Wettschureck, N. and S. Offermanns, 2005. Mammalian G proteins and their cell type specific functions. Physiol. Rev., 85(4): 1159-1204. Wickman, K.D. and D.E. Clapham, 1995. G-protein regulation of ion channels. Curr. Opin. Neurobiol., 5(3): 278-285. Xie, G.X. and PP. Palmer 2007. How regulators of G protein signaling achieve selective regulation. J. Mol. Biol., 366(2): 349-365. Zhong, M., M. Yang and BM. Sanborn, 2003. Extracellular signal-regulated kinase 1/2 activation by myometrial oxytocin receptor involves Galpha(q)Gbetagamma and epidermal growth factor receptor tyrosine kinase activation. Endocrinology, 144(7): 2947-2956.2pub2712pub

    Improving Estimates of Gross Primary Productivity by Assimilating Solar-Induced Fluorescence Satellite Retrievals in a Terrestrial Biosphere Model Using a Process-Based SIF Model

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    Abstract Over the last few years, solar-induced chlorophyll fluorescence (SIF) observations from space have emerged as a promising resource for evaluating the spatio-temporal distribution of gross primary productivity (GPP) simulated by global terrestrial biosphere models. SIF can be used to improve GPP simulations by optimizing critical model parameters through statistical Bayesian data assimilation techniques. A prerequisite is the availability of a functional link between GPP and SIF in terrestrial biosphere models. Here we present the development of a mechanistic SIF observation operator in the ORCHIDEE (Organizing Carbon and Hydrology In Dynamic Ecosystems) terrestrial biosphere model. It simulates the regulation of photosystem II fluorescence quantum yield at the leaf level thanks to a novel parameterization of non-photochemical quenching as a function of temperature, photosynthetically active radiation, and normalized quantum yield of photochemistry. It emulates the radiative transfer of chlorophyll fluorescence to the top of the canopy using a parametric simplification of the SCOPE (Soil Canopy Observation Photosynthesis Energy) model. We assimilate two years of monthly OCO-2 (Orbiting Carbon Observatory-2) SIF product at 0.5° (2015?2016) to optimize ORCHIDEE photosynthesis and phenological parameters over an ensemble of grid points for all plant functional types. The impact on the simulated GPP is considerable with a large decrease of the global scale budget by 28 GtC/year over the period 1990?2009. The optimized GPP budget (134/136 GtC/year over 1990?2009/2001?2009) remarkably agrees with independent GPP estimates, FLUXSAT (137 GtC/year over 2001?2009) in particular and FLUXCOM (121 GtC/year over 1990?2009). Our results also suggest a biome dependency of the SIF-GPP relationship that needs to be improved for some plant functional types.Peer reviewe

    The validity and reliability of the Breathing Vigilance Questionnaire (Breathe-VQ)

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    Presented at: British Thoracic Society Winter Meeting 2022, QEII Centre, Broad Sanctuary, Westminster, London SW1P 3EE. Part of the stream: ‘Chariots of fire’ – Interventions and assessment in respiratory physiotherapy.Copyright © Author(s) (or their employer(s)) 2022. Introduction and Objectives: Dysfunctional breathing (DB) is common among people with and without primary respiratory pathology. While anxiety is known to contribute to DB, the underpinning mechanisms are unclear. One likely explanation is that anxiety induces excessive conscious monitoring of breathing, which disrupts ‘automatic’ breathing mechanics. We aimed to validate a new patient-reported outcome measure that allows quantification of such breathing-related ‘hypervigilance’: the Breathing Vigilance Questionnaire (Breathe-VQ). Methods: Three-hundred-and-forty healthy adults (Mean age =27.3 years, range: 18–71; 161 men) were recruited online. The initial Breathe-VQ (11 items, 1–5 Likert scale) was adapted from the Pain Vigilance and Awareness Scale based on feedback from people with and without DB, and expert clinicians and researchers. At baseline all participants completed the Breathe-VQ, background questions, Nijmegen Questionnaire (NQ), Movement Specific Reinvestment Scale and State-Trait Anxiety Inventory (form 2). To assess test-retest reliability, two weeks later 83 people completed the Breathe-VQ again. Validation involved screening of individual items’ behaviour and factor analyses, after which we estimated (retest-)reliability, measurement error, and concurrent/discriminant validity of the finalised Breathe-VQ scale. Results: We removed five items based on item-level and factor analyses. The final six-item Breathe-VQ questionnaire (score range: 6–30) showed excellent internal consistency (ICC=.810) and test-retest reliability (alpha=.892). Minimal detectable change was 6.5 on an individual level, and there were no floor or ceiling effects. Concurrent validity was excellent with significant moderate correlations with measures of general trait anxiety(r’s=.35-.46). Participants at high-risk of having DB (NQ>23; N=76) had significantly higher total scores on the Breathe-VQ (M=19.1, SD=5.4) than low-risk peers (N=225; M=13.8, SD=5.0) p<.001. Further, within this ‘high-risk’ group, Breathe-VQ scores were significantly associated with NQ-scores. Figure 1 shows the final validated Breathe-VQ. Conclusion: The Breathe-VQ is a valid and reliable tool to measure vigilance of breathing. Our data suggest that breathing vigilance may be a contributing factor in DB, and could represent a therapeutic target. Further research is now warranted using the Breathe-VQ in clinical populations of individuals with DB, chronic respiratory disease and COVID-19. Further research could assess the effects of breathing re-training, pulmonary rehabilitation and arts-in-health interventions on vigilance of breathing

    Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial

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    Background: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. Methods: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. Findings: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0–30·9; range 9·5–49·7) in the lower dose cohort, 31·1 months (16·0–64·7; 6·8–72·7) in the higher dose cohort, and 18·7 months (10·1–31·5; 5·9–39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0–49·5; range 2·1–54·7) for lower dose participants, 27·6 months (24·6–29·1; 3·4–41·0) for higher dose participants, and 28·3 months (9·7–46·9; 5·7–32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). Interpretation: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. Funding: Astellas Gene Therapies

    Gene therapy for children with X-linked myotubular myopathy: a plain language summary of publication for the ASPIRO study

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    What is this summary about? This summary describes the results of a research study (clinical trial) called ASPIRO that was published in the Lancet Neurology in 2023. This study looked at an investigational gene therapy called resamirigene bilparvovec (also known as AT132) as a possible treatment for children with a disease called X-linked myotubular myopathy (abbreviated as XLMTM)
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