Core outcome set for gene therapy in haemophilia: Results of the coreHEM multistakeholder project.

BACKGROUND: Gene therapy trial results show potential to cure haemophilia A and haemophilia B. Securing broad access to a cure for a lifelong chronic disease is anticipated to face barriers at the individual and healthcare system levels, which can be partly mitigated by harmonized planning of clinical research studies. The aim of the coreHEM project was to determine the set of outcome measures required to evaluate efficacy, safety, comparative effectiveness and value of gene therapy for haemophilia. METHODS: Modified Delphi consensus process, based on methods adapted from the COMET Initiative. RESULTS: Forty-nine participants (five patients, five clinicians, five researchers, four regulators, three research agencies, six health technology assessors, nine payers and 12 drug developers) took part in the study, with over 90% participation. The frequency of bleeds, factor activity level, duration of expression, chronic pain, healthcare resource use and mental health were identified as the core outcomes to be measured in addition to regulatory-mandated adverse effects. CONCLUSIONS: For the first time in haemophilia, a core outcome set has been developed, with the involvement of representatives of all relevant stakeholder groups. The core set has been expanded to include outcomes supporting assessment of comparative effectiveness and value, with the goal of streamlining regulatory approval, health technology assessment and market access decisions. Patient involvement ensures that outcomes are meaningful and relevant to those living with haemophilia. Active dialogue among drug developers, regulators and payers throughout the process is expected to facilitate broad uptake of the core outcomes in forthcoming clinical trials.

Development of a new system for guidewire-assisted tracheal intubation: manikin and cadaver evaluation.

Guided intubation using a tracheal tube and semi-rigid introducer is associated with technical difficulties, failure and traumatic complications. We describe the development of a new system of guidewire-assisted tracheal intubation that may circumvent these problems. A reinforced silicone tracheal tube was modified with a guide channel built inside its wall, and a nitinol non-kinking guidewire was matched to this channel. Both anterograde and retrograde tracheal intubation were evaluated in a test rig, an airway manikin and then in preserved and fresh cadavers. There was minimal resistance to passage of the guidewire through the guide channel when the modified tube was in an anatomical configuration, in contrast to moderate resistance when an Airway Exchange Catheter was passed through a PVC tracheal tube. Intubation using the new equipment required increased force in the manikin and preserved cadavers, but minimal force in fresh cadavers. Resistance to tracheal tube advancement in preserved cadavers was overcome by withdrawal followed by 90° rotation, but this manoeuvre was not required in fresh cadavers. We suggest that the combination of the modified tracheal tube and matching guidewire may allow easy and reliable single-step guided tracheal intubation when used in patients.

Building our global family--achieving treatment for all.

SUMMARY: Building our global family by reaching out to women, children and youth and those in sub-Saharan Africa to achieve Treatment for All. The World Federation of Hemophilia (WFH) has committed to recognizing and incorporating the critical and important challenges that are faced by women with bleeding disorders within our global family. The next crucial steps include the development of outreach and registry programmes which can be adapted globally to accelerate the identification of such women, and to educate and guide them to the appropriate clinical care setting. Equally important, awareness must be raised within the broader medical community where women would typically first present with clinical symptoms. Family practitioners, nurse-midwives, obstetricians, gynaecologists and community health clinics will increasingly be strategic and central to WFH outreach efforts, in addition to serving as new care partners essential to the multidisciplinary model of care. Adapting and implementing the WFH development model regionally within Africa is proving to be a successful approach both for the introduction as well as the development of sustainable national care programmes for patients with bleeding disorders. The targeted development of solid national programmes such as in South Africa, Senegal and Kenya has expanded the training capacity of the WFH, as well as providing key regional examples. Local medical professionals are now responsible for providing the training in many regional programmes. Children with bleeding disorders in low-income countries are at great risk of dying young. WFH data demonstrate that among such patients, as the economic capacity of a country decreases so does the ratio of adults to children. The organization of care, training of a multi-disciplinary healthcare team, and education of patients and their families lead to improved mortality independent of economic capacity or increased clotting factor concentrate availability. Additionally, through enhanced youth education, awareness and engagement, we will assure continuity within WFH national member organizations, build greater unity within our global family and capture the innovation and creativity of their ideas to improve Treatment for All.

WFH--the cornerstone of global development: 45 years of progress.

The World Federation of Hemophilia (WFH) has been the cornerstone of global development for 45 years. The WFH has identified and optimized the essential elements of a model for the development of a sustainable national care programme. The five elements of the WFH Development Model are integrated and interdependent: ensuring accurate laboratory diagnosis, achieving government support for a national programme, improving the care delivery system, increasing the availability of treatment products and building a strong national patient organization. It can been demonstrated that patient organizations, healthcare providers and the Ministry of Health working together in coalition is essential to achieving sustainable care. Equally important, the provision of care by a multidisciplinary team of trained professionals within a comprehensive care setting is fundamentally important to optimize outcomes. Using data from the WFH Global Survey, it is evident that the WFH Development Model brings about sustainable improvements in care. To support the Model, the WFH has created a vast range of tools, guides and programmes tailored to specific development needs. The Global Alliance for Progress is the preeminent WFH development program. Five years of outcomes data document a narrowing of the care gap between developed and developing nations. To ensure the continued advance towards the WFH vision of Treatment for All, it is vital that global collaboration occur on the research front as well. The WFH is well positioned to meet the challenges ahead and to continue serving as the cornerstone of global collaboration and development.

The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project: development and evaluation of a questionnaire assessing patient reported outcomes in people with haemophilia.

BACKGROUND: The interest of health care agencies, private payers and policy makers for patient-reported outcomes (PRO) is continuously increasing. There is a substantial need to improve capacity to collect and interpret relevant PRO data to support implementation of patient-centered research and optimal care in haemophilia. The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project aims to develop a patient-led research network, to develop a standardized questionnaire to gather patient-reported outcomes and to perform a feasibility study of implementing the PROBE questionnaire. METHODS: A pilot questionnaire was developed using focus group methodology. Content and face validity were assessed by a pool of persons living with haemophilia (PWH) and content experts through interactive workshops. The PROBE questionnaire was translated with the forward-backward approach. PROBE recruited national haemophilia patient non-governmental organizations (NGOs) to administer the questionnaire to people with and without haemophilia. PROBE measured the time to complete the questionnaire and gathered feedback on its content and clarity; staff time and cost required to implement the questionnaire were also collected. RESULTS: The PROBE questionnaire is comprised of four major sections (demographic data, general health problems, haemophilia-related health problems and health-related quality of life using EQ-5D-5L and EQ-VAS). Seventeen NGOs participated in the pilot study of the PROBE Project, recruiting 656 participants. Of these, 71% completed the questionnaire within 15 min, and all participants completed within 30 min. The median total staff and volunteer time required for the NGOs to carry out the study within their country was 9 h (range 2 to 40 h). NGO costs ranged from $22.00 to $543.00 USD per country, with printing and postage being the most commonly reported expenditures. CONCLUSIONS: The PROBE questionnaire assesses patient-important reported outcomes in PWH and control participants, with a demonstrated short completion time. PROBE proved the feasibility to engage diverse patient communities in the structured generation of real-world outcome research at all stages. TRIAL REGISTRATION: Trial registration: NCT02439710.

The dynamics of voluntarism in rural dementia care.

In this article, we contribute to the social sciences literature on voluntarism by examining the dynamics of voluntary service provision for people living with dementia in rural settings. Although volunteer-based organizations provide community support services across a range of Western countries, little attention has been directed towards understanding the organization and actions of volunteers and voluntarism in dementia care. To address this gap, we conducted a case study of Alzheimer support organizations in Ontario, Canada, using questionnaires with service providers (N=20) and semi-structured interviews with people with dementia (N=46) and partners in care (N=43). In our analysis, we identify challenges related to increasing demands for support, partner relations, reaching rural communities, a lack of early stage supports, a lack of volunteers for programs that families have requested, and loss of volunteers in programs families depended on. Moreover, we argue that the current model of voluntary sector service provision for people living with dementia is unevenly developed and potentially unsustainable.

Localization of cochlear implant electrodes in radiographs.

Multielectrode cochlear implantation is the most effective treatment for profound sensorineural hearing loss. In vivo three-dimensional 3-D localization of cochlear implant electrodes is important for modeling of the electrical field in the cochlea, design of electrode arrays, and may improve speech processor programming for better speech recognition. The prerequisite for 3-D localization of the electrodes is their 2-D localization in x-ray radiographs. In this paper, we develop a practical method to localize the electrodes with high efficiency, accuracy, and reproducibility. In this method, a priori knowledge of the electrodes and their approximate positions are utilized, an intelligent thresholding and segmentation mechanism is embedded, and the electrode center is computed as the weighted geometric center of segmented electrode pixels. Experiments with physical phantoms and human data demonstrate the feasibility and utility of this method. The PC-based program developed for this project is disseminated on the Web.

Spiral CT image deblurring for cochlear implantation.

Cochlear implantation is the standard treatment for profound hearing loss. Preimplantation and postimplantation spiral computed tomography (CT) is essential in several key clinical and research aspects. The maximum image resolution with commercial spiral CT scanners is insufficient to define clearly anatomical features and implant electrode positions in the inner ear. In this paper, we develop an expectation-maximization (EM)-like iterative deblurring algorithm to achieve spiral CT image super-resolution for cochlear implantation, assuming a spatially invariant linear spiral CT system with a three-dimensional (3-D) separable Gaussian point spread function (PSF). We experimentally validate the 3-D Gaussian blurring model via phantom measurement and profile fitting. The imaging process is further expressed as convolution of an isotropic 3-D Gaussian PSF and a blurred underlying volumetric image. Under practical conditions, an oblique reconstructed section is approximated as convolution of an isotropic two-dimensional (2-D) Gaussian PSF and the corresponding actual cross section. The spiral CT image deblurring algorithm is formulated with sieve and resolution kernels for suppressing noise and edge artifacts. A typical cochlear cross section is used for evaluation, demonstrating a resolution gain up to 30%40% according to the correlation criterion. Physical phantoms, preimplantation and postimplantation patients are reconstructed into volumes of 0.1-mm cubic voxels. The patient images are digitally unwrapped along the central axis of the cochlea and the implanted electrode array respectively, then oblique sections orthogonal to the central axis formed. After deblurring, representation of structural features is substantially improved in all the cases.

Effect of amplification on the intelligibility of speech produced with an electrolarynx.

The purpose of this study was to look at the effect of orolabial amplification on the intelligibility of speech spoken with a neck model electrolarynx for two distance conditions, three noise conditions, and in relative quiet. A speaker using a neck model electrolarynx read single-answer questions to six listeners. The questions were read with and without amplification at 1.5 and 2.5 m distance, in relative quiet as well as in 66 dB, 72 dB, and 76 dBSPL (A-weighted) prerecorded cafeteria noise. The results of the study showed that speech-to-noise ratios were improved for amplified speech, with improvement in intelligibility for speech spoken in moderate background noise (66 and 72 dBSPL). The effect of the "buzz" of the artificial larynx is reduced, and speakers are better understood in moderate background noise with this amplification system.

Optimization of speech processor fitting strategies for Chinese-speaking cochlear implantees.

OBJECTIVES: To compare speech recognition performance in Chinese-speaking cochlear implant patients with a speech processor program selected by the clinical audiologist in Taiwan and with a new speech processor program based on the Washington University clinical procedure developed by Skinner et al. STUDY DESIGN: Six adult Chinese-speaking patients implanted with the Nucleus cochlear implant system participated in this study. METHODS: A fitting procedure developed in 1995 by Skinner et al. at Washington University School of Medicine was used to create a new speech processor program to optimize each patient's hearing in everyday life. Speech tests (vowels, consonants, tones, and words), sound-field thresholds, and a self-report questionnaire were used to evaluate each patient's performance with his or her previous speech processor program and a new one. RESULTS: Four of the six patients had significant changes from the previous to the new speech processor program. These changes were associated with improvement in score on at least one speech test, more sensitive sound field thresholds, and reported improvement in some everyday listening situations on the questionnaire. CONCLUSIONS: These results suggest that use of this procedure with adult cochlear implantees may improve benefit in everyday life. Analysis of the speech test stimuli and patients' responses provides a basis for modification or creation of new Mandarin Chinese speech tests for preoperative and postoperative evaluation of adult cochlear implant patients.

Comparison of benefit from vibrotactile aid and cochlear implant for postlinguistically deaf adults.

Four postlinguistically deaf adults were evaluated presurgically with a one- or two-channel vibrotactile aid and postsurgically with a multichannel, multielectrode, intracochlear implant. Although the vibrotactile aid provided awareness of sound and enhanced flow of conversation, benefit to lipreading was small on videotaped tests and speech tracking. Scores on recorded, sound-only speech tests were not significantly above chance except in discrimination of noise from voice. With the cochlear implant, benefit to lipreading was significantly greater than with the vibrotactile aid, and scores on sound-only tests were significantly above chance. Communication was markedly better with the implant than with the vibrotactile aid. In counseling those who get no benefit from a hearing aid, the results of this study provide data on the amount of benefit one- or two-channel vibrotactile aids provide postlinguistically deaf adults who are subsequently implanted.

Study of the performance of four prelinguistically or perilinguistically deaf patients with a multi-electrode, intracochlear implant.

Individuals who are born deaf or become deaf in early childhood and are implanted as adults (or in late adolescence) with a multi-electrode, intracochlear implant often cannot understand speech by audition alone. Test results of four implanted patients were analyzed to determine 1. if there was a difference in performance between patients; 2. if there was a relation between performance and history of auditory stimulation; and 3. which tests revealed performance differences. On audition-only and audition-plus-vision tests, overall performance was rank-ordered from lowest to highest for patients 1, 2, 3, and 4, respectively. Patient 4 recognized a few words audition-only. Patients 1 and 2 had long periods of no auditory stimulation; patients 3 and 4 had long periods of auditory stimulation with hearing aids prior to implantation. Tests not revealing differences in performance were identified.

Unwrapping Cochlear implants by spiral CT.

Multielectrode, intracochlear implants were designed for individuals with profound sensorineural hearing loss who derive little or no benefit form acoustic hearing aids. Determination of each electrode's position in a patient's inner ear may improve speech processor programming to maximize speech recognition. In this paper, an approach is described to use as input a volumetric spiral computed tomography (CT) image of the Nucleus electrode array (Cochlear Pty. Ltd, Lane Cove, NSW, Australia) to unwrap it, and to measure its implanted length given starting and end points. Representative curvilinear structures were digitally synthesized in image volumes of isotropic 0.1-mm voxels. The electrode array was spirally CT-scanned in vitro and in vivo, and reconstructed on an isotropic grid in 0.1-mm steps. Two algorithms were constructed to track and measure these curvilinear structures. The first algorithm is Karhunen-Loeve (K-L)-transform based, in which the K-L transform is locally applied at a current main axis position to determine the eigenvectors of the main axis voxels, the next main axis position is estimated from the current position along the principal eigendirection, adjusted to the mass center of the orthogonal cross section passing through the estimated position, and then scaled to have a prespecified step. The second algorithm is similar to the first one but avoids use of the K-L transform. In the second algorithm, the next position is directly estimated along the local direction and then processed with the same correction and scaling operations. With user-specified starting and end points as well as a local direction at the starting point, a curvilinear structure can be automatically tracked using either of the algorithms. The first algorithm is more robust, while the second one is more efficient. In the numerical and in vitro studies, the lengths of the curvilinear structures were accurately measured. Given local directions determined in the tracking process, an electrode array image can be unwrapped into a linear array with the central electrode axis as the abscissa. The unwrapping approach allows longitudinally and cross-sectionally accurate measurement and better visualization of cochlear implant images. With preimplantation knowledge of length, width, and center electrode distance, the position of individual electrodes can be estimated after unwrapping.

Digital X-ray stereophotogrammetry for cochlear implantation.

Multielectrode, intracochlear implant systems are effective treatment for profound sensorineural hearing loss. In some cases, these systems do not perform well, which may be partially due to variations in implant location within the cochlea. Determination of each electrode's position in a patient's inner ear provides an in vivo basis for both the cochlear modeling of electrical fields and the future design of electrode arrays that deliver electrical stimulation to surviving auditory neurons, and may improve speech processor programming for better speech recognition. We developed an X-ray stereophotogrammetric approach to localize implanted electrodes in three dimensions. Stereophotogrammetry of implanted electrodes is formulated in weak perspective geometry, with knowledge of a three-dimensional (3-D) reference structure and electrode positions in each of two digital stereo-images. The localization error is theoretically, numerically, and experimentally quantified. Both numerical and experimental results demonstrate the feasibility of the technique.

Temporal bone volumetric image deblurring in spiral computed tomography scanning.

RATIONALE AND OBJECTIVES: We developed a method for volumetric image deblurring in spiral (helical) computed tomography (CT) scanning with a three-dimensional (3D) Gaussian point spread function (PSF) to improve the quality of temporal bone spiral CT images for assessing the position of cochlear implants electrodes. METHODS: A patient was scanned after cochlear implantation, and the temporal bone was reconstructed into a volume with 128 voxels per dimension, 0.1 mm per voxel side, and x 10 gray-scale expansion. The 3D PSF in spiral CT imaging was assumed to be Gaussian separable transversely and longitudinally. Standard deviations of the PSF were derived and subjectively adjusted. The image was then deconvolved using Wiener filtering and maximum-likelihood deconvolution methods. Image quality was assessed both visually and quantitatively using cross-sectional area at half of the maximum (CAHM) of the implanted array as the figure of merit. RESULTS: Substantial image deblurring was achieved via deconvolution. Subjectively, anatomic structures were more clearly shown. Deconvolution reduced the CAHM by approximately one third, on average. Three-dimensional deconvolution had better image quality than two-dimensional deconvolution. The maximum-likelihood method produced superior image quality but took longer to process relative to Wiener filtering. CONCLUSION: Volumetric image deblurring is practical with a Gaussian PSF. The maximum-likelihood method is preferred if time permits. Deconvolution facilitates the study of fine details of the temporal bone and cochlear implant.