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.

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.

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.

Continuous intra-articular infusion of ropivacaine after unilateral total knee arthroplasty.

Intra-articular infusion of local anaesthetic after joint arthroplasty is attractive in that it is simple and will not cause motor block. However the efficacy of the technique has yet to be established. We enrolled 66 patients scheduled for unilateral total knee arthroplasty under general anaesthesia and single-shot femoral and sciatic nerve blocks. All patients had an intra-articular Painbuster device sited at the end of the procedure. Patients were then randomised to control or one of two treatment arms - low-dose and high-dose ropivacaine. In the control group the balloon was filled with saline, in the low-dose group with 0.2% ropivacaine and in the high-dose group 0.375% ropivacaine. The catheters were infused continuously for 48 hours and then removed. Patients were followed up daily for three days to determine pain scores, opioid consumption and subjective assessment of the analgesic efficacy of the catheter Data were analysed for 30 controls and 31 in the treatment arms. Both groups were similar There were no significant differences between the control and treatment groups at all time points after adjustment for age. Patients in the high-dose group had higher pain scores and higher opioid consumption than the control groups from 24 to 48 hours. There were two cases of infection, both in the treatment groups. No positive benefit of intra-articular infusion of local anaesthetic after total knee arthroplasty could be identified. On the contrary there may be negative effects in terms of expense, pain and possibly infection risks.

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.

Treatment for all: a vision for the future.

The World Federation of Hemophilia (WFH) has defined a new strategic plan which maps out where the organization is going and what it can do for our members. The plan embraces the vision of Treatment for All; i.e. one day, treatment will be available for all those with inherited bleeding disorders, regardless of where they live. Treatment for All means proper diagnosis, management, and care by a multidisciplinary team of trained specialists. It means safe, effective treatment products are available for all people with inherited bleeding disorders. It means expanding services beyond haemophilia, to those with von Willebrand's disease, rare factor deficiencies, and inherited platelet disorders. Today, more than 75% of the global bleeding disorders community receive either inadequate or no treatment whatsoever. Our mission is to improve treatment where it is limited or does not exist. At the same time, we must sustain the many gains we have achieved thus far. The challenge is immense. Making our vision a reality requires us to be focused and deliberate about the programmes we undertake and the commitments we make. Building on past strategic plans, this plan presents a vision for the continued success of the WFH over the next 3-5 years.

What is a cure and how do we get there?

The absence of adequate treatment for most of the world's 400 000 individuals with haemophilia makes the development of a cure compelling. Advances in the basic molecular sciences over the past 20 years have resulted in the feasibility of curing haemophilia through the application of gene therapy. However, the reality of this therapeutic strategy is highly complex. In addition, challenges to achieving a cure exist beyond the basic scientific hurdles. Thoughtful attention must also be given to a number of interrelated issues, including ethical considerations in patient recruitment, informed consent and geographical variables of global clinical trials. The global inequalities in healthcare mean that the ethics of international medical research, especially when it includes countries where people usually do not receive quality care, become much more complicated. The majority of haemophiliacs lives in developing countries and is a valuable resource of human subjects who could be enrolled in clinical trials. When recruiting subjects globally, investigators must be ever mindful that the patient population is a precious resource, which must be treated with respect and care. This presents a major challenge for investigators engaged in trials of haemophilia gene therapy to ensure that the informed consent process is current and comprehensive, that therapeutic misconceptions are appropriately managed, and that the roles of the researcher and physician are clear. Global clinical gene-therapy trials are an important and appropriate component in the quest to achieve a cure for haemophilia. When trials follow identical internationally accepted standards, a successful outcome can be achieved for trials including developing countries, if country specific cultural and economic aspects are considered.

Evaluation of the Intubating Laryngeal Mask Airway used by occasional intubators in simulated trauma.

This observational study assessed the potential role of the intubating laryngeal mask airway (ILMA) for use by emergency care givers with limited laryngoscopy skills. Six ambulance officers with advanced airway training, five doctors with intubation experience and five doctors without intubation experience were given a short instruction course on the use of the ILMA. They subsequently used the device on 80 consenting subjects anaesthetized for elective surgery after the application of cricoid pressure and manual in-line stabilization of the cervical spine. All patients were successfully ventilated via the ILMA. Mean (SD) times in seconds to ventilation were 27 (10), 33 (18) and 47 (22) respectively in the occasional intubator ambulance officers, occasional intubator doctor and naive intubator groups. The numbers (percentage) failures to intubate via the ILMA in each group were 2 (7%), 5 (20%) and 4 (16%) respectively. Mean (SD) times in seconds to intubation were 32 (23), 32 (17) and 36 (25). There was no evidence of "learning" with repeated use. The feedback forms were strongly supportive of a prehospital trial and also of having an ILMA available during all intubations. Participants almost universally rated the ILMA as easy to use. This study supports further evaluation of the ILMA in a large prehospital trial.

Cochlear implants: three-dimensional localization by means of coregistration of CT and conventional radiographs.

With use of radiopaque implanted objects as internal fiducial markers, the authors developed and evaluated a technique for coregistering computed tomographic (CT) and computed radiographic images to help determine three-dimensional location information for implant electrodes in the cochlea in phantoms and patients. Three-dimensional positional data from CT were assigned on a radiograph, which permitted identification of individual cochlear electrode locations that were not depicted at CT.

Do anaesthetists need to wear surgical masks in the operating theatre? A literature review with evidence-based recommendations.

Many operating theatre staff believe that the surgical face mask protects the healthcare worker from potentially hazardous biological infections. A questionnaire-based survey, undertaken by Leyland' in 1993 to assess attitudes to the use of masks, showed that 20% of surgeons discarded surgical masks for endoscopic work. Less than 50% did not wear the mask as recommended by the Medical Research Council. Equal numbers of surgeons wore the mask in the belief they were protecting themselves and the patient, with 20% of these admitting that tradition was the only reason for wearing them. Policies relating to the wearing of surgical masks by operating theatre staff are varied. This indicates some confusion about the role of the surgical mask in modern surgical and anaesthetic practice. This review was undertaken to collate current evidence and make recommendations based on this evidence.

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.

Three-dimensional modeling and visualization of the cochlea on the Internet.

Three-dimensional (3-D) modeling and visualization of the cochlea using the World Wide Web (WWW) is an effective way of sharing anatomic information for cochlear implantation over the Internet, particularly for morphometry-based research and resident training in otolaryngology and neuroradiology. In this paper, 3-D modeling, visualization, and animation techniques are integrated in an interactive and platform-independent manner and implemented over the WWW. Cohen's template shape with mean cross-sectional areas of the human cochlea is extended into a 3-D geometrical model. Also, spiral computer tomography data of a patient's cochlea is digitally segmented and geometrically represented. The cochlear electrode array is synthesized according to its specification. Then, cochlear implantation is animated with both idealized and real cochlear models. Insertion length, angular position, and characteristic frequency of individual electrodes are estimated online during the virtual insertion. The optimization of the processing parameters is done to demonstrate the feasibility of this technology for clinical applications.