Ethical Considerations of Genetic Presymptomatic Testing for Huntington\u27s Disease

The aim of this literature review was to determine if there is adequate ethical justification for presymptomatic genetic testing on potential Huntington\u27s disease patients. Huntington\u27s disease is a neurological genetic disorder characterized by midlife onset which consists of cognitive, physical, and emotional deterioration. Although genetic testing has traditionally been guided by the principle of autonomy, severe psychological consequences such as depression, anxiety, survival guilt, and suicide have complicated the ethical issue of providing a presymptomatic yet definitive diagnosis for an incurable disease. An analysis of available articles yielded inconclusive findings, namely due to insufficient evidence, self-selection bias of test participants, or lack of a longitudinal design. Additional results indicated psychological distress is not solely associated with test result, but rather with individual characteristics including, but not limited to, psychological history, test motivation, level of preparation, social support, and age. In the interest of upholding the principles of autonomy, beneficence, nonmaleficence, and justice, it is recommended that medical professionals follow strict protocol, provide extensive counseling, and employ vigilance when assessing at-risk individuals for HD presymptomatic test eligibility to ensure psychological well-being

Human factors assessments of the STS-57 SpaceHab-1 mission

SpaceHab-1 (STS-57) was the first of six scheduled Commercial Middeck Augmentation Module (CMAM) missions seeking to offer entrepreneurial companies an opportunity to use the resource of microgravity. The SpaceHab module, which occupies about one-fourth of the payload bay, is approximately 2-3/4 meters (9 feet) long and 4 meters (13.5 feet) in diameter. It provides a shirt-sleeve working environment and contains the storage space equivalent of 50 middeck lockers, considerably over and above the number of experiments that can be carried in the orbiter middeck alone. A modified Spacelab tunnel links the SpaceHab module to the middeck. While in orbit, the orbiter payload bay doors remain open, exposing the padded exterior of the lab and tunnel to space until preparation for reentry at the end of the flight. The crew for SpaceHab-1 was comprised of four males and two females, each of whom participated in some part of the human factors assessment (HFA) evaluation. The HFA was one of over twenty experiments manifested on this maiden flight of the SpaceHab module. HFA consisted of HFA-EPROC, HFA-LIGHT, HFA-SOUND, HFA-QUEST, and HFA-TRANS. The goal of HFA-EPROC was to assess the advantages and disadvantages of paper versus computer presentation for procedural tasks. The next two evaluations investigated the module's lighting and acoustic environment. HFA-TRANS sought to evaluate the design of the SpaceHab tunnel and to characterize translation through it. HFA-QUEST represented a consolidation of the in-flight questions generated by the HFA principal investigators involved in the acoustic, lighting, and translation studies

Vedolizumab for Treating Moderately to Severely Active Crohn’s Disease After Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn’s disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company’s submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo-controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naïve to tumour necrosis factor alpha antagonist (anti-TNF-α) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF-α agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6–52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn’s disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be £21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-α-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above £30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-α-naïve and anti-TNF-α-failure populations) and in patients who were anti-TNF-α naïve only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company’s model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues

Protocol for a pilot randomised controlled clinical trial to compare the effectiveness of a graduated three layer straight tubular bandaging system when compared to a standard short stretch compression bandaging system in the management of people with venous ulceration: 3VSS2008

<p>Abstract</p> <p>Background</p> <p>The incidence of venous ulceration is rising with the increasing age of the general population. Venous ulceration represents the most prevalent form of difficult to heal wounds and these problematic wounds require a significant amount of health care resources for treatment. Based on current knowledge multi-layer high compression system is described as the gold standard for treating venous ulcers. However, to date, despite our advances in venous ulcer therapy, no convincing low cost compression therapy studies have been conducted and there are no clear differences in the effectiveness of different types of high compression.</p> <p>Methods/Design</p> <p>The trial is designed as a pilot multicentre open label parallel group randomised trial. Male and female participants aged greater than 18 years with a venous ulcer confirmed by clinical assessment will be randomised to either the intervention compression bandage which consists of graduated lengths of 3 layers of elastic tubular compression bandage or to the short stretch inelastic compression bandage (control). The primary objective is to assess the percentage wound reduction from baseline compared to week 12 following randomisation. Randomisation will be allocated via a web based central independent randomisation service (nQuery v7) and stratified by study centre and wound size ≤ 10 cm²or >10 cm². Neither participants nor study staff will be blinded to treatment. Outcome assessments will be undertaken by an assessor who is blinded to the randomisation process.</p> <p>Discussion</p> <p>The aim of this study is to evaluate the efficacy and safety of two compression bandages; graduated three layer straight tubular bandaging (3L) when compared to standard short stretch (SS) compression bandaging in healing venous ulcers in patients with chronic venous ulceration. The trial investigates the differences in clinical outcomes of two currently accepted ways of treating people with venous ulcers. This study will help answer the question whether the 3L compression system or the SS compression system is associated with better outcomes.</p> <p>Trial Registration</p> <p>ACTRN12608000599370</p

Colorectal cancer screening using the faecal occult blood test (FOBt): a survey of GP attitudes and practices in the UK

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is the third most common cancer in the UK. Five-year survival rates are less than 50%, largely because of late diagnosis. Screening using faecal occult blood tests (FOBt) can detect bowel cancer at an earlier stage than symptomatic presentation, and has the potential to significantly decrease colorectal cancer mortality. However, uptake of screening is currently low, despite the introduction of the NHS Bowel Cancer Screening Programme (NHSBCSP), and it has been suggested that GP recommendations of screening can improve patient compliance. GP recommendation of CRC screening is argued to be affected by attitudes towards it, along with perceptions of its efficacy.</p> <p>Methods</p> <p>This paper presents the findings of a cross-sectional postal survey of GPs in the UK which aimed to investigate GPs' attitudes in relation to colorectal cancer screening and the use of FOBt in routine practice. An 'attitude' score was calculated, and binary logistic regression used to evaluate the association of socio-demographic and general practice attributes with attitudes towards CRC screening and FOBt.</p> <p>Results</p> <p>Of 3,191 GPs surveyed, 960 returned usable responses (response rate 30.7%). Positive attitudes were associated with personal experience of CRC screening and Asian or Asian British ethnicity. GPs from practices located in more deprived locations were also more likely to have positive attitudes towards FOBt and its recommendation to patients.</p> <p>Conclusions</p> <p>The success of population-based screening for CRC will largely be determined by GP attitudes and support, particularly with regard to FOBt. Previous research has implied that South Asian GPs are more likely to have negative attitudes towards FOBt screening, however, our research suggests that this is not a group requiring targeted interventions to increase their support for the NHSBCSP. Of the available CRC screening tests, GPs perceived FOBt to be the most appropriate for population-based screening.</p

Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

Introduction: Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. Methods: We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Results: Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. Conclusion: These data highlight the need for a range of functional studies to be performed in order to identify variants with partially compromised function. The results also raise the possibility that A1708V and R1699Q may be associated with a low or moderate risk of cancer. While data pooling strategies may provide more information for multifactorial analysis to improve the interpretation of the clinical significance of these variants, it is likely that the development of current multifactorial likelihood approaches and the consideration of alternative statistical approaches will be needed to determine whether these individually rare variants do confer a low or moderate risk of breast cancer

Use of health services by remote dwelling Aboriginal infants in tropical northern Australia: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Australia is a wealthy developed country. However, there are significant disparities in health outcomes for Aboriginal infants compared with other Australian infants. Health outcomes tend to be worse for those living in remote areas. Little is known about the health service utilisation patterns of remote dwelling Aboriginal infants. This study describes health service utilisation patterns at the primary and referral level by remote dwelling Aboriginal infants from northern Australia.</p> <p>Results</p> <p>Data on 413 infants were analysed. Following birth, one third of infants were admitted to the regional hospital neonatal nursery, primarily for preterm birth. Once home, most (98%) health service utilisation occurred at the remote primary health centre, infants presented to the centre about once a fortnight (mean 28 presentations per year, 95%CI 26.4-30.0). Half of the presentations were for new problems, most commonly for respiratory, skin and gastrointestinal symptoms. Remaining presentations were for reviews or routine health service provision. By one year of age 59% of infants were admitted to hospital at least once, the rate of hospitalisation per infant year was 1.1 (95%CI 0.9-1.2).</p> <p>Conclusions</p> <p>The hospitalisation rate is high and admissions commence early in life, visits to the remote primary health centre are frequent. Half of all presentations are for new problems. These findings have important implications for health service planning and delivery to remote dwelling Aboriginal families.</p

Pathway to Hope: an indigenous approach to healing child sexual abuse

Background. The Alaska Native (AN) population has endured multiple historical traumatic events. This population has poorer health outcomes on nearly all factors compared with Alaska non-Natives with more than 75% reportedly being physically assaulted in their lifetime, and child sexual abuse nearly 6 times the national average. Objective. This article describes the Pathway to Hope (PTH) program, which is an indigenous approach to ending silence and denial related to child sexual abuse and encourages multigenerational healing. Design. PTH was developed by ANs who believe that each community is unique, thus strategies for ending denial and support for healing must be woven from the historical context, cultural strengths of individual communities. Strengths-based solutions built on truth, honesty, compassion and shared responsibility for healing and protecting today&#x2019;s children have been profound and successful. The PTH curriculum addresses child sexual abuse from a historical perspective; that the higher rates of sexual abuse among certain Tribes, regions and communities is linked in part to years of victimisation, but may also be perpetuated by internalised oppression and lateral violence among Tribal members. Results. Data suggest that community-based dialogue and wisdom of Native elders and spiritual leaders paired with readiness of community service providers are necessary for sustained change. At all levels, this Indigenous model for learning, sharing, helping and healing brings hope for an end to denial and silence about child sexual abuse for Native people. Conclusions. The PTH program utilises the wisdom and values that have sustained Native people for generations. Ending silence and denial about child sexual abuse and building upon strengths have assisted many Indigenous communities begin the journey toward wellness. Through the PTH, communities have taken steps to accept the challenges associated with establishing safety for children, supporting child victims in healing and to holding offenders accountable

Policymakers\u27 experience of a capacity-building intervention designed to increase their use of research: A realist process evaluation

Background: An intervention’s success depends on how participants interact with it in local settings. Process evaluation examines these interactions, indicating why an intervention was or was not effective, and how it (and similar interventions) can be improved for better contextual fit. This is particularly important for innovative trials like Supporting Policy In health with Research: an Intervention Trial (SPIRIT), where causal mechanisms are poorly understood. SPIRIT was testing a multi-component intervention designed to increase the capacity of health policymakers to use research. Methods: Our mixed-methods process evaluation sought to explain variation in observed process effects across the six agencies that participated in SPIRIT. Data collection included observations of intervention workshops (n = 59), purposively sampled interviews (n = 76) and participant feedback forms (n = 553). Using a realist approach, data was coded for context-mechanism-process effect configurations (retroductive analysis) by two authors. Results: Intervention workshops were very well received. There was greater variation of views regarding other aspects of SPIRIT such as data collection, communication and the intervention’s overall value. We identified nine inter-related mechanisms that were crucial for engaging participants in these policy settings: (1) Accepting the premise (agreeing with the study’s assumptions); (2) Self-determination (participative choice); (3) The Value Proposition (seeing potential gain); (4) ‘Getting good stuff’ (identifying useful ideas, resources or connections); (5) Self-efficacy (believing ‘we can do this!’); (6) Respect (feeling that SPIRIT understands and values one’s work); (7) Confidence (believing in the study’s integrity and validity); (8) Persuasive leadership (authentic and compelling advocacy from leaders); and (9) Strategic insider facilitation (local translation and mediation). These findings were used to develop tentative explanatory propositions and to revise the programme theory. Conclusion: This paper describes how SPIRIT functioned in six policy agencies, including why strategies that worked well in one site were less effective in others. Findings indicate a complex interaction between participants’ perception of the intervention, shifting contextual factors, and the form that the intervention took in each site. Our propositions provide transferable lessons about contextualised areas of strength and weakness that may be useful in the development and implementation of similar studies

Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening

This is a summary of independent research funded by the National Institute for Health. Research (NIHR)’s Programme Grants for Applied Research Programme (RP-PG-0609–10106