Predictive genetic testing for Huntington's disease: Exploring participant experiences of uncertainty and ambivalence between clinic appointments.

Ambivalence and uncertainty are key themes throughout the psychology of healthcare literature. This is especially so for individuals at risk of Huntington's disease (HD) deliberating the decision to undergo genetic testing because there is currently no treatment that modifies disease progression. A better understanding of the experience of making a decision about genetic prediction will help practitioners support and guide individuals through this process. Our aim was to capture participants' experiences of uncertainty and ambivalence in between their genetic counseling appointments. We explored these issues through the experiences of nine participants who were referred for predictive HD testing at four regional genetics services in England and Wales. Data consisted of recordings of clinic consultations, diaries, and an in-depth interview conducted at the end of the testing process. Data were analyzed thematically. Four themes were identified representing four possible futures, each future dependent on the decision to undergo testing and the result of that test. Our results showed that participants, as well as attending more to a future that represents their current situation of not having undergone predictive testing, also attended more to a distant future where a positive predictive result is received and symptoms have started. Participants attended less to the two futures that were more immediate once testing was undertaken (a future where a positive result is received and symptoms have not started and a future where a negative result is received). The use of diaries gave us a unique insight into these participants' experiences of ambivalence and uncertainty, psychological distress, and the emotional burden experienced. These findings help inform discussions within the clinic appointment as well as encourage researchers to consider diary use as a method of exploring what happens for individuals outside of clinical encounters.

Ethical preparedness in health research and care: the role of behavioural approaches.

BACKGROUND: Public health scholars have long called for preparedness to help better negotiate ethical issues that emerge during public health emergencies. In this paper we argue that the concept of ethical preparedness has much to offer other areas of health beyond pandemic emergencies, particularly in areas where rapid technological developments have the potential to transform aspects of health research and care, as well as the relationship between them. We do this by viewing the ethical decision-making process as a behaviour, and conceptualising ethical preparedness as providing a health research/care setting that can facilitate the promotion of this behaviour. We draw on an implementation science and behaviour change model, COM-B, to demonstrate that to be ethically prepared requires having the capability (ability), opportunity, and motivation (willingness) to work in an ethically prepared way. METHODS: We use two case examples from our empirical research-one pandemic and one non-pandemic related-to illustrate how our conceptualisation of ethical preparedness can be applied in practice. The first case study was of the UK NHSX COVID-19 contact tracing application case study involved eight in-depth interviews with people involved with the development/governance of this application. The second case involved a complex case regarding familial communication discussed at the UK Genethics Forum. We used deductive qualitative analysis based on the COM-B model categories to analyse the transcripbed data from each case study. RESULTS: Our analysis highlighted that being ethically prepared needs to go beyond merely equipping health professionals with skills and knowledge, or providing research governance actors with ethical principles and/or frameworks. To allow or support these different actors to utilise their skills and knowledge (or principles and frameworks), a focus on the physical and social opportunity is important, as is a better understanding the role of motivation. CONCLUSIONS: To understand ethical preparedness, we need to view the process of ethical decision-making as a behaviour. We have provided insight into the specific factors that are needed to promote this behaviour-using examples from both in the pandemic context as well as in areas of health research and medicine where there have been rapid technological developments. This offers a useful starting point for further conceptual work around the notion of being ethically prepared.

When genomic medicine reveals misattributed genetic relationships-the debate about disclosure revisited.

PURPOSE: Accidental discovery of misattributed parentage is an age-old problem in clinical medicine, but the ability to detect it routinely has increased recently as a result of high-throughput DNA sequencing technologies coupled with family sequencing studies. Problems arise at the clinical-research boundary, where policies and consent forms guaranteeing nondisclosure may conflict with standard clinical care. METHODS: To examine the challenges of managing misattributed parentage within hybrid translational research studies, we used a case study of a developmentally delayed child with a candidate variant found through a large-scale trio genome sequencing study in which data from unrelated samples were routinely excluded. RESULTS: We discuss whether genetic parentage should be explicitly confirmed during clinical validation, thus giving greater weight to the diagnosis according to American College of Medical Genetics and Genomics variant interpretation guidelines, and what tensions this approach would create. CONCLUSION: We recommend that the possibility of finding and disclosing misattributed parentage should be addressed during the consent or pretest counseling process, and that clinical relevance should determine whether or not to disclose results in the clinic. This proposition has implications for research governance, and implies that it may not always be possible to uphold nondisclosure commitments as investigations move from research to clinical care.

Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR.

Recent studies have demonstrated that a locus at 11p15.5 confers susceptibility to insulin dependent diabetes mellitus (IDDM). This locus has been shown to lie within a 19 kb region. We present a detailed sequence comparison of the predominant haplotypes found in this region in a population of French Caucasian IDDM patients and controls. Identification of polymorphisms both associated and unassociated with IDDM has allowed us to define further the region of association to 4.1 kb. Ten polymorphisms within this region are in strong linkage disequilibrium with each other and extend across the insulin gene locus and the variable number tandem repeat (VNTR) situated immediately 5' to the insulin gene. These represent a set of candidate disease polymorphisms one or more of which may account for the susceptibility to IDDM.

Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus.

The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1-kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By 'cross-match' haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent-of-origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.

Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes.

We describe a codon 299 mutation in the glucokinase gene in a British pedigree with maturity-onset diabetes of the young (MODY) resulting in a substitution of glycine to arginine. One out of fifty patients diagnosed with classical late-onset type 2 diabetes mellitus was also found to have this mutation. All nine relatives of this patient who have inherited the mutation have type 2 diabetes, although six others without the mutation are also present with diabetes. The discovery that glucokinase mutations can cause MODY and was also found in ten affected members of a pedigree with type 2 diabetes in which MODY had not previously been considered indicates that diagnosis based on molecular pathology will be helpful in understanding the aetiology of type 2 diabetes.

Genomic medicine: challenges and opportunities for physicians.

Medicine has always striven to personalise or stratify approaches towards individual patients, but recently these terms have been applied particularly to denote improved disease sub-classification achieved through new genetic and genomic technologies. Techniques to analyse a person's genetic code have improved in sensitivity exponentially over recent years and at the same time the cost of such analyses has become affordable to routine NHS care. This article highlights the significant opportunities that genomics brings to healthcare, as well as some of the practical and ethical challenges.

The environmental sustainability of data-driven health research: A scoping review.

Data-Driven and Artificial Intelligence technologies are rapidly changing the way that health research is conducted, including offering new opportunities. This will inevitably have adverse environmental impacts. These include carbon dioxide emissions linked to the energy required to generate and process large amounts of data; the impact on the material environment (in the form of data centres); the unsustainable extraction of minerals for technological components; and e-waste (discarded electronic appliances) disposal. The growth of Data-Driven and Artificial Intelligence technologies means there is now a compelling need to consider these environmental impacts and develop means to mitigate them. Here, we offer a scoping review of how the environmental impacts of data storage and processing during Data-Driven and Artificial Intelligence health-related research are being discussed in the academic literature. Using the UK as a case study, we also offer a review of policies and initiatives that consider the environmental impacts of data storage and processing during Data-Driven and Artificial Intelligence health-related research in the UK. Our findings suggest little engagement with these issues to date. We discuss the implications of this and suggest ways that the Data-Driven and Artificial Intelligence health research sector needs to move to become more environmentally sustainable.

Sustainable biobanks: a case study for a green global bioethics.

This paper argues that as we move to redefine global bioethics, there is a need to be attentive to the ethical issues associated with the environmental sustainability of data and digital infrastructures in global health systems. We show that these infrastructures have thus far featured little in environmental impact discussions in the context of health, and we use a case study approach of biobanking to illustrate this. We argue that this missing discussion is problematic because biobanks have environmental impacts associated with data and digital infrastructures. We consider several ethical questions to consider these impacts: what ethical work does the concept of environmental sustainability add to the debate; how should this concept be prioritised in decision-making; and who should be responsible for doing so? We call on global bioethics to play a role in advancing this dialogue and addressing these questions.

Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers.

BACKGROUND: The most commonly reported phenotypes described in patients with PTEN mutations are Bannayan-Riley-Ruvalcaba syndrome (BRRS), with childhood onset, macrocephaly, lipomas and developmental delay, and Cowden Syndrome (CS), an adult-onset condition recognised by mucocutaneous signs, with a risk of cancers, in particular those of the thyroid and breast. It has been suggested that BRRS and CS are the same condition, but the literature continues to separate them and seek a genotype-phenotype correlation. OBJECTIVE: To study the clinical features of patients with known PTEN mutations and observe any genotype-phenotype correlation. METHODS: In total, 42 people (25 probands and 17 non-probands) from 26 families of all ages with PTEN mutations were recruited through the UK clinical genetics services. A full clinical history and examination were undertaken. RESULTS: We were unable to demonstrate a genotype-phenotype correlation. Furthermore, our findings in a 31-year-old woman with CS and an exon 1 deletion refutes previous reports that whole exon deletions are only found in patients with a BRRS phenotype. CONCLUSION: Careful phenotyping gives further support for the suggestion that BRRS and CS are actually one condition, presenting variably at different ages, as in other tumour-suppressor disorders such as neurofibromatosis type 1. This has important counselling implications, such as advice about cancer surveillance, for children diagnosed with BRRS.

The Opinions, Expectations and Experiences of Women with a Family History of Breast Cancer Who Consult Their GP and Are Referred to Secondary Care.

Objectives: The purpose of this work was to explore the views, expectations and experiences of the increasing number of women with a family history of breast cancer who present to their GP and are referred to secondary care. Methods: A prospective descriptive study was carried out with 193 women referred by their GP regarding a family history of breast cancer to a genetics clinic or breast clinic in Oxfordshire and Northamptonshire over a one-year period. Results: Women who presented to primary care about a family history of breast cancer wanted their GP to provide them with information (90%) and to discuss their risks of developing breast cancer (87%). Women often had unrealistic expectations of what they might expect from a referral to secondary care, especially with regards to being offered genetic testing. Within 1 month of attending the secondary care appointment, 11% of women had returned to see their GP regarding their family history and what had happened at the specialist clinic. Conclusions: Women want information and the opportunity to discuss their breast cancer family history concerns in a primary care setting. For women who are referred, information provision in primary care is important to ensure realistic expectations of the secondary care visit and to provide ongoing reassurance and support throughout the often lengthy referral process. For women who are not referred, information provision in primary care is even more important, as this may be their only source of information and advice. Copyright 2002 S. Karger AG, Basel

EORTC Receptor and Biomarker Study Group Report: a sandwich enzyme-linked immunosorbent assay for vascular endothelial growth factor in blood and tumor tissue extracts.

A four-antibody sandwich enzyme-linked immunosorbent assay (ELISA) for vascular endothelial growth factor (VEGF) for application in blood (serum and plasma) and tumor tissue extracts was set up within the framework of the EORTC Receptor and Biomarker Study Group (RBSG). Polyclonal antibodies against VEGF165 were raised in chickens and rabbits, and used in a previously described assay format. The assay was validated and characterized for use in serum, plasma and tumor tissue extracts. The resulting VEGF ELISA was found to be specific for VEGF165 and VEGF121, the main isoforms of VEGF. The assay showed good precision and parallelism in serial dilutions of samples. The assay was not susceptible to interference by heterophilic antibodies because avian antibodies (duck anti-chicken and chicken anti-VEGF) were used in the pre-analyte stage and mammalian antibodies (rabbit anti-VEGF and goat anti-rabbit) in the post-analyte stage. In conclusion, a sensitive, robust and specific VEGF ELISA has been developed. Research into the prognostic value of VEGF employing this assay is currently underway.

[Therapeutic angiogenesis as a new experimental treatment for vascular disease]. / Therapeutische angiogenese als nieuwe experimentele behandeling voor vaatpatiënten.

Currently, our treatment modalities for patients with severe coronary artery disease consist of combinations of medication, percutaneous transluminal coronary angioplasty (PTCA) and coronary revascularization operations. Still, the number of patients who cannot be treated adequately in these ways is growing. In recent years progress has been made in the field of angiogenesis: the process of the development of new capillaries. It is now known that blood vessel growth is an essential phenomenon in a range of disease. It is possible to inhibit or stimulate this process, offering hope for new treatments in a wide array of diseases. Stimulation of angiogenesis has already been successful in animal models of chronic peripheral and myocardial ischaemia. Results of experimental treatments of coronary patients have been reported since 1998. 'Therapeutic angiogenesis' may evolve as our fourth treatment modality for the treatment of coronary artery insufficiency.

[Circulatory arrest following sulprostone administration in postpartum hemorrhage]. / Circulatiestilstand na gebruik van sulproston bij fluxus post partum.

In a woman aged 39 cardiac arrest occurred 3.5 hours after administration of 250 micrograms sulprostone directly into the uterine wall for a post-partum haemorrhage after manual removal of the placenta. A long period of resuscitation was necessary. After further evaluation the woman demonstrated specific contraindications to the administration of sulprostone. as formulated by the French authorities: age > 35 years, heavy cigarette smoking, and cardiovascular risk factors. In the Netherlands sulprostone is registered for intravenous administration only. We would strongly advise against administration directly into the uterine wall.

Regulation of insulin gene expression by the IDDM associated, insulin locus haplotype.

A 4.1 kb genomic region, spanning the insulin (INS) gene, confers genetic susceptibility to Type 1 or insulin-dependent diabetes mellitus (IDDM). Ten polymorphisms within this region form two predominant, complementary haplotypes. We have been studying the effects of these polymorphisms on the levels of insulin mRNA. Cloned genomic DNA fragments representing these two separate haplotypes were transiently transfected into a rodent pancreatic beta cell line, HIT-T15. These studies revealed that insulin mRNA levels were consistently higher in the transfectants expressing the diabetic haplotype. Over-expression of insulin mRNA may provide the basic mechanism for the diabetic susceptibility encoded at the INS locus.