Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks?

Presymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87%) or ovarian cancer (10-60%) and may opt for intensive breast and ovary surveillance or prophylactic surgery (mastectomy/oophorectomy).We studied general and cancer related distress in 85 healthy women with a 25% or 50% risk of being carrier of a BRCA1/BRCA2 gene mutation and 66 partners in the six to eight week period between genetic counselling/blood sampling and disclosure of the test result. Questionnaire and interview data are analysed. Associations are explored between levels of distress and (1) expected consequences of being identified as a mutation carrier, (2) personality traits, (3) sociodemographic variables, and (4) experiences related to HBOC.Mean pre-test anxiety and depression levels in women at risk of being a carrier and partners were similar to those of a normal Dutch population. In about 25% of those at risk of being a carrier and 10% of the partners, increased to high levels of general and cancer related distress were found. Increased levels of distress were reported by women who (1) anticipated an increase in problems after an unfavourable test outcome, (2) considered prophylactic mastectomy if found to be mutation carrier, (3) had an unoptimistic personality, (4) tended to suppress their emotions, (5) were younger than 40 years, and (6) were more familiar with the serious consequences of HBOC. Recently obtained awareness of the genetic nature of cancer in the family was not predictive of distress.The majority of the women and their partners experienced a relatively calm period before the disclosure of the test result and seemed to postpone distressing thoughts until the week of disclosure of the result. The low distress levels may partly be explained by the use of strategies to minimise the emotional impact of a possibly unfavourable test outcome. However, a minority reported feeling very distressed. Several factors were found to be predictive for increased distress levels.     

Should genetic testing for BRCA1/2 be permitted for minors? Opinions of BRCA mutation carriers and their adult offspring

Although professional guidelines recommend against testing minors for adult-onset genetic conditions, the genetic testing of minors for BRCA1/2 alterations has been debated in the literature. To better understand the opinions of BRCA mutation carriers regarding the genetic testing of minors and the cognitive and affective processes underlying these opinions, we interviewed BRCA mutation carriers and their adult offspring who had learned of their parent's BRCA mutation. Semi-structured interviews were conducted with 53 parents and 22 offspring. In response to a closed-ended question, 52% (n = 39) of participants were opposed to the testing of minors. Responses to an open-ended question indicate that many participants (24%, n = 18) feel that testing could be permitted for some minor offspring. Psychological risks and the insufficient maturity of minors were frequent concerns of participants opposed to testing minors. The potential to impact health behaviors was frequently cited as a reason to support the genetic testing of minors. These preliminary results suggest that many BRCA mutation carriers and their adult offspring have concerns about, or are opposed to the genetic testing of minors. However, a significant minority in our study would support testing minors. Greater support for testing among offspring could indicate increasing requests for early genetic diagnosis. Further research is necessary to explore the risks and benefits of providing genetic testing to minors for adult-onset hereditary cancer syndromes in order to inform clinical practice and public policy and to ensure optimal psychosocial and medical outcomes for all members in families at risk for genetically determined disease.     

Haematopoietic stem cell transplantation and gene therapy in the fetus: ready for clinical use?

Allogeneic haematopoietic stem cell transplantation in utero has been successfully used for the prenatal treatment of severe combined immunodefiency syndrome. However, this treatment has not been successful in the therapy of other conditions in which the fetus is immunologically competent. The main obstacles to success are lack of competitive advantage of donor versus host stem cells, preventing stable engraftment and graft rejection. Several strategies are being explored to overcome these problems, and some of them have been successful in animal studies. Prenatal gene therapy, using ex-vivo transduced autologous haematopoietic cells or direct gene targeting in utero, is another potential approach in the treatment of immunocompetent fetal recipients. Although this has been shown to be feasible in animal models, safety concerns regarding transduction of fetal germ cells or maternal cells should be addressed in preclinical experiments prior to initiation of clinical trials.     

Informed consent documents for BRCA1 and BRCA2 screening: how large is the readability gap?

The decision to undergo testing for the BRCA1 and BRCA2 mutations, which are associated with an increased risk of breast and ovarian cancer, can have long-term consequences on women's lives. Women who decide to undergo such testing are required to sign informed consent documents, which indicate that they understand the test and its risks and benefits. These documents are generally written for advanced-level readers. However, the reading abilities of many women are substantially lower than the level of the consent forms, resulting in a 'readability gap'. This disparity suggests that women may not fully understand the documents they are asked to sign. The 'readability gap' poses the serious issues about informed consent, raising questions about institutional review boards and the effectiveness of the documents that are currently in use.     

Dalbavancin in clinical practice: a particular place for the elderly?

European Journal of Clinical Microbiology & Infectious Diseases - We investigate dalbavancin efficiency and tolerance among elderly in Grenoble-Alpes 32 university hospital. Among the 65...     

How can genetic tests be evaluated for clinical use? Experience of the UK Genetic Testing Network

The UK Department of Health supported the establishment of the UK Genetic Testing Network (UKGTN) in 2002. The UKGTN is a collaborative network of NHS molecular genetic laboratories that offer tests for human single gene germ-line disorders. Its objective is to provide high quality and equitable services for patients and their families who require genetic advice, diagnosis and management. The UKGTN has developed a 'Gene Dossier' process to evaluate genetic tests and recommend which tests will be provided by the National Health Service. This paper describes the UKGTN organisation and the 'Gene Dossier' process. A brief review of the UKGTN genetic test evaluation experience is presented.     

Screening for enteroviral meningitis in infants and children—Is it useful in clinical practice?

Enteroviral meningitis in infants and children commonly leads to hospital admission. Diagnosing viral meningitis can be difficult clinically. We examined the usefulness of enteroviral polymerase chain reaction (PCR) testing using cerebrospinal fluid (CSF) samples on clinical practice by comparing positive enteroviral CSF PCR cases (n = 39/136) to negative controls using both clinical outcomes and laboratory parameters. A positive result correlated with a reduced admission to high dependency unit, reduced the duration of antibiotics and a shorter length of stay (P < .05). Adjusted CSF white cell count > 5/μL correlated with positive PCR (P < .05) but would have missed 32% of cases of enteroviral meningitis. Following these findings, an algorithm for the management of suspected viral meningitis has been introduced.     

A gift or a yoke? Women’s and men’s responses to genetic risk information from BRCA1 and BRCA2 testing

This qualitative study explored the impact of genetic risk information from BRCA1/2 testing on individuals' subjective understandings of self and self-identity. In-depth interviews were conducted with 39 participants (34 women and 5 men) who had received test results from BRCA1/2 testing. Themes emerging from qualitative data analysis revealed that participants linked their positive results to becoming more aware of their physical selves (embodied self), their selves in relation to family (familial-relational self) and their selves in relation to wider kinship or social groups (social self). Genetic information was generally viewed as enabling; it allowed participants to take measures (surveillance or prophylactic surgery) to confront the disease. However, for a small minority of women, knowledge about their genetic risk had a profound and limiting effect on their agency. Rather than giving them a sense of control, they saw little opportunity to fight the disease. For a few people, identification of a genetic mutation thrust them into an uncertain state, that is in a position of being neither ill nor completely well. In one case, BRCA information led to a disruption of social identity. Further work is needed to assess the impact of age and life stage on psychological responses to genetic information on cancer susceptibility.     

Is there a correlation between the structure of hair and breast cancer or BRCA1/2 mutations?

It has been suggested that the small angle x-ray scattering (SAXS) pattern of human hair can be used to diagnose breast cancer and possibly to identify BRCA1/2 mutation carriers, who are at significantly elevated risk for developing breast cancer. In particular, the presence of a diffuse ring in the SAXS pattern was said to be diagnostic of either breast cancer or an increased risk thereof. To test this hypothesis, we measured SAXS from the pubic hair of 56 subjects with known BRCA1/2 and breast cancer status. We found that there is no clear association between the pattern of SAXS seen in human pubic hair and the risk of breast cancer or the presence of BRCA1/2 mutations. The possible use of SAXS to diagnose cancer remains conjectural, but this and previous studies do not suggest that SAXS can be used as a reliable method of identifying either BRCA1/2 mutation carriers or women who have had breast cancer.     

Variability in use of cut-off scores and formats on the Edinburgh Postnatal Depression Scale – implications for clinical and research practice

Summary Objectives: i) To highlight the increasing use in the literature of unvalidated cut-off scores on the Edinburgh Depression Scale (EDS/EPDS), as well as different wording and formatting in the scale; ii) to investigate and discuss the possible impact of using an unvalidated cut-off score; iii) to highlight possible reasons for these ‘errors’; and iv) to make recommendations to clinicians and researchers who use the EDS/EPDS. Method: A convenience sample of studies that have used unvalidated cut-off scores, or different formatting, are cited as evidence that these types of ‘errors’ are occurring fairly frequently. Examination of previous data from one of the authors is undertaken to determine the effect of using an unvalidated cut-off score. Summary: Many studies report rates of high scorers on the EDS/EPDS using different cut-off scores to the validated ones. The effect of doing this on the overall rate can be substantial. The effect of using different formatting is not known, though excluding items from the EDS/EPDS must also make a substantial difference. Recommendations: We recommend that i) the validated score of 13 or more is used when reporting on probable major depression in postnatal English-speaking women, and 15 or more when reporting on antenatal English-speaking women; ii) that the wording used is “13 or more” (or equivalent), and not other terms that may cause confusion (e.g., ‘>12’; ‘more than 12’; ‘13’ etc), iii) if a different cut-off score to the validated one is used, a clear explanation is given as to why this has been done; and iv) that the scale should be worded and formatted as originally described by its authors.     

Specialty choice in UK junior doctors: Is psychiatry the least popular specialty for UK and international medical graduates?

Background  

In the UK and many other countries, many specialties have had longstanding problems with recruitment and have increasingly relied on international medical graduates to fill junior and senior posts. We aimed to determine what specialties were the most popular and desirable among candidates for training posts, and whether this differed by country of undergraduate training.     

Is it time for BRCA1/2 mutation screening in the general adult population?: impact of population characteristics

Genet Med advance online publication 06 November 2014     

Is the routine recording of primary care consultations possible … and desirable? Lessons for researchers from a consultation with multiple stakeholders

Objective

To explore stakeholders’ attitudes towards routine, longitudinal recording of primary care consultations for research purposes, and to identify legal, ethical, and practical barriers and facilitators.

Methods

183 stakeholders (including patients, researchers and practice staff) were identified using a purposeful sampling strategy. Stakeholders participated in focus groups and interviews. The data was analysed thematically in an iterative manner with themes and questions from earlier discussions being raised with later participants.

Results

Most participants supported the creation of a database and believed it would benefit patient care. They suggested it could be used to train doctors, aid understanding of conditions, and feed information back to practices to improve performance. However, enthusiasm was tempered by concerns about the ownership security and access of the data; quality and limitations of the dataset; impact on behaviour; and workload. Safeguards were suggested that protected vulnerable individuals, enabled participation, gave control to participants, and clarified data use.

Conclusion

The findings show that collecting such longitudinal data is possible, valuable and acceptable providing certain safeguards are in place.

Practice implications

Future studies employing routine recordings of consultations should:

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Attend to confidentiality, access and governance of the archive.

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Collect quality data, and store it securely.

     

Is copper pro- or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation

The anti-inflammatory role of copper is well-known although still largely unexplained. On the other hand, the capacity of copper to induce the formation of damaging ·OH radicalsin vivo is no longer debated. These two aspects of the physiological activity of copper have been considered to be paradoxical. Arguments developed here show that they may actually derive from a single chemical process, the type of physiological effect observed depending on the ligand bound to the copper ions involved in Fenton chemistry.Both iron and copper are Fenton catalysts. Given its intrinsic coordination properties, however, copper induces more site-specific ·OH damage to the ligands bound to it. It, therefore, appears that copper complexes with specific·OH-inactivating ligands (OILs) can be used as lures for the Fenton reaction, ·OH radicals preferentially formed on these being immediately inactivated.The hypothesis is thus put forward here thatcopper-OIL complexes acting as effective Fenton catalysts are potential catalase-like anti-inflammatory drugs.     

Immunopathological patterns from EAE and Theiler's virus infection: Is multiple sclerosis a homogenous 1-stage or heterogenous 2-stage disease?

Multiple sclerosis (MS) is a disease which can presents in different clinical courses. The most common form of MS is the relapsing-remitting (RR) course, which in many cases evolves into secondary progressive (SP) disease. Autoimmune models such as experimental autoimmune encephalomyelitis (EAE) have been developed to represent the various clinical forms of MS. These models along with clinico-pathological evidence obtained from MS patients have allowed us to propose ‘1-stage’ and ‘2-stage’ disease theories to explain the transition in the clinical course of MS from RR to SP. Relapses in MS are associated with pro-inflammatory T helper (Th) 1/Th17 immune responses, while remissions are associated with anti-inflammatory Th2/regulatory T (Treg) immune responses. Based on the ‘1-stage disease’ theory, the transition from RR to SP disease occurs when the inflammatory immune response overwhelms the anti-inflammatory immune response. The ‘2-stage disease’ theory proposes that the transition from RR to SP-MS occurs when the Th2 response or some other responses overwhelm the inflammatory response resulting in the sustained production of anti-myelin antibodies, which cause continuing demyelination, neurodegeneration, and axonal loss. The Theiler's virus model is also a 2-stage disease, where axonal degeneration precedes demyelination during the first stage, followed by inflammatory demyelination during the second stage.