The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a ...screening trial of individuals at high risk of ovarian cancer.
The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis.
In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001).
These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.
Summary Background Ovarian cancer has a high case–fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer ...Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. Methods Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50–74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening MMS; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov , number NCT00058032. Findings In the prevalence screen, 50 078 (98·9%) women underwent MMS, and 48 230 (95·2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12·0%) women in the USS group required a repeat test, and 167 (0·3%) women in the MMS group and 1894 (3·9%) women in the USS group required clinical evaluation. 97 of 50 078 (0·2%) women from the MMS group and 845 of 48 230 (1·8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48·3%; 95% CI 35·0–61·8) of the invasive cancers were stage I/II, with no difference (p=0·396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89·4%, 99·8%, and 43·3% for MMS, and 84·9%, 98·2%, and 5·3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89·5%, 99·8%, and 35·1% for MMS, and 75·0%, 98·2%, and 2·8% for USS, respectively. There was a significant difference in specificity (p<0·0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers. Interpretation The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined. Funding Medical Research Council, Cancer Research UK and the Department of Health, UK; with additional support from the Eve Appeal, Special Trustees of Bart's and the London, and Special Trustees of University College London Hospital.
To establish the performance characteristics of annual transvaginal ultrasound and serum CA125 screening for women at high risk of ovarian/fallopian tube cancer (OC/FTC) and to investigate the impact ...of delayed screening interval and surgical intervention.
Between May 6, 2002, and January 5, 2008, 3,563 women at an estimated ≥ 10% lifetime risk of OC/FTC were recruited and screened by 37 centers in the United Kingdom. Participants were observed prospectively by centers, questionnaire, and national cancer registries.
Sensitivity for detection of incident OC/FTC at 1 year after last annual screen was 81.3% (95% CI, 54.3% to 96.0%) if occult cancers were classified as false negatives and 87.5% (95% CI, 61.7% to 98.5%) if they were classified as true positives. Positive and negative predictive values of incident screening were 25.5% (95% CI, 14.3 to 40.0) and 99.9% (95% CI, 99.8 to 100) respectively. Four (30.8%) of 13 incident screen-detected OC/FTCs were stage I or II. Compared with women screened in the year before diagnosis, those not screened in the year before diagnosis were more likely to have ≥ stage IIIc disease (85.7% v 26.1%; P = .009). Screening interval was delayed by a median of 88 days before detection of incident OC/FTC. Median interval from detection screen to surgical intervention was 79 days in prevalent and incident OC/FTC.
These results in the high-risk population highlight the need for strict adherence to screening schedule. Screening more frequently than annually with prompt surgical intervention seems to offer a better chance of early-stage detection.
Background: Children with disabilities stand to gain from an array of services and interventions to support their development. However, relationships between parents of children with disabilities and ...professionals can be fraught, with the potential that professionals undermine the role of parents and overlook their agency.Aim: The aim of this study was to examine the nature of partnerships between parents of children with disabilities and professionals in the Early Childhood Development (ECD) sector, and the influences that shape partnerships within a particular context.Setting: This article documents the experiences of parents of children with disabilities from a national organisation, in respect of their partnerships with professionals.Methods: The research was a qualitative case study of a national organisation of parents of disabled children, the Disabled Children’s Action Group (DICAG), that has engaged in many different partnerships within different provinces of South Africa. Data generation techniques were document analysis and focus group discussion with staff and provincial branch members of the national DICAG office in Cape Town.Results: The findings of the study provide a nuanced and contextually situated understanding of the complexity of parent–professional partnerships in the disability sector. A key issue that emerges is that to recognise and disrupt pervasive dominant discourses and their potential to weaken partnerships, professionals need to critically attune themselves to the situated experiences of those whom they seek to support.Conclusion: The findings suggest that there is a need for a rights-based social justice agenda to underpin parent–professional relationships, to address the power dynamics and pervasive discourses that oppress the parent actors.
Interprofessional primary care teams have been introduced across Canada to improve access (e.g., a regular primary care provider, timely access to care when needed) to and quality of primary care. ...However, the quality and speed of team implementation has not kept pace with increasing access issues. The aim of this research was to use an implementation framework to categorize and describe barriers and enablers to team implementation in primary care.
A narrative review that prioritized systematic reviews and evidence syntheses was conducted. A search using pre-defined terms was conducted using Ovid MEDLINE, and potentially relevant grey literature was identified through ad hoc Google searches and hand searching of health organization websites. The Consolidated Framework for Implementation Research (CFIR) was used to categorize barriers and enablers into five domains: (1) Features of Team Implementation; (2) Government, Health Authorities and Health Organizations; (3) Characteristics of the Team; (4) Characteristics of Team Members; and (5) Process of Implementation.
Data were extracted from 19 of 435 articles that met inclusion/exclusion criteria. Most barriers and enablers were categorized into two domains of the CFIR: Characteristics of the Team and Government, Health Authorities, and Health Organizations. Key themes identified within the Characteristics of the Team domain were team-leadership, including designating a manager responsible for day-to-day activities and facilitating collaboration; clear governance structures, and technology supports and tools that facilitate information sharing and communication. Key themes within the Government, Health Authorities, and Health Organizations domain were professional remuneration plans, regulatory policy, and interprofessional education. Other key themes identified in the Features of Team Implementation included the importance of good data and research on the status of teams, as well as sufficient and stable funding models. Positive perspectives, flexibility, and feeling supported were identified in the Characteristics of Team Members domain. Within the Process of Implementation domain, shared leadership and human resources planning were discussed.
Barriers and enablers to implementing interprofessional primary care teams using the CFIR were identified, which enables stakeholders and teams to tailor implementation of teams at the local level to impact the accessibility and quality of primary care.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Interprofessional primary care teams (IPCTs) work together to enhance care. Despite evidence on the benefits of IPCTs, implementation remains challenging. This research aims to 1) identify and ...prioritize barriers and enablers, and 2) co-develop team-level strategies to support IPCT implementation in Nova Scotia, Canada.
Healthcare providers and staff of IPCTs were invited to complete an online survey to identify barriers and enablers, and the degree to which each item impacted the functioning of their team. Top ranked items were identified using the sum of frequency x impact for each response. A virtual knowledge sharing event was held to identify strategies to address local barriers and enablers that impact team functioning.
IPCT members (n = 117), with a mix of clinic roles and experience, completed the survey. The top three enablers identified were access to technological tools to support their role, standardized processes for using the technological tools, and having a team manager to coordinate collaboration. The top three barriers were limited opportunity for daily team communication, lack of conflict resolution strategies, and lack of capacity building opportunities. IPCT members, administrators, and patients attended the knowledge sharing event (n = 33). Five strategies were identified including: 1) balancing patient needs and provider scope of practice, 2) holding regular and accessible meetings, 3) supporting team development opportunities, 4) supporting professional development, and 5) supporting involvement in non-clinical activities.
This research contextualized evidence to further understand local perspectives and experiences of barriers and enablers to the implementation of IPCTs. The knowledge exchange event identified actionable strategies that IPCTs and healthcare administrators can tailor to support teams and care for patients.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background: Community-based rehabilitation (CBR) is a complex concept and strategy that has been implemented in diverse ways globally and in South Africa. Internationally, some stakeholders have ...described CBR as confusing, and this may influence implementation. A southern African study reports that there is insufficient evidence of the understanding of CBR in the region to influence training, policy and practice.Objectives: The aim of this study was to investigate South African stakeholders’ knowledge of CBR.Method: This article reports on an electronic survey that was part of a larger mixed methods study. Based on the sample of 86 respondents, descriptive statistics were used to analyse the quantitative data and thematic analysis for the qualitative data.Results: The majority of respondents had had exposure to CBR, but almost a quarter had no knowledge of the CBR guidelines and matrix. The results revealed varying knowledge concerning the key concepts of CBR, its beneficiaries and its funders. Respondents identified persons with disabilities as having a central role in the implementation of CBR. Problems with the visibility of CBR programmes were noted, as well as misunderstandings by many therapists.Conclusion: The implementation of CBR, and its goal of ensuring the rights of persons with disabilities, is negatively affected by the confusion attached to the understanding of what CBR is. The misunderstandings about, and lack of visibility of, CBR in South Africa may hinder its growing implementation in the country in line with new government policies.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The White Paper on the Rights of Persons with Disabilities encapsulates the vision not only for persons with disabilities in South Africa, but for every member of a diverse society. This paper ...discusses the vision of inclusion and mainstreaming contained in the White Paper and critiques the specific provisions for early childhood development, exploring their implications for training and practice of occupational therapists. Recommendations are made as to how these can be strengthened in achieving the vision of an inclusive society in which young children with disabilities are able to realise their potential. Key words: children with disabilities, early childhood development, inclusion, mainstreaming, policy
There have been significant recent developments in the policy arena in South Africa in respect of disability and of early childhood development viz. the "White Paper on the Rights of Persons with ...Disabilities and the National Integrated Early Childhood Development Policy." Using Bacchi's analytical framework encapsulated in the question, What's the problem represented to be?, these policies were subjected to scrutiny, analysing how disability and inclusion are represented within them, and how these representations shape the lives of young children with disabilities. Among the underlying assumptions contained in these policies is that barriers excluding persons with disabilities are socially constructed and their removal will result in inclusion. Further, the policies imply that marginalisation and vulnerability are inherent traits of children with disabilities. Inclusion is portrayed as an ideology rather than a practice. Amongst unproblematised elements of the polices is the supposition that children with disabilities are a homogenous group, and that there is a distinction between children with and without disabilities. The effects of these representations manifest in a focus on social barriers, which downplays the importance of habilitation and rehabilitation for the individual child and may result in children with disabilities being portrayed as passive recipients of services. It may also undermine choice and agency of children and their families. Further, the analysis indicates that defining the principle of inclusion too broadly makes it difficult to measure.
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ...ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.
Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.
We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval CI = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).
Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.
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