Projecting the Supply and Demand for Certified Genetic Counselors: a Workforce Study.

As of May 2017, there were 4242 Certified Genetic Counselors (CGC) (American Board of Genetic Counseling, Inc. 2017) and 41 graduate-level genetic counseling training programs (Accreditation Council for Genetic Counseling 2017) in North America, and the demand for CGCs continues to increase. In the Fall of 2015 the Genetic Counselor Workforce Working Group, comprised of representatives from the American Board of Genetic Counseling (ABGC), the Accreditation Council for Genetic Counseling (ACGC), the Association of Genetic Counseling Program Directors (AGCPD), the American Society of Human Genetics (ASHG), and the National Society of Genetic Counselors (NSGC) commissioned a formal workforce study to project supply of and demand for CGCs through 2026. The data indicate a shortage of genetic counselors engaged in direct patient care. Assuming two scenarios for demand, supply is expected to reach equilibrium between 2024 and 2030. However, given the rate of growth in genetic counseling training programs in the six months since the study was completed, it is reasonable to expect that the number of new programs may be higher than anticipated by 2026. If true, and assuming that growth in programs is matched by equivalent growth in clinical training slots, the supply of CGCs in direct patient care would meet demand earlier than these models predict.

Audit feedback on reading performance of screening mammograms: An international comparison.

OBJECTIVE: Providing feedback to mammography radiologists and facilities may improve interpretive performance. We conducted a web-based survey to investigate how and why such feedback is undertaken and used in mammographic screening programmes. METHODS: The survey was sent to representatives in 30 International Cancer Screening Network member countries where mammographic screening is offered. RESULTS: Seventeen programmes in 14 countries responded to the survey. Audit feedback was aimed at readers in 14 programmes, and facilities in 12 programmes. Monitoring quality assurance was the most common purpose of audit feedback. Screening volume, recall rate, and rate of screen-detected cancers were typically reported performance measures. Audit reports were commonly provided annually, but more frequently when target guidelines were not reached. CONCLUSION: The purpose, target audience, performance measures included, form and frequency of the audit feedback varied amongst mammographic screening programmes. These variations may provide a basis for those developing and improving such programmes.

Cardiovascular safety of the glucagon-like peptide-1 receptor agonist taspoglutide in people with type 2 diabetes: an individual participant data meta-analysis of randomized controlled trials.

AIMS: To study the short-term cardiovascular effects of the once-weekly glucagon-like peptide-1 receptor agonist taspoglutide. METHODS: We conducted a meta-analysis of individual-participant data from nine randomized controlled trials in the T-Emerge programme, which assessed the efficacy and safety of taspoglutide in type 2 diabetes. Our primary outcome was a composite of death from cardiovascular disease (CVD) and acute myocardial infarction, stroke and hospitalization for unstable angina. RESULTS: Overall, 7056 individuals were included in the analysis, and there were 67 primary endpoint events during 7478 person-years of follow-up (40 vs 27 events in the intervention vs control groups, respectively). The odds ratio for the composite endpoint among people randomized to taspoglutide was 0.94 (95% confidence interval 0.57-1.56), which was robust across multiple subgroups. Longer-term data were not available as the development of taspoglutide was stopped because of gastrointestinal intolerance and serious hypersensitivity reactions. CONCLUSIONS: The available data suggest that short-term, once-weekly administration of taspoglutide was not associated with an excess risk of CVD, and provide insights relevant to the development of other novel once-weekly incretin mimetics.

PKR negatively regulates leukemia progression in association with PP2A activation, Bcl-2 inhibition and increased apoptosis.

Reduced expression and activity of the proapoptotic, double-stranded RNA-dependent protein kinase, PKR (protein kinase R) is observed in breast, lung and various leukemias, suggesting that loss of PKR potentiates transformation. Now we report that decreased PKR activity inhibits chemotherapy-induced apoptosis of leukemia cells both in vitro and in vivo. Inhibition of PKR expression or activity reduces protein phosphatase 2A (PP2A) activity, a B-cell lymphoma 2 (Bcl-2) phosphatase, resulting in enhanced Bcl-2 phosphorylation. Thus, inhibition of PKR activity leads to hyperphosphorylation of Bcl-2, stabilization of Bcl-2/Bax interaction and decreased Bax insertion into the outer mitochondrial membrane. Treatment with the PP2A activator, FTY720, restores Bcl-2 dephosphorylation and apoptosis in cells with reduced PKR expression following stress. Significantly, xenografts of REH leukemic cells with reduced PKR display significantly increased tumor volume, increased resistance to doxorubicin treatment and shorter survival. Importantly, FTY720 treatment restores sensitivity to chemotherapy and prolongs overall survival of these mice. Collectively, these findings suggest that PP2A activation is a downstream target of PKR and the PKR/PP2A signaling axis is required for rapid and potent stress-induced apoptosis. Importantly, loss of PKR promotes leukemia progression and may serve as a biomarker for predicting chemosensitivity.

An observational study to evaluate the performance of units using two radiographers to read screening mammograms.

AIM: To examine the performance of screening units in which a proportion of mammograms were double read using "non-discordant radiographer only (double) reading" (NDROR). MATERIALS AND METHODS: NDROR was used by seven pilot units between 2006 and 2009, and six further units in 2009 only. There were 51 comparison units. Screening performance outcome measures were calculated, and logistic regression was used to compare performance between the pilot and comparison units. RESULTS: Phase 1 pilot units read between on average 15 and 48% of mammograms per year using NDROR between 2006 and 2009 (median, 33%) and in 2009, phase 2 pilot units used NDROR to read between 4 and 77% of mammograms (median, 34%). The results showed an increase in recall rates in the phase 1 pilot units relative to the comparison units at both prevalent and incident screens (adjusted OR 1.09, 95% CI 1.05, 1.14; and adjusted OR 1.10, 95% CI 1.07, 1.14, respectively). There were also increases in the phase 2 pilot units relative to the comparison units; adjusted OR 1.08 (95% 1.00, 1.17) at prevalent screens, and adjusted OR 1.07 (95% CI 1.02, 1.14) at incident screens. There was no evidence to suggest a difference in cancer-detection rates between the pilot units and the comparison units. CONCLUSIONS: Evidence from the present study suggests that recall rates may increase as a result of units using radiographers to double read a proportion of their mammograms. However, there is little evidence to suggest that NDROR, as practiced by the pilot units in the present study, is likely to have major impacts on performance in the UK National Health Service Breast Screening Programme (NHSBSP), particularly if it is fully supported and closely monitored (particularly recall rates).

Screening outcomes in women over age 70 who self-refer in the NHSBSP in England.

SETTING: The NHS breast screening programme (NHSBSP) in England currently invites women aged 50-70 every three years. Whilst screening is acknowledged as efficacious for women aged 50-69, several countries routinely invite women up to the age of 74. The NHSBSP in England is beginning to invite women up to the age of 73. Although the incidence of breast cancer increases with age, the possible benefits of screening older women must be balanced against shorter life expectancies and possible overdiagnosis. In England women can self-refer after reaching the invitation upper age limit. OBJECTIVE: We examined the extent to which older women in England self-referred over a three-year period and studied the screening outcomes in these women. METHODS: Routinely collected data from screening units in England were used to calculate screening performance measures for women who self-referred between 1 April 2005 and 31 March 2008. The tumour characteristics of all screen-detected cancers were examined by previous screening history and age group (71-74 and ≥75 years). RESULTS: During the three-year period 139,910 women aged over 70 self-referred; equivalent to 4% of the female population aged over 70 having been screened. The majority of women who self-referred had been screened within the previous five years (76% of those aged 71-74 and 65% of those aged 75 or over). Approximately 4% of these women were recalled for assessment and cancer detection rates were similar in both age groups. CONCLUSION: Only a small proportion of all women aged over 70 utilize the self-referral policy of the NHSBSP, and most such women are aged below 80.

Pathological and mammographic prognostic factors for screen detected cancers in a multi-centre randomised, controlled trial of mammographic screening in women from age 40 to 48 years.

AIM: To assess pathological and radiological prognostic factors for cancers detected by screening within a multi-centre RCT trial of mammographic screening of younger women. METHOD: The survival of 232 women with screen detected invasive cancer was ascertained. Data on invasive cancer size, histological grade, nodal status, vascular invasion, mammographic spiculation, comedo calcification and mammographic background were assessed. Kaplan-Meier and Cox proportional hazards methods were used to examine survival. RESULTS: Univariate analysis indicated that women with cancers with the following features had poorer survival; ≥ 30 mm, histologically grade 3, heavily node positive (4 or more positive nodes), vascular invasion positive and displaying mammographic comedo calcification. In a multivariate model survival remained poorer in women with four or more nodes positive (HR 8.36, 95% CI 2.31, 30.17) and in those with comedo calcification (HR 3.00,95% CI 1.13, 7.99). CONCLUSION: Nodal status and the presence of mammographic comedo calcification have independent prognostic significance in young women with screen detected cancer.

Interval cancers in the NHS breast cancer screening programme in England, Wales and Northern Ireland.

BACKGROUND: The United Kingdom NHS Breast Screening Programme was established in 1988, and women aged between 50 and 70 are routinely invited at three yearly intervals. Expected United Kingdom interval cancer rates have been calculated previously, but this is the first publication from an exercise to collate individual-based interval cancer data at a national level. METHODS: Interval cancer case ascertainment is achieved by the regular exchange of data between Regional Breast Screening Quality Assurance Reference Centres and Cancer Registries. The present analysis includes interval cancers identified in women screened between 1st April 1997 and 31st March 2003, who were aged between 50 and 64 at the time of their last routine screen. RESULTS: In the periods >0-<12 months, 12-<24 months and 24-<36 months after a negative screen, we found overall interval cancer rates and regional ranges of 0.55 (0.43-0.76), 1.13 (0.92-1.47) and 1.22 (0.93-1.57) per 1000 women screened, respectively. Rates in the period 33-<36 months showed a decline, possibly associated with early re-screening or delayed presentation. CONCLUSIONS: Interval cancer rates were higher than the expected rates in the 24-month period after a negative screen, but were similar to published results from other countries. Increases in background incidence may mean that the expected rates are underestimated. It is also possible that, as a result of incomplete case ascertainment, interval cancers rates were underestimated in some regions in which rates were less than the expected.

Evaluation of extension of breast screening to women aged 65-70 in England using screening performance measures.

The objective of this study was to investigate screening performance measures in the English screening units that began inviting women aged 65-70 between 1 April 2001 and 1 April 2004. We analysed results after each unit commenced inviting women aged 65-70. In addition, we analysed data from units that invited this age group for a second time between 1 April 2004 and 31 March 2007. Results for women aged 65-70 were compared to women aged 50-64 and 60-64. Average uptake was 72.8% for women aged 65-70 and 76.7% for women aged 50-64. For women screened within the last 5 years, uptake was 88.7% for older women and 89.1% for younger women. For women previously screened within 5 years the invasive cancer detection rate was 17% higher in the 65-70 age group than in the 60-64 age group. The rates of recall to assessment and PPV were 3.5 and 27.6% in women aged 65-70 and 3.4 and 24.6% in women aged 50-64 respectively. These results suggest that, as in the earlier demonstration studies, uptake rates remain high in older women, and many more older women attend following an invitation than had previously self-referred. The cancer detection rate is higher in this older age group, whereas rates of recall are generally similar to those in younger women; consequently the PPV is also higher in older women.

Coverage in the National Health Service Breast Screening Programme, 1996-2005: correcting for the first invitation of women between 50 and 52 years.

BACKGROUND: Coverage measures the ability of the National Health Service Breast Screening Programme (NHSBSP) to reach the eligible population and has a target of 70%. OBJECTIVE: To estimate coverage accurately for women aged 50-64. METHODS: Routine data from the KC63 return were used to calculate coverage for women aged 50-64 using an adjusted method that allows for the fact that women receive a first invitation to screening between 50 and 52.9 years. RESULTS: The adjusted average coverage between 1996 and 2005, for women aged 50-64 was 74.3% and the standard unadjusted average measure for the same period was 68.3%. Therefore, previous measures of coverage for this age group have underestimated coverage by approximately 9% and the adjusted figure is actually well above the target. CONCLUSION: In terms of coverage the programme has been performing better than previously reported. It is important to monitor the effect of an increasing workload on the programmes ability to re-invite women within three years of their last screen as maintaining coverage is an important factor in ensuring that the NHSBSP is effective in reducing mortality from breast cancer.

Results from the UK NHS Breast Screening Programme 2000-05.

OBJECTIVE: To present results from the UK NHS breast screening programme (NHSBSP) for the six-year period from 1 April 1999 to 31 March 2005, and to compare these with targets. METHODS: Data are collected annually from all UK screening units on standard KC62 return forms. RESULTS: The prevalence of screen-positive cancer (cancer detection rate) has increased at both rounds during the six-year period. At the incident round, cancer detection rates increased by 24%, from 5.4 per 1000 in 2000 to 6.7 per 1000 in 2005 and the detection of small cancers (< or = 10 mm) has increased by 40%. Generally, quality measures in the programme continue to improve. However, while rates of recall at the incident screen decreased from 3.8% in 2000 to 3.6% in 2005, at the prevalent round, in 2005, 22% of units continued to recall more than 10% of women to assessment. CONCLUSIONS: The results suggest that the performance of the programme continues to improve. In the future, analysis of data on interval cancers will assist the interpretation of cancer detection rates.

Should a standard be defined for the Positive Predictive Value (PPV) of recall in the UK NHS Breast Screening Programme?

The UK NHSBSP defines standards for both cancer detection rate and recall rate for assessment but has not explicitly set a defined standard for positive predictive value (PPV) of recall. However, as PPV is defined as the percentage of women who are recalled and have a final diagnosis of cancer, a standard for PPV is an implicit consequence of the standards for cancer detection rate and recall rate. The standards are defined in terms of a lower level of acceptability known as the 'minimum standard' and a higher level of acceptability referred to as the 'target'. The target can be shown to be a PPV of more than 5.1% for prevalent screens and more than 8.4% for incident screens. This paper will explore the role of PPV as a performance measure and show how making moderate increases in PPV for programmes with the lowest PPVs could lead to major improvements in the overall efficiency of the programme.

Does the accuracy of single reading with CAD (computer-aided detection) compare with that of double reading?: A review of the literature.

AIM: To examine current evidence to determine whether the accuracy of single reading with computed-aided detection (CAD) compares with that of double reading. METHODS: We performed a literature review to identify studies where both protocols had been investigated and compared. We identified eight studies that compared single reading with CAD against double reading, of which six reported on comparisons of both sensitivity and specificity. RESULTS: Of the six studies identified, three showed no differences in either sensitivity or specificity. One showed single reading with CAD had a higher sensitivity at the same specificity, another that single reading with CAD had a higher specificity at the same sensitivity. However, one study, in a real-life setting, showed that single reading with CAD had a higher sensitivity but a lower specificity. CONCLUSION: As the majority of the studies were not in a real-life setting, used test sets, lacked sufficient training in the use of CAD and simulated double reading (using a protocol of recall if one suggests), current evidence is therefore limited as to the accuracy, in terms of sensitivity and specificity, of single reading with CAD in comparison with the most common practice in the UK of double reading using a protocol of consensus or arbitration.

The effect of data quality at the time of introduction of population-based screening on the estimate of programme impact using surrogate outcome measures.

OBJECTIVE: The aim of this study was to examine the availability and quality of surrogate outcome measure data to enable the evaluation of the breast screening programme. As the observed effect on mortality of a screening programme occurs many years after the introduction of screening, surrogate outcome measures offer an attractive alternative, allowing estimates of the effect to be calculated earlier. METHODS: The exercise was undertaken by the Oxford Cancer Intelligence Unit and the Cancer Screening Evaluation Unit in collaboration with cancer registries in England, Scotland and Wales. RESULTS: The conclusion of the exercise was that, in general, the available data quality was insufficient to allow a precise estimate of the overall mortality reduction from breast screening to be made using surrogate measures. CONCLUSIONS: When a screening programme is started, it is vital that forward planning is undertaken to ensure that the necessary information is ready to be collected before the start of the programme. The use of surrogate measures is dependent on high-quality data in the uninvited group of women (pre-screening or from a staggered start over areas), and improving data quality over time after the start of the programme is of very limited value for a surrogate measures approach. The collection of appropriate high-quality information before the programme starts is, therefore, critical to measuring the success of the programme. Cancer registries and staff within the screening programme need to be ready to collect the appropriate data before the introduction of a screening programme. The exercise undertaken therefore has important implications where new screening programmes are being considered.

Gunshot wounds to the head: gang- and non-gang-related injuries and outcomes.

PRIMARY OBJECTIVE: This study examined the differences between gang and non-gang-related incidents of penetrative missile injuries in terms of demographics, motivation, intra-cranial pathology, transit time, injury time and clinical outcome. RESEARCH DESIGN: Retrospective and prospective chart review. METHODS AND PROCEDURES: Between 1985-1992, 349 patients with penetrating missile injuries to the brain presenting to LAC-USC were studied. EXPERIMENTAL INTERVENTIONS: Inclusion criteria were implemented to keep the cohort as homogenous as possible. Patients excluded were those with multiple gunshot wounds, non-penetrating gunshot wounds to the head, systemic injuries and cases in which the motivation for the incident was unknown. MAIN OUTCOMES AND RESULTS: Gang-related shooting slightly out-numbered non-gang-related incidents. Demographic analysis showed both a male and Hispanic predominance for both gang- and non-gang-related victims and significant differences in gender, race and age. Occipital entrance sites were more common in the gang-related vs temporal entrance sites in the non-gang-related. Mean transit time to the emergency department for gang-related shootings was less than non-gang-related shootings (24.4 vs 27.8 minutes). Most shooting incidents took place between 6pm and 3am. No difference between survival and outcome was noted between gang and non-gang victims. CONCLUSIONS: Significant differences were found between gang- and non-gang-related shooting victims in terms of demographics, entrance site and transit time. No difference was found between injury time, survival and outcome between gang and non-gang populations.

Is radiologists' volume of mammography reading related to accuracy? A critical review of the literature.

The current UK quality assurance guidelines for radiologists in the NHS breast screening programme require those reporting screening mammograms to read a minimum of 5000 cases per year. We aimed to review the evidence for this and to assess whether there was justification for lowering the required level. A literature search was conducted to identify relevant studies where accuracy of reporting mammograms was related to reading volume. Three of the five studies reviewed suggested a positive association between reading volume and sensitivity, but there were few data on volumes above 5000 cases per year. The available evidence did not provide any basis for reducing the threshold volume. Further work is needed, in a UK or European setting, to study the relationship between reading volume and accuracy at higher volume levels and also the separate effects of reading volume and reading experience.

The effect of changing from one to two views at incident (subsequent) screens in the NHS breast screening programme in England: impact on cancer detection and recall rates.

AIM: To assess the effect on cancer detection and recall rates of changing from one to two views for incident (subsequent) screens. METHODS: Controlled, comparative, observational study of programmes in NHS breast screening programme in England. SUBJECTS: women aged 50-64 years were screened by the NHSBSP between 1 April 2001 and 31 March 2003. RESULTS: The effect of changing to two-view mammography was a 20% increase in overall incident screen cancer detection rate, with the biggest effect seen for small (<15 mm) invasive cancers. This increased detection rate was achieved with an 11% drop-in recall rate. CONCLUSION: The introduction of two-view mammography for incident screens has resulted in considerable improvements in overall NHS breast screening performance.

Spatial variation of refractive index in a pane of float glass.

In the statistical interpretation of forensic glass evidence it is standard practice to make the assumption of homogeneity of the refractive index (RI) of the source glass, or of localized homogeneity. However, the work of Locke and Hayes showed that, for toughened windscreen glass, this assumption might not be true. This work is well cited, but there appears to have been little follow-on published research. Furthermore, the toughening process is something known to affect the refractive index, and is a process that float glass does not undergo. Float glass is a major component of casework in New Zealand and for that reason it would be interesting to know whether the findings of Locke and Hayes apply when dealing with float glass. In this paper we describe an experiment similar to that of Locke and Hayes, systematically examining the variation of RI in a pane of float window glass. It was found that, although there were no systematic differences in refractive index, there were observable differences across the pane.

Does individual programme size affect screening performance? Results from the United Kingdom NHS breast screening programme.

OBJECTIVE: The size (number of women screened) of the 95 individual NHS breast screening programmes (NHSBSPs) varies by a factor of 10. This study investigates the impact of size on the performance of individual programmes. METHOD: Data were collated from the 95 United Kingdom screening programmes on the standard statistical returns for the past 5 years (1 April 1995-31 March 2000). Additional information was obtained from questionnaires. The number of women screened between 1 April 1999 and 31 March 2000 determined the size of a programme. The bottom 25% were defined as small, the middle 50% as medium, and the top 25% as large. On average large programmes screened about four times as many women as small programmes and medium programmes about twice as many. Performance was evaluated using cancer detection rates, referral rates for assessment, and positive predictive value (PPV) of assessment using PPV referral diagrams. RESULTS: The performance of smaller programmes was shown to be marginally poorer than medium and large sized programmes in that they detected fewer cancers and had a lower PPV. The smallest 25% of programmes had an invasive cancer detection rate 13% less than the medium and large programmes. However, if these programmes had an equivalent detection rate to the medium/large programmes the national detection rate would only increase by about 2%. This is because the 75% of programmes described as medium and large screen about 90% of all women. It is therefore important to place the clinical importance of these findings in context when considering any envisaged possible solutions. CONCLUSIONS: Although the performance of smaller programmes was shown to be poorer than that of the larger programmes, it is not clear from this study exactly why this is so. A likely contributory factor based on experience of evaluating the NHSBSP is that performance problems in larger programmes have been easier to detect by quality assurance staff. The size of the small programmes and the few screen detected cancers (and inherent statistical instability in detection rates) mean that problems are difficult to identify. As a consequence small programmes which are genuinely performing marginally below specific standards are likely to receive less attention than larger programmes, and even under close scrutiny the causes are less likely to be found.

A RecA homologue in Ustilago maydis that is distinct and evolutionarily distant from Rad51 actively promotes DNA pairing reactions in the absence of auxiliary factors.

Two RecA homologues have been identified to date in Ustilago maydis. One is orthologous to Rad51 while the other, Rec2, is structurally quite divergent and evolutionarily distant. DNA repair and recombination proficiency in U. maydis requires both Rec2 and Rad51. Here we have examined biochemical activities of Rec2 protein purified after overexpression of the cloned gene. Rec2 requires DNA as a cofactor to hydrolyze ATP and depends on ATP to promote homologous pairing and DNA strand exchange. ATPgammaS was found to substitute for ATP in all pairing reactions examined. With superhelical DNA and a homologous single-stranded oligonucleotide as substrates, Rec2 actively promoted formation and dissociation of D-loops. When an RNA oligonucleotide was substituted it was found that R-loops could also be formed and utilized as primer/template for limited DNA synthesis. In DNA strand exchange reactions using oligonucleotides, we found that Rec2 exhibited a pairing bias that is opposite that of RecA. Single-stranded oligonucleotides were activated for DNA strand exchange when attached as tails protruding from a duplex sequence due to enhanced binding of Rec2. The results indicate that Rec2 is competent, and in certain ways even better than Rad51, in the ability to provide the fundamental DNA pairing activity necessary for recombinational repair. We propose that the emerging paradigm for homologous recombination featuring Rad51 as the essential catalytic component for strand exchange may not be universal in eukaryotes.