Implications of using whole genome sequencing to test unselected populations for high risk breast cancer genes: a modelling study.

BACKGROUND: The decision to test for high risk breast cancer gene mutations is traditionally based on risk scores derived from age, family and personal cancer history. Next generation sequencing technologies such as whole genome sequencing (WGS) make wider population testing more feasible. In the UK's 100,000 Genomes Project, mutations in 16 genes including BRCA1 and BRCA2 are to be actively sought regardless of clinical presentation. The implications of deploying this approach at scale for patients and clinical services are unclear. In this study we aimed to model the effect of using WGS to test an unselected UK population for high risk BRCA1 and BRCA2 gene variants to inform the debate around approaches to secondary genomic findings. METHODS: We modelled the test performance of WGS for identifying pathogenic BRCA1 and BRCA2 mutations in an unselected hypothetical population of 100,000 UK women, using published literature to derive model input parameters. We calculated analytic and clinical validity, described potential health outcomes and highlighted current areas of uncertainty. We also performed a sensitivity analysis in which we re-ran the model 100,000 times to investigate the effect of varying input parameters. RESULTS: In our models WGS was predicted to identify correctly 93 pathogenic BRCA1 mutations and 151 BRCA2 mutations in 120 and 200 women respectively, resulting in an analytic sensitivity of 75.5-77.5 %. Of 244 women with identified pathogenic mutations, we estimated that 132 (range 121-198) would develop breast cancer, so could potentially be helped by intervention. We also predicted that breast cancer would occur in 41 women (range 36-62) incorrectly identified with no pathogenic mutations and in 12,460 women without BRCA1 or BRCA2 mutations. There was considerable uncertainty about the penetrance of mutations in people without a family history of disease and the appropriate threshold of absolute disease risk for clinical action, which impacts on judgements about the clinical utility of intervention. CONCLUSIONS: This simple model demonstrates the need for robust processes to support the testing for secondary genomic findings in unselected populations that acknowledge levels of uncertainty about the clinical validity and clinical utility of testing positive for a cancer risk gene

Clinical Presentation of Ocular Surface Squamous Neoplasia in Kenya.

IMPORTANCE: There is a trend toward treating conjunctival lesions suspected to be ocular surface squamous neoplasia (OSSN) based on the clinical impression. OBJECTIVE: To describe the presentation of OSSN and identify clinical features that distinguish it from benign lesions and subsequently evaluate their recognizability. DESIGN, SETTING, AND PARTICIPANTS: Prospective multicenter study in Kenya from July 2012 through July 2014 of 496 adults presenting with conjunctival lesions. One histopathologist examined all specimens. Six additional masked ophthalmologists independently examined photographs from 100 participants and assessed clinical features. EXPOSURES: Comprehensive history, slitlamp examination, and photography before excision biopsy. MAIN OUTCOMES AND MEASURES: Frequency of clinical features in OSSN and benign lesions were recorded. Proportions and means were compared using χ2, Fisher exact test, or t test as appropriate. Interobserver agreement was estimated using the κ statistic. Examiners' assessments were compared with a reference. RESULTS: Among 496 participants, OSSN was the most common (38%) histological diagnosis, followed by pterygium (36%) and actinic keratosis (19%). Patients with OSSN were slightly older (mean [SD] age, 41 [11.6] vs 38 [10.9] years; P = .002) and tended to have lower levels of education than patients with benign lesions (P = .001). Females predominated (67% of OSSN vs 64% of benign lesions; P = .65). Human immunodeficiency virus infection was common among patients with OSSN (74%). The most common location was the nasal limbus (61% OSSN vs 78% benign lesions; P < .001). Signs more frequent in OSSN included feeder vessels (odds ratio [OR], 5.8 [95% CI, 3.2-10.5]), moderate inflammation (OR, 3.5 [95% CI, 1.8-6.8]), corneal involvement (OR, 2.7 [95% CI, 1.8-4.0]), leukoplakia (OR, 2.6 [95% CI, 1.7-3.9]), papilliform surface (OR, 2.1 [95% CI, 1.3-3.5]), pigmentation (OR, 1.5 [95% CI, 1.0-2.2]), temporal location (OR, 2.0 [95% CI, 1.2-3.2]), circumlimbal location (6.7% vs 0.3%; P < .001), severe inflammation (6.7% vs 0.3%; P < .001), and larger mean (SD) diameter (6.8 [3.2] vs 4.8 [2.8] mm; P < .001). All OSSN signs were also observed in benign lesions. There was slight to fair interobserver agreement in assessment of most signs and diagnosis (κ, 0.1-0.4). The positive predictive value of clinical appearance in identifying OSSN was 54% (interquartile range, 51%-56%) from photographs in which prevalence was 32%. CONCLUSIONS AND RELEVANCE: With overlapping phenotypes and modest interobserver agreement, OSSN and benign conjunctival lesions are not reliably distinguished clinically. Point-of-care diagnostic tools may help

Topical fl uorouracil after surgery for ocular surface squamous neoplasia in Kenya: a randomised, double-blind, placebo-controlled trial

Background Ocular surface squamous neoplasia (OSSN) is an aggressive eye tumour particularly aff ecting people with HIV in Africa. Primary treatment is surgical excision; however, tumour recurrence is common. We assessed the eff ect of fl uorouracil 1% eye drops after surgery on recurrence. Methods We did this multicentre, randomised, placebo-controlled trial in four centres in Kenya. We enrolled patients with histologically proven OSSN aged at least 18 years. After standard surgical excision, participants were randomly allocated to receive either topical fl uorouracil 1% or placebo four times a day for 4 weeks. Randomisation was stratifi ed by surgeon, and participants and trial personnel were masked to assignment. Patients were followed up at 1 month, 3 months, 6 months, and 12 months. The primary outcome was clinical recurrence (supported by histological assessment where available) by 1 year, and analysed by intention to treat. The sample size was recalculated because events were more common than anticipated, and trial enrolment was stopped early. The trial was registered with Pan-African Clinical Trials Registry (PACTR201207000396219). Findings Between August, 2012, and July, 2014, we assigned 49 participants to fl uorouracil and 49 to placebo. Four participants were lost to follow-up. Recurrences occurred in fi ve (11%) of 47 patients in the fl uorouracil group and 17 (36%) of 47 in the placebo group (odds ratio 0·21, 95% CI 0·07–0·63; p=0·01). Adjusting for passive smoking and antiretroviral therapy had little eff ect (odds ratio 0·23; 95% CI 0·07–0·75; p=0·02). Adverse eff ects occurred more commonly in the fl uorouracil group, although they were transient and mild. Ocular discomfort occurred in 43 of 49 patients in the fl uorouracil group versus 36 of 49 in the placebo group, epiphora occurred in 24 versus fi ve, and eyelid skin infl ammation occurred in seven versus none. Interpretation Topical fl uorouracil after surgery substantially reduced recurrence of OSSN, was well-tolerated, and its use recommended

Topical fl uorouracil after surgery for ocular surface squamous neoplasia in Kenya: a randomised, double-blind, placebo-controlled trial

Background Ocular surface squamous neoplasia (OSSN) is an aggressive eye tumour particularly aff ecting people with HIV in Africa. Primary treatment is surgical excision; however, tumour recurrence is common. We assessed the eff ect of fl uorouracil 1% eye drops after surgery on recurrence. Methods We did this multicentre, randomised, placebo-controlled trial in four centres in Kenya. We enrolled patients with histologically proven OSSN aged at least 18 years. After standard surgical excision, participants were randomly allocated to receive either topical fl uorouracil 1% or placebo four times a day for 4 weeks. Randomisation was stratifi ed by surgeon, and participants and trial personnel were masked to assignment. Patients were followed up at 1 month, 3 months, 6 months, and 12 months. The primary outcome was clinical recurrence (supported by histological assessment where available) by 1 year, and analysed by intention to treat. The sample size was recalculated because events were more common than anticipated, and trial enrolment was stopped early. The trial was registered with Pan-African Clinical Trials Registry (PACTR201207000396219). Findings Between August, 2012, and July, 2014, we assigned 49 participants to fl uorouracil and 49 to placebo. Four participants were lost to follow-up. Recurrences occurred in fi ve (11%) of 47 patients in the fl uorouracil group and 17 (36%) of 47 in the placebo group (odds ratio 0·21, 95% CI 0·07–0·63; p=0·01). Adjusting for passive smoking and antiretroviral therapy had little eff ect (odds ratio 0·23; 95% CI 0·07–0·75; p=0·02). Adverse eff ects occurred more commonly in the fl uorouracil group, although they were transient and mild. Ocular discomfort occurred in 43 of 49 patients in the fl uorouracil group versus 36 of 49 in the placebo group, epiphora occurred in 24 versus fi ve, and eyelid skin infl ammation occurred in seven versus none. Interpretation Topical fl uorouracil after surgery substantially reduced recurrence of OSSN, was well-tolerated, and its use recommended

Toluidine Blue 0.05% Vital Staining for the Diagnosis of Ocular Surface Squamous Neoplasia in Kenya.

IMPORTANCE: Clinical features are unreliable for distinguishing ocular surface squamous neoplasia (OSSN) from benign conjunctival lesions. OBJECTIVE: To evaluate the adverse effects, accuracy, and interobserver variation of toluidine blue 0.05% vital staining in distinguishing OSSN, confirmed by histopathology, from other conjunctival lesions. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in Kenya from July 2012 through July 2014 of 419 adults with suspicious conjunctival lesions. Pregnant and breastfeeding women were excluded. EXPOSURES: Comprehensive ophthalmic slitlamp examination was conducted. Vital staining with toluidine blue 0.05% aqueous solution was performed before surgery. Initial safety testing was conducted on large tumors scheduled for exenteration looking for corneal toxicity on histology before testing smaller tumors. We asked about pain or discomfort after staining and evaluated the cornea at the slitlamp for epithelial defects. Lesions were photographed before and after staining. MAIN OUTCOMES AND MEASURES: Diagnosis was confirmed by histopathology. Six examiners assessed photographs from a subset of 100 consecutive participants for staining and made a diagnosis of OSSN vs non-OSSN. Staining was compared with histopathology to estimate sensitivity, specificity, and predictive values. Adverse effects were enumerated. Interobserver agreement was estimated using the κ statistic. RESULTS: A total of 143 of 419 participants (34%) had OSSN by histopathology. The median age of all participants was 37 years (interquartile range, 32-45 years) and 278 (66%) were female. A total of 322 of the 419 participants had positive staining while 2 of 419 were equivocal. There was no histological evidence of corneal toxicity. Mild discomfort was reported by 88 (21%) and mild superficial punctate keratopathy seen in 7 (1.7%). For detecting OSSN, toluidine blue had a sensitivity of 92% (95% CI, 87%-96%), specificity of 31% (95% CI, 25%-36%), positive predictive value of 41% (95% CI, 35%-46%), and negative predictive value of 88% (95% CI, 80%-94%). Interobserver agreement was substantial for staining (κ = 0.76) and moderate for diagnosis (κ = 0.40). CONCLUSIONS AND RELEVANCE: With the high sensitivity and low specificity for OSSN compared with histopathology among patients with conjunctival lesions, toluidine blue 0.05% vital staining is a good screening tool. However, it is not a good diagnostic tool owing to a high frequency of false-positives. The high negative predictive value suggests that a negative staining result indicates that OSSN is relatively unlikely

Lyon House

Prepared by the Fall 2008 Conservation of Historic Building Materials class. This Historic Structure Report contains historical information of the Lyon House and the surrounding acreage, architectural descriptions, conditions assessments, maintenance plans, and recommended treatments and uses for the building and site features. The purpose of this document is to serve the stewards of the Lyon property as a reference point for any and all projects suggested for the building and site. The report is a dynamic resource that facilitates the documentation of preservation practices applied to the property.https://scholarworks.gsu.edu/history_heritagepreservation/1026/thumbnail.jp

Topical fluorouracil after surgery for ocular surface squamous neoplasia in Kenya: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Ocular surface squamous neoplasia (OSSN) is an aggressive eye tumour particularly affecting people with HIV in Africa. Primary treatment is surgical excision; however, tumour recurrence is common. We assessed the effect of fluorouracil 1% eye drops after surgery on recurrence. METHODS: We did this multicentre, randomised, placebo-controlled trial in four centres in Kenya. We enrolled patients with histologically proven OSSN aged at least 18 years. After standard surgical excision, participants were randomly allocated to receive either topical fluorouracil 1% or placebo four times a day for 4 weeks. Randomisation was stratified by surgeon, and participants and trial personnel were masked to assignment. Patients were followed up at 1 month, 3 months, 6 months, and 12 months. The primary outcome was clinical recurrence (supported by histological assessment where available) by 1 year, and analysed by intention to treat. The sample size was recalculated because events were more common than anticipated, and trial enrolment was stopped early. The trial was registered with Pan-African Clinical Trials Registry (PACTR201207000396219). FINDINGS: Between August, 2012, and July, 2014, we assigned 49 participants to fluorouracil and 49 to placebo. Four participants were lost to follow-up. Recurrences occurred in five (11%) of 47 patients in the fluorouracil group and 17 (36%) of 47 in the placebo group (odds ratio 0·21, 95% CI 0·07-0·63; p=0·01). Adjusting for passive smoking and antiretroviral therapy had little effect (odds ratio 0·23; 95% CI 0·07-0·75; p=0·02). Adverse effects occurred more commonly in the fluorouracil group, although they were transient and mild. Ocular discomfort occurred in 43 of 49 patients in the fluorouracil group versus 36 of 49 in the placebo group, epiphora occurred in 24 versus five, and eyelid skin inflammation occurred in seven versus none. INTERPRETATION: Topical fluorouracil after surgery substantially reduced recurrence of OSSN, was well-tolerated, and its use recommended. FUNDING: British Council for Prevention of Blindness and the Wellcome Trust

Barriers and facilitators to primary care research: views of GP trainees and trainers

Background: Primary care plays an important role in the conception and delivery of transformational research but GP engagement lacks, prompting calls for the promotion of academic opportunities in primary care. Aim: To identify potential barriers and facilitators amongst GP trainees and trainers in primary care research to inform support given by Local Clinical Research Networks (LCRNs). Design & setting: A cross sectional online survey was developed and distributed by the CRN to GP trainees and trainers in the North East and North West. Method: The survey covered areas including demographics, career intentions, current and potential engagement with research as well as their general understanding of research in primary care, that included barriers and facilitators to primary care research. Results: Trainees had low intentionality to pursue research and half of trainees did not engage with any research activity. Despite 1 in five trainees reporting intentions to include research in their career, only 1% would undertake a solely academic career. Medical school region is the only strongly associated factor with academic career intention. Just under 30% of trainers reported engagement in research, but far fewer (8.6%) were interested in contributing to research, and only 10% felt prepared to mentor in research. Conclusion: Among trainees, there is limited engagement in, and intentionality to pursue research and this is crucially reflected by responses from trainers. This study identifies the need for LCRN’s to assist with training in research mentoring and skills, funding opportunities and to develop resources to promote research in primary care