Ten modifiers of BRCA1 penetrance validated in a Norwegian series

BACKGROUND: Common genetic variants have been shown to modify BRCA1 penetrance. The aim of this study was to validate these reports in a special cohort of Norwegian BRCA1 mutation carriers that were selected for their extreme age of onset of disease. METHODS: The ten variants rs13387042, rs3803662, rs8170, rs9397435, rs700518, rs10046, rs3834129, rs1045485, rs2363956 and rs16942 were selected to be tested on samples from our biobank. We selected female BRCA1 mutation carriers having had a diagnosis of breast or ovarian cancer below 40 years of age (young cancer group, N = 40), and mutation carriers having had neither breast nor ovarian cancer above 60 years of age (i.e., old no cancer group, N = 38). Relative risks and odd ratios of belonging to the young cancer versus old no cancer groups were calculated as a function of having or not having the SNPs in question. RESULTS: Five of the ten variants were found to be significantly associated with early onset cancer. Some of the variation between our results and those previously reported may be ascribed to stochastic effects in our limited number of patient studies, and/or genetic drift in linkage disequilibrium in the genetically isolated Norwegian population. This is in accordance with the understanding that the SNPs are markers in linkage disequilibrium with their respective disease-causing genetic variants, and that this may vary between different populations. CONCLUSIONS: The results confirmed associations previously reported, with the notion that the degree of association may differ between other populations, which must be considered when discussing the clinical use of the associations described

O mito protetivo e seus reflexos sobre o sistema de invalidades na esfera justrabalhista

Orientador: Aldacy Rachid CoutinhoMonografia (graduação) - Universidade Federal do Paraná, Setor de Ciências Jurídicas, Curso de Graduação em DireitoO estudo analisa o princípio protetivo do trabalhador partindo da premissa de que este constitui um mito. Para tanto, investiga as características 1) do referido princípio, buscando evidenciar que o laborador não é o único destinatário das normas trabalhistas; 2) do mito da doação, mostrando que os direitos dos trabalhadores foram, em verdade, uma conquista; e 3) da falta de efetividade normativa, destacando-se a dificuldade de concreção da CLT. O sistema de invalidades, nesse contexto, é utilizado para demonstrar em que medida os efeitos do mito protetivo do laborador se refletem no ordenamento jurídico. Porém, antes de abordar a questão no Direito do Trabalho, realiza-se o exame do sistema correspondente no Direito Civil, pelo fato de este ramo jurídico haver lançado as bases de compreensão do tema. Por fim, são apontadas as diferenças existentes entre o ramo justrabalhista e o civil, construídas sob o escopo de adaptar o sistema às peculiaridades do Direito do Trabalho

Propuesta de gestión logística en los almacenes de repuestos de la Distribuidora Santa Mónica S.A.C para reducir sus costos operacionales

RESUMEN La presente tesis es un trabajo de investigación que se enfoca en desarrollar un sistema de gestión logística en los almacenes de repuestos de una distribuidora, que incluye la adquisición, recepción, almacenamiento y correcta entrega de mercadería a los diversos clientes. El conocimiento y aplicación de indicadores y/o métodos permitirá administrar y gestionar; además será el inicio de una serie de acciones a realizar orientadas hacia la mejora continua. Las exigencias de los clientes respecto a la rápida atención de sus requerimientos son cada vez mayores, asimismo el mercado exige ser bastante competitivo en costos, por lo cual un elemento diferenciador, será el analizar la mejora en los procesos logísticos y eliminar todo lo que no genera valor, e identificar y eliminar las causas con la finalidad de automatización de procesos y reducción de los costos operacionales. Finalmente la gestión logística en los almacenes propuesto permite la fácil coordinación de información y distribución dentro del almacén que supera las expectativas del mercado local en una distribuidora generando un impacto positivo en la viabilidad económica tal como: VAN S/. 510,601.54 y TIR 107.37%, adicionalmente se logró desarrollar actividades logísticas de la empresa como: disminución de pérdidas en un 85%, aumento de atenciones a clientes y mayor rapidez del mismo en un 46% y disminución de pedidos en un 35%. Asimismo tiene como ventajas: validar información de proveedores, disminuir niveles de inventario, agilizar rotación artículos y coordinar efectivamente al personal.ABSTRACT The present thesis is a work of investigation that focuses in developing a system of logistic management in the repair parts stocks of a distributor, who includes the acquisition, reception, storage and correcto delivery of merchandise to the diverse clients. The knowledge and application of indicators and/or methods will allow to administer and to manage; in addition it will be the beginning of a series of action to realice oriented towards the continuous improvement. The exigencies of the clients with respect to the fast attention of their requirements are very time majors, also the market demands to be quite competitive in costs, thus an element differentiator, the improvement in the logistic processes will be to analyze and to eliminate everything what it does not generate value, and to identify and to eliminate the causes for the purposes of automatization of processes and reduction of the operational costs. Finally the logistic management in the warehouses proposed allows the easy coordination of information and distribution within the warehouse that surpasses the expectations of the local market in a distributor generating a positive impact in the economic viability as: VAN S/. 510,601.54 and TIR 107.37%, additionally were managed to develop logistics operations of the Company like: diminution of losses in a 85%, increase of attentions in clients and major rapidity of the same in a 46% and diminution of orders in a 35%. Also it has like advantages: to validate information of suppliers, to diminish inventory levels, to make agile rotation articles and to indeed coordinate the personnel

Hereditary breast cancer in South-Eastern Norway BRCA1/2- testing of breast cancer patients. Mutation spectrum and potential modifiers in Norwegian BRCA1/2 carriers

The studies making up the thesis «Hereditary Breast Cancer in South-Eastern Norway. BRCA1/2- testing of breast cancer patients. Mutation spectrum and potential modifiers in Norwegian BRCA1/2 carriers» have been conducted within the field of clinical cancer genetics. The project was run by Cecilie Heramb (M.D.) at the Norwegian National Advisory Unit on Women`s Health and the Department of Medical Genetics, Oslo University Hospital (OUS), It was made possible by a PhD grant from Norwegian Women`s Public Health Association/The Norwegian Foundation for Health and Rehabilitation. The main supervisor was Lovise Olaug Mæhle, Section of Hereditary Cancer, OUS. The research questions were, firstly, to evaluate how current criteria-based BRCA1/2 testing performs in detecting mutation carriers. Secondly, to describe the current BRCA1/2 mutation spectrum in South - Eastern Norway, especially looking at the frequency of Norwegian founder mutations and lastly, to validate in Norwegian BRCA1/2 carriers, findings from international GWAS studies regarding modification of breast cancer risk by SNPs. The methods applied included descriptive statistics and relative risk calculation. The studies have been performed in different cohorts of breast cancer patients and mutation carriers, and through comparing extreme groups of BRCA1/2 mutation carriers. There were several interesting findings. Firstly, ten per cent of breast cancer patients identified as mutation carriers did not fulfill current testing criteria, while 37 % of carriers did fulfill criteria prior to contracting cancers themselves. Also, testing all breast cancer patients < 60 years identified 90 % of carriers. Secondly, the relative amount of founder mutation carriers was lower than previously described. Finally, the modifying effects of the SNPs were not sufficiently present in the Norwegian study group of BRCA1 mutation carriers to inform individual risk prediction

Debutsymptomer hos barn med primær immunsvikt

Early symptoms in children with primary immunodeficiency diseases Primary immunodeficiency diseases are rare. They represent a heterogenous group of disorders characterized by an increased susceptibility to infections. In Norway, 372 patients are diagnosed in a population of 4, 5 million people. Among these are 117 children. Ninety-three of them have been included in this study. The goal has been to evaluate what symptoms the children present early in their disease. What brings them to the doctor and what symptoms do they present at the very first visit? Sixty-five of the 93 patients in the study were boys. Seventy-one, more boys than girls, reported symptoms before one year of age. In total, 33 reported symptoms from the skin or mucosa. Twenty-seven reported upper and 24 lower respiratory symptoms. Only a few presented with serious disease requiring hospitalisation. Children with antibody deficiencies reported more upper respiratory infections, and a high number of otitis. Children with combined deficiencies and other immunodeficiency syndromes reported eczema, bleeding tendency and lower respiratory infections. Phagocytic diseases showed a high number of upper respiratory infections and skin infections compared to the other groups. Immunodeficiencies associated with other congenital diseases presented a high number of stomatitis.. Thirty-seven of 93 (40 %) had a family history of immunodeficiency disease defined as either diagnosed or suspected disease, explained or unexplained childhood deaths, or both. It was surprising to find that only six children contacted a doctor because of family history. Increased attention among doctors and active interviewing about family history are therefore important to discover new cases

Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers

Background: Identification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway. Methods: 1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated. Results: A pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%. Conclusions: Mutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family

BRCA mutation carrier detection. A model-based cost-effectiveness analysis comparing the traditional family history approach and the testing of all patients with breast cancer.

Background: Identification of BRCA mutation carriers among patients with breast cancer (BC) involves costs and gains. Testing has been performed according to international guidelines, focusing on family history (FH) of breast and/or ovarian cancer. An alternative is testing all patients with BC employing sequencing of the BRCA genes and Multiplex Ligation Probe Amplification (MLPA). Patients and methods: A model-based cost-effectiveness analysis, employing data from Oslo University Hospital, Ullevål (OUH-U) and a decision tree, was done. The societal and the healthcare perspectives were focused and a lifetime perspective employed. The comparators were the traditional FH approach used as standard of care at OUH-U in 2013 and the intervention (testing all patients with BC) performed in 2014 and 2015 at the same hospital. During the latter period, 535 patients with BC were offered BRCA testing with sequencing and MLPA. National 2014 data on mortality rates and costs were implemented, a 3% discount rate used and the costing year was 2015. The incremental cost-effectiveness ratio was calculated in euros (€) per life-year gained (LYG). Results: The net healthcare cost (healthcare perspective) was €40 503/LYG. Including all resource use (societal perspective), the cost was €5669/LYG. The univariate sensitivity analysis documented the unit cost of the BRCA test and the number of LYGs the prominent parameters affecting the result. Diagnostic BRCA testing of all patients with BC was superior to the FH approach and cost-effective within the frequently used thresholds (healthcare perspective) in Norway (€60 000–€80 000/LYG)

Mainstreamed genetic testing of breast cancer patients in two hospitals in South Eastern Norway

Studies have shown that a significant number of eligible breast cancer patients are not offered genetic testing or referral to genetic counseling. To increase access to genetic testing in South Eastern Norway, testing has since 2014 been offered directly to breast cancer patients by surgeons and oncologists. This practice is termed “mainstreamed genetic testing”. The aim of this study was to investigate to what extent patients in South Eastern Norway are offered testing. Three hundred and sixty one patients diagnosed in 2016 and 2017 at one regional and one university hospital in South Eastern Norway were included. Data on whether the patients fulfilled the criteria, whether they had been offered testing and if they were tested were collected. In total, 26.6% (96/361) fulfilled the criteria for testing. Seventy five percent (69/92) of these were offered testing, and 71.7% (66/92) were tested. At the university hospital, 90.2% (37/41) of eligible patients were offered testing, and at the regional hospital 62.7% (32/51). Fifty two percent (12/23) of eligible patient not offered testing were younger than 50 years at time of diagnosis. As many as 95.4% (125/131) of all patients who were offered testing, wanted to be tested. The majority of patients who fulfilled the criteria were offered testing, supporting the practice of mainstreamed genetic testing. There were nevertheless differences in rates of testing between the hospitals that affected all groups of patients, indicating that genetic testing may not be equally accessible to all patients. We suggest that efforts should be made to increase awareness and improve routines for genetic testing of breast cancer patients in Norway

“It was an important part of my treatment”: a qualitative study of Norwegian breast Cancer patients’ experiences with mainstreamed genetic testing

Background In South-Eastern Norway, genetic testing for BRCA1 and BRCA2 is offered to breast cancer patients by their treating surgeon or oncologist. Genetic counselling from a geneticist or a genetic counsellor is offered only to those who test positive for a pathogenic variant or have a family history of cancer. This practice is termed “mainstreamed genetic testing”. The aim of this study was to learn about patients’ experience of this healthcare service. Methods Qualitative in-depth interviews were conducted with 22 breast cancer patients who had been diagnosed during the first half of 2016 or 2017 at one regional and one university hospital and who had been offered testing by their treating physician. A six-phase thematic approach was used to analyse the data. Results The participants had varied experiences of how and when testing was offered. Three main themes emerged from the analysis: 1. informational and communicational needs and challenges during a chaotic time, 2. the value of genetic testing and 3. the importance of standardised routines for mainstreamed genetic testing. Conclusions Despite the shock of their diagnosis and the varying experiences they had in respect of how and when testing was offered, all of the participants emphasised that genetic testing had been an important part of their diagnosis and treatment. Our results indicate that there is a need for continuous collaboration between geneticists, surgeons, oncologists and laboratory specialists in order to establish simple and robust routines so as to ensure that all eligible breast cancer patients are offered testing at a point when the test result can have an impact on treatment