Challenges in periodic revision of genetic testing results: Comparison of the main classification guidelines and report of a retrospective analysis involving BRCA1/BRCA2 variants of uncertain significance.

In the context of cancer predisposition syndromes, it is widely known that the correct interpretation of germline variants identified in multigene panel testing is essential for adequate genetic counseling and clinical decision making, in which variants of uncertain significance (VUS) are not considered actionable findings. Thus, their periodic re-evaluation using appropriate guidelines is notably important. In the present study, we compared the performance of the main variant classification guidelines (ACMG, Sherloc and ENIGMA) in variant reassessment, using as input a BRCA1/2 VUS case series (retrospective analysis) from Brazil, an ethnically diverse and admixed country with substantial challenges in VUS reclassification. As main findings, two of the 15 VUS analyzed were reclassified as likely pathogenic by the 3 guidelines, BRCA1 c.4987-3C > G (rs397509213) and BRCA2 c.7868A > G (rs80359012). Moreover, challenges in variant classification and reassessment are described and additional in silico data about structural impact of the variant BRCA2 c.7868A > G are provided. We hypothesize that the establishment of a framework to reassess VUS could improve this process in health centers that have not yet implemented this practice. Results of this study underscore that periodic monitoring of the functional, clinical, and bioinformatics data of a VUS by a multidisciplinary team are of utmost importance in clinical practice. When there is a specific guideline for a given gene, such as ENIGMA for BRCA1/2, it should be considered the first option for variant assessment. Finally, recruitment of VUS carriers and their relatives to participate in variant segregation studies and publication of VUS reclassification results in the international scientific literature should be encouraged.

Primary cells derived from Tuberous Sclerosis Complex patients show autophagy alteration in the haploinsufficiency state.

Tuberous sclerosis complex (TSC) is an autosomal dominant cancer predisposition disorder caused by heterozygous mutations in TSC1 or TSC2 genes and characterized by mTORC1 hyperactivation. TSC-associated tumors develop after loss of heterozygosity mutations and their treatment involves the use of mTORC1 inhibitors. We aimed to evaluate cellular processes regulated by mTORC1 in TSC cells with different mutations before tumor development. Flow cytometry analyses were performed to evaluate cell viability, cell cycle and autophagy in non-tumor primary TSC cells with different heterozygous mutations and in control cells without TSC mutations, before and after treatment with rapamycin (mTORC1 inhibitor). We did not observe differences in cell viability and cell cycle between the cell groups. However, autophagy was reduced in mutated cells. After rapamycin treatment, mutated cells showed a significant increase in the autophagy process (p=0.039). We did not observe differences between cells with distinct TSC mutations. Our main finding is the alteration of autophagy in non-tumor TSC cells. Previous studies in literature found autophagy alterations in tumor TSC cells or knock-out animal models. We showed that autophagy could be an important mechanism that leads to TSC tumor formation in the haploinsufficiency state. This result could guide future studies in this field.

Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diagnosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chompret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p.Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and independent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligomerization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H heterozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants.

Tuberous Sclerosis Complex with rare associated findings in the gastrointestinal system: a case report and review of the literature.

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a complex and heterogeneous genetic disease that has well-established clinical diagnostic criteria. These criteria do not include gastrointestinal tumors. CASE PRESENTATION: We report a 45-year-old patient with a clinical and molecular diagnosis of TSC and a family history of cancer, presenting two rare associated findings: gastrointestinal polyposis and pancreatic neuroendocrine tumor. This patient was subjected to a genetic test with 80 cancer predisposing genes. The genetic panel revealed the presence of a large pathogenic deletion in the TSC2 gene, covering exons 2 to 16 and including the initiation codon. No changes were identified in the colorectal cancer and colorectal polyposis genes. DISCUSSION AND CONCLUSIONS: We describe a case of TSC that presented tumors of the gastro intestinal tract that are commonly unrelated to the disease. The patient described here emphasizes the importance of considering polyposis of the gastrointestinal tract and low grade neuroendocrine tumor as part of the TSC syndromic phenotype.

Synchronous Periampullary Tumors in a Patient With Pancreas Divisum and Neurofibromatosis Type 1.

INTRODUCTION: In this study, we describe for the first time a Neurofibromatosis type 1 patient with pancreas divisum, multiple periampullary tumors and germline pathogenic variants in NF1 and CFTR genes. CASE REPORT: A 62-year-old female NF1 patient presented with weakness, choluria, nausea, and diffuse abdominal pain to an emergency room service. Magnetic resonance imaging revealed an abdominal mass involving the periampullary region and pancreas divisum. After surgical resection, three synchronous neoplasms were detected including two ampullary tumors (adenocarcinoma of the major ampulla and a neuroendocrine tumor of the minor ampulla) and a gastrointestinal stromal tumor (GIST). Germline multigene panel testing (MGPT) identified two pathogenic heterozygous germline variants: NF1 c.838del and CFTR c.1210-34TG[12]T[5]. CONCLUSION: This is the first report of a Neurofibromatosis type 1 patient with pancreas divisum and multiple periampullary tumors harboring pathogenic germline variants in NF1 and CFTR genes. The identification of two germline variants and a developmental anomaly in this patient may explain the unusual and more severe findings and underscores the importance of comprehensive molecular analyses in patients with complex phenotypes.

Haplotypic characterization of BRCA1 c.5266dupC, the prevailing mutation in Brazilian hereditary breast/ovarian cancer.

Specific pathogenic mutations associated with breast cancer development can vary between ethnical groups. One example is BRCA1 c.5266dupC that was first described as a founder mutation in the Ashkenazi Jewish population, but was later also found in other populations. In Brazil, this mutation corresponds to 20% of pathogenic BRCA1 variants reported. Our objective was to investigate the haplotype component of a group of Brazilian families who inherited c.5266dupC in the BRCA1 gene and to verify the ancestry contribution from European, African, and Amerindian origins. Fourteen probands carrying c.5266dupC and 16 relatives (carriers and non-carriers) were investigated. The same haplotype was observed segregating within all the families analyzed, revealing no recombinants in a region of 0.68 Mb. Ancestry analysis demonstrated that the European component was predominant among probands. The BRCA1 c.5266dupC analysis indicates that there was a founder effect in the Brazilian population.

Estudio SEPHCAT: análisis de los servicios de emergencias prehospitalarios en Cataluña / Prehospital emergency services in Catalonia: the SEPHCAT análisis

Objetivo: Describir las principales características de todos los servicios de emergencias prehospitalarios (SEPH) existentes en Cataluña. Método: Una encuestadora profesional entrevistó a los responsables clínicos de todos los SEPH de Cataluña. La encuesta fue preparada por los autores, y abordaba diversos aspectos organizativos, profesionales, laborales, formativos, docentes y de investigación. Las preguntas contenidas en la encuesta solo permitían respuestas cerradas, y hacían referencia a la situación en 2015. Resultados: Se identificaron 13 SEPH (11 públicos, 2 privados), que recibieron 2.482.627 consultas (16,4% a SEPH privados) y realizaron 943.849 atenciones (11,8% por SEPH privados). Había 336 bases de soporte vital básico y 73 de avanzado, con instalaciones mayoritariamente consideradas de tamaño suficiente y calidad buena. Se contrataron 1.374.845 horas anuales (753.995 de médico y 620.850 de enfermero), el 23,4% de ellas por SEPH privados, que globalmente corresponderían a 815 puestos de trabajo a jornada completa (447 de médico, 368 de enfermero). La dotación de médicos/enfermeros era relativamente estable durante el día, pero decaía un 31%/9% de madrugada. La especialidad médica mayoritaria era medicina familiar y comunitaria (56,8%), el 21,3% no tenía formación especializada, y el 6,5% tenía título de doctor. Había médicos/enfermeros profesores universitarios de grado en el 61,5%/46,2% de los SEPH; y de postgrado en el 46,2%/84,6%. Recibían estudiantes de medicina/enfermería en prácticas de grado el 15,4%/15,4% de los SEPH, y de postgrado el 69,2%/76,9%. Conclusiones: La actividad de los SEPH en Cataluña es elevada; un 12% la desarrollan SEPH privados, y globalmente implica a un número alto de médicos y enfermeros, los cuales además desarrollan un rol docente y, en menor medida, investigador

Objective: To describe the main characteristics of all prehospital emergency services (SEPHs, the Catalan acronym) in Catalonia (the SEPHCAT study). Methods: A professional survey researcher interviewed the medical directors of all services in Catalonia, using a questionnaire prepared by the authors. Questions covered aspects related to organization, professional staffing and employment conditions, as well as the staff’s training, instructional activity and research. Only closed answers were collected. The survey reflected the situation in 2015. Results: We identified 13 SEPHs (11 in the public health service and 2 private companies). Together they received 2 482 627 calls (16.4% to private services) and attended 943 849 emergencies (11.8% attended by private companies). Three hundred thirty-six basic life support units and 73 advanced life support units were reported. They were mostly considered to be of sufficient size and quality. The SEPHs contracted 1 374 845 person-hours/y (753 995 physician-hours and 620 850 nurse-hours; 23.4% in private companies). These figures correspond to 815 full-time staff positions (447 for physicians and 368 for nurses). The numbers of physicians and nurses working were relatively stable during the morning, afternoon and evening shifts but decreased during the midnight-to-early-morning shift (physicians, by 31%; nurses, by 9%). A majority of the physicians employed were trained in family and community medicine (56.8%), but 21.3% had no specialized training; 6.5% had PhD degrees. SEPH physicians (61.5%) and nurses (46.2%) also taught undergraduate medical students; 46.2% of physicians and 84.6% of nurses taught postgraduate medical courses. Both undergraduate medical and nursing students were received in the same measure for practical training by 15.4% of the SEPHs; 69.2% also offered practical training for physicians at the postgraduate level and 76.9% trained postgraduate nurses. Conclusions: SEPHs in Catalonia are very active, and private companies account for nearly 12% of the activity. Together the public and private sectors employ a large number of physicians and nurses. Staff members are involved in training others but are less involved in research

Prehospital emergency services in Catalonia: the SEPHCAT analysis. / Estudio SEPHCAT: análisis de los servicios de emergencias prehospitalarios en Cataluña.

OBJECTIVES: To describe the main characteristics of all prehospital emergency services (SEPHs, the Catalan acronym) in Catalonia (the SEPHCAT study). MATERIAL AND METHODS: A professional survey researcher interviewed the medical directors of all services in Catalonia, using a questionnaire prepared by the authors. Questions covered aspects related to organization, professional staffing and employment conditions, as well as the staff's training, instructional activity and research. Only closed answers were collected. The survey reflected the situation in 2015. RESULTS: We identified 13 SEPHs (11 in the public health service and 2 private companies). Together they received 2 482 627 calls (16.4% to private services) and attended 943 849 emergencies (11.8% attended by private companies). Three hundred thirty-six basic life support units and 73 advanced life support units were reported. They were mostly considered to be of sufficient size and quality. The SEPHs contracted 1374845 person-hours/y (753995 physician-hours and 620 850 nurse-hours; 23.4% in private companies). These figures correspond to 815 full-time staff positions (447 for physicians and 368 for nurses). The numbers of physicians and nurses working were relatively stable during the morning, afternoon and evening shifts but decreased during the midnight-to-early-morning shift (physicians, by 31%; nurses, by 9%). A majority of the physicians employed were trained in family and community medicine (56.8%), but 21.3% had no specialized training; 6.5% had PhD degrees. SEPH physicians (61.5%) and nurses (46.2%) also taught undergraduate medical students; 46.2% of physicians and 84.6% of nurses taught postgraduate medical courses. Both undergraduate medical and nursing students were received in the same measure for practical training by 15.4% of the SEPHs; 69.2% also offered practical training for physicians at the postgraduate level and 76.9% trained postgraduate nurses. CONCLUSION: SEPHs in Catalonia are very active, and private companies account for nearly 12% of the activity. Together the public and private sectors employ a large number of physicians and nurses. Staff members are involved in training others but are less involved in research.

OBJETIVO: Describir las principales características de todos los servicios de emergencias prehospitalarios (SEPH) existentes en Cataluña. METODO: Una encuestadora profesional entrevistó a los responsables clínicos de todos los SEPH de Cataluña. La encuesta fue preparada por los autores, y abordaba diversos aspectos organizativos, profesionales, laborales, formativos, docentes y de investigación. Las preguntas contenidas en la encuesta solo permitían respuestas cerradas, y hacían referencia a la situación en 2015. RESULTADOS: Se identificaron 13 SEPH (11 públicos, 2 privados), que recibieron 2.482.627 consultas (16,4% a SEPH privados) y realizaron 943.849 atenciones (11,8% por SEPH privados). Había 336 bases de soporte vital básico y 73 de avanzado, con instalaciones mayoritariamente consideradas de tamaño suficiente y calidad buena. Se contrataron 1.374.845 horas anuales (753.995 de médico y 620.850 de enfermero), el 23,4% de ellas por SEPH privados, que globalmente corresponderían a 815 puestos de trabajo a jornada completa (447 de médico, 368 de enfermero). La dotación de médicos/enfermeros era relativamente estable durante el día, pero decaía un 31%/9% de madrugada. La especialidad médica mayoritaria era medicina familiar y comunitaria (56,8%), el 21,3% no tenía formación especializada, y el 6,5% tenía título de doctor. Había médicos/enfermeros profesores universitarios de grado en el 61,5%/46,2% de los SEPH; y de postgrado en el 46,2%/84,6%. Recibían estudiantes de medicina/enfermería en prácticas de grado el 15,4%/15,4% de los SEPH, y de postgrado el 69,2%/76,9%. CONCLUSIONES: La actividad de los SEPH en Cataluña es elevada; un 12% la desarrollan SEPH privados, y globalmente implica a un número alto de médicos y enfermeros, los cuales además desarrollan un rol docente y, en menor medida, investigador.

Performance of the Gail and Tyrer-Cuzick breast cancer risk assessment models in women screened in a primary care setting with the FHS-7 questionnaire.

Breast cancer (BC) risk assessment models base their estimations on different aspects of a woman's personal and familial history. The Gail and Tyrer-Cuzick models are the most commonly used, and BC risks assigned by them vary considerably especially concerning familial history. In this study, our aim was to compare the Gail and Tyrer-Cuzick models after initial screening for familial history of cancer in primary care using the FHS-7 questionnaire. We compared 846 unrelated women with at least one positive answer to any of the seven FHS-7 questions (positive group) and 892 unrelated women that answered negatively (negative group). Concordance between BC risk estimates was compared by Bland-Altman graphics. Mean BC risk estimates were higher using the Tyrer-Cuzick Model in women from the positive group, while women from the negative group had higher BC risk estimates using the Gail model. With increasing estimates, discordance also increased, mainly in the FHS-7 positive group. Our results show that in women with a familial history of cancer, the Gail model underestimates risk and the Tyrer-Cuzick seems to be more appropriate. FHS-7 can be a useful tool for the identification of women with higher breast cancer risks in the primary care setting.

Screening and characterization of BRCA2 c.156_157insAlu in Brazil: Results from 1380 individuals from the South and Southeast.

Portuguese immigration to Brazil occurred in several waves and greatly contributed to the genetic composition of current Brazilian population. In this study, we evaluated the frequency of a Portuguese founder Alu insertion in BRCA2 exon 3 (c.156_157insAlu) among individuals fulfilling Hereditary Breast and Ovarian Cancer (HBOC) syndrome criteria in 1,380 unrelated families originated from three distinct Brazilian States. We identified the c.156_157insAlu BRCA2 mutation in nine (9/1,380; 0.65%) probands analised. In carrier probands, European ancestry had the highest proportion (80%), followed by the African (10%) and Amerindian and in most families with the rearrangement, haplotype analyses were compatible with the Portuguese ancestral haplotype. In conclusion, the present study reports a low albeit relevant frequency of the Portuguese BRCA2 founder mutation c.156_157insAlu in Brazilian patients at-risk for HBOC Brazilian population.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Correction: BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

[This corrects the article DOI: 10.1371/journal.pone.0187630.].

Clinical and molecular characterization of neurofibromatosis in southern Brazil.

OBJECTIVES: Neurofibromatoses (type 1: NF1; type 2: NF2) are autosomal dominant tumor predisposition syndromes mostly caused by loss-of-function mutations in the tumor suppressor genes NF1 and NF2, respectively. Genotyping is important for correct diagnosis of these diseases. The authors aimed to characterize NF1 and NF2 variants in patients from Southern Brazil. METHODS: Ninety-three unrelated probands with NF1 and 7 unrelated probands with NF2 features were recruited from an Oncogenetics center in Southern Brazil. Two next generation sequencing panels were customized to identify point mutations: NF1 (NF1, RNF135, and SUZ12 genes) and NF2 (NF2 and SMARCB1 genes). Large rearrangements were assessed by Multiplex Ligation-dependent Probe Amplification. RESULTS: Sixty-eight heterozygous NF1 variants were identified in 75/93 probands (80%) and 3 heterozygous NF2 variants were identified in 3/7 probands (43%). In NF1, 59 (87%) variants were pathogenic (4 large rearrangements - 6%), 6 (9%) were likely pathogenic, 3 (4%) were variants of uncertain significance and 28 (41%) were novel. In NF2, all variants were pathogenic. No novel genotype-phenotype correlations were observed; however, previously described correlations were confirmed in our cohort. CONCLUSION: The clinical and molecular characterization of neurofibromatoses in different populations is very important to provide further insights into the pathogenesis of these diseases.

SUHCAT study, part 5: Comparison of staff and chiefs' perceptions of emergency department quality in Catalonia. / Estudio SUHCAT-5: comparación de la percepción de la calidad de los servicios de urgencias de Cataluña entre los profesionales sanitarios y sus responsables.

OBJECTIVES: To study the perceptions of Catalan Society of Emergency Medicine (SoCMUE) members who staff hospital emergency departments regarding measures taken to cope with overcrowding, staff rest areas, and staff size. MATERIAL AND METHODS: Descriptive cross-sectional analysis of a survey sent to SoCMUE members. We compared opinions expressed by physicians and nurses in this survey and also compared them to opinions expressed by heads of departments in prior SUHCAT studies. RESULTS: Responses were received from 363 members who worked in hospital departments. More nurses than physicians expressed the opinion that ambulance unloading was habitually blocked (P=.045), patients were being redirected (P<.001), and staffing was inadequate (P=.007). When the results of our SoCMUE survey were compared to those of the earlier SUHCAT surveys of department chiefs, we found that more SoCMUE members believed that measures to cope with overcrowding are frequently applied, quality in rest areas is poorer, and staffing is inadequate. CONCLUSION: Physicians and nurses who are members of SoCMUE and work in hospital emergency departments have different views on measures taken to cope with overcrowding, quality of rest areas, and staff size. In addition, the SoCMUE members' opinions differed from those of respondents in prior SUHCAT studies.

OBJETIVO: Conocer la percepción de los socios de la Societat Catalana de Medicina d'Urgències i Emergències (SoCMUE) con actividad laboral en servicios de urgencias hospitalarios (SUH) respecto a las medidas frente al colapso, las áreas de descanso y la dimensión de la plantilla, y compararla con la de sus responsables. METODO: Estudio descriptivo transversal mediante encuesta enviada a los socios de SoCMUE. Se compararon las respuestas dadas entre el estamento médico y enfermero, y con los resultados de los estudios SUHCAT 1 y 2. RESULTADOS: Participaron 363 socios. Los enfermeros opinan más frecuentemente que los médicos que es habitual impedir la descarga de ambulancias (p = 0,045), redireccionar pacientes (p < 0,001) y que sus plantillas son insuficientes (p = 0,007). Los socios de SoCMUE perciben mayor frecuencia en la puesta en marcha de todas las medidas para hacer frente al colapso, peor calidad de las áreas de descanso y una plantilla insuficiente en comparación con la opinión de los responsables de los SUH. CONCLUSIONES: Los médicos y enfermeros socios de la SoCMUE que trabajan en los SUH tienen una percepción diferente en aspectos relacionados con las medidas frente al colapso, áreas de descanso y dimensión de la plantilla, que difiere también de la opinión de sus responsables.

Estudio SUHCAT-5: comparación de la percepción de la calidad de los servicios de urgencias de Cataluña entre los profesionales sanitarios y sus responsables / SUHCAT study, part 5: Comparison of staff and chiefs' perceptions of emergency department quality in Catalonia

Objetivo. Conocer la percepción de los socios de la Societat Catalana de Medicina d'Urgències i Emergències (SoCMUE) con actividad laboral en servicios de urgencias hospitalarios (SUH) respecto a las medidas frente al colapso, las áreas de descanso y la dimensión de la plantilla, y compararla con la de sus responsables. Método. Estudio descriptivo transversal mediante encuesta enviada a los socios de SoCMUE. Se compararon las respuestas dadas entre el estamento médico y enfermero, y con los resultados de los estudios SUHCAT 1 y 2. Resultado. Participaron 363 socios. Los enfermeros opinan más frecuentemente que los médicos que es habitual impedir la descarga de ambulancias (p = 0,045), redireccionar pacientes (p < 0,001) y que sus plantillas son insuficientes (p = 0,007). Los socios de SoCMUE perciben mayor frecuencia en la puesta en marcha de todas las medidas para hacer frente al colapso, peor calidad de las áreas de descanso y una plantilla insuficiente en comparación con la opinión de los responsables de los SUH. Conclusión. Los médicos y enfermeros socios de la SoCMUE que trabajan en los SUH tienen una percepción diferente en aspectos relacionados con las medidas frente al colapso, áreas de descanso y dimensión de la plantilla, que difiere también de la opinión de sus responsables (AU)

Objective. To study the perceptions of Catalan Society of Emergency Medicine (SoCMUE) members who staff hospital emergency departments regarding measures taken to cope with overcrowding, staff rest areas, and staff size. Methods. Descriptive cross-sectional analysis of a survey sent to SoCMUE members. We compared opinions expressed by physicians and nurses in this survey and also compared them to opinions expressed by heads of departments in prior SUHCAT studies. Results. Responses were received from 363 members who worked in hospital departments. More nurses than physicians expressed the opinion that ambulance unloading was habitually blocked (P=.045), patients were being redirected (P< 001), and staffing was inadequate (P=.007). When the results of our SoCMUE survey were compared to those of the earlier SUHCAT surveys of department chiefs, we found that more SoCMUE members believed that measures to cope with overcrowding are frequently applied, quality in rest areas is poorer, and staffing is inadequate. Conclusion. Physicians and nurses who are members of SoCMUE and work in hospital emergency departments have different views on measures taken to cope with overcrowding, quality of rest areas, and staff size. In addition, the SoCMUE members' opinions differed from those of respondents in prior SUHCAT studies (AU)

TP53 p.Arg337His germline mutation prevalence in Southern Brazil: Further evidence for mutation testing in young breast cancer patients.

Premenopausal breast cancer (BC) is a core tumor of Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) Syndromes, predisposition disorders caused by germline mutations in TP53 gene. In the Southern and Southeastern regions of Brazil, a specific TP53 germline mutation, c.1010G>A (p.Arg337His), was identified at a population frequency of 0.3%, the highest value ever described for a TP53 germline variation. In Brazilian BC patients, carrier frequency can vary from 0.5% to 8.7%. The current study assessed carrier frequency by genotyping TP53 c.1010G>A in 2 BC groups: 1) 315 patients unselected for age of diagnosis and family history (FH) and 2) 239 patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. One carrier was identified in group 1 (0.3%; CI 95% 0.1-1.76%) and six carriers in group 2 (2.5%; CI 95% 0.93-5.39%). The frequencies differed significantly between groups (p = 0.04). The mutation carrier frequency observed in group 2 could justify mutation testing in BC patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. Further studies in larger samples of BC patients of different ages and regions of the country are necessary to provide more definitive TP53 p.Arg337His carrier frequencies in different scenarios.

[Occupational aspects of emergency medicine practice in Catalonia: the OPENCAT opinion survey]. / Opinión de los profesionales acerca de diversos aspectos laborales de los servicios de urgencias y emergencias de Cataluña: Estudio OPENCAT.

OBJECTIVES: To gather information on the contracting and training of members of the Catalan Society of Emergency Medicine (SoCMUE) who work in emergency medicine and services in Catalonia. To survey their opinions on certain aspects of resource availability and working conditions. MATERIAL AND METHODS: Cross-sectional descriptive study based on a survey sent to SoCMUE members. We studied the opinions of 5 types of respondent: hospital physicians, out-of-hospital physicians, hospital nurses, out-of-hospital nurses, and emergency medical technicians. Responses were grouped to compare the opinions of physicians and nurses and workers in hospital and prehospital settings. RESULTS: We received 616 responses from 1273 members (48.4% response rate). More physicians than nurses come from outside Catalonia and have contracts specifically linked to emergency care; in addition, physicians have done less postgraduate training in emergency medicine. More hospital staff than prehospital staff have permanent contracts linked to the department where they work. More hospital physicians are specialized in internal medicine than in family and community medicine. The opinion that emergency services are inadequately staffed was widespread. Most respondents believed that patient transport is good or adequate. However, respondents working in prehospital services expressed a lower opinion of transport. Great difficulty in combining work with family (life achieving work-life balance) was expressed by 13.5% overall, and more often by hospital staff. Some type of aggression was experienced by 88.2%; 60% reported the event to superiors. Nurses reported aggression more often than physicians. A police report was filed by 10.1%. CONCLUSION: Emergency medicine working conditions can be improved in Catalonia according to members of SoCMUE. Relations between groups of professionals are not optimum in some aspects.

OBJETIVO: Investigar las condiciones contractuales y formativas de los socios de la Societat Catalana de Medicina d'Urgències i Emergéncies (SoCMUE) que trabajan en el ámbito de la Medicina de Urgencias y Emergencias (MUE) en Cataluña, y su percepción acerca de algunos recursos disponibles y aspectos de su práctica laboral. METODO: Estudio descriptivo transversal mediante encuesta enviada a los socios de SoCMUE. Se distinguieron médicos hospitalarios y extrahospitalarios, enfermeros hospitalarios y extrahospitalarios, y técnicos en emergencia sanitaria (TES). Se realizaron agrupaciones de médico/enfermero y hospitalario/extrahospitalario. RESULTADOS: Respondieron 616 de 1.273 socios (48,4%). Respecto a los enfermeros, los médicos tienen mayor porcentaje de profesionales no comunitarios, contratos más vinculados a urgencias/emergencias, y han realizado menos formación de postgrado en MUE. Los profesionales hospitalarios, respecto a los extrahospitalarios, tienen mayor proporción de contratos fijos y vinculados al propio servicio, han realizado menos formación de postgrado, y la proporción de especialistas en medicina interna es mayor y en medicina familiar y comunitaria menor. Existe la percepción generalizada de plantillas insuficientes. La transferencia de pacientes es considerada mayoritariamente buena o correcta, pero es peor percibida por extrahospitalaria. El 13,5% refiere una conciliación familiar imposible, más frecuentemente en el ámbito hospitalario. El 88,2% ha sufrido algún tipo de agresión, el 60% lo comunicó a sus superiores (enfermeros más que médicos) y el 10,1% lo denunció judicialmente. CONCLUSIONES: Para los socios de la SoCMUE, en la práctica de la MUE en Cataluña, existen algunas condiciones laborales mejorables y la relación entre colectivos de profesionales es poco óptima en algunos aspectos.

Opinión de los profesionales acerca de diversos aspectos laborales de los servicios de urgencias y emergencias de Cataluña: Estudio OPENCAT / Occupational aspects of emergency medicine practice in Catalonia: the OPENCAT opinion survey

Objetivo. Investigar las condiciones contractuales y formativas de los socios de la Societat Catalana de Medicina d'Urgencies i Emergencies (SoCMUE) que trabajan en el ámbito de la Medicina de Urgencias y Emergencias (MUE) en Cataluña, y su percepción acerca de algunos recursos disponibles y aspectos de su práctica laboral. Método. Estudio descriptivo transversal mediante encuesta enviada a los socios de SoCMUE. Se distinguieron médicos hospitalarios y extrahospitalarios, enfermeros hospitalarios y extrahospitalarios, y técnicos en emergencia sanitaria (TES). Se realizaron agrupaciones de medico/enfermero y hospitalario/extrahospitalario. Resultados. Respondieron 616 de 1.273 socios (48,4%). Respecto a los enfermeros, los médicos tienen mayor porcentaje de profesionales no comunitarios, contratos más vinculados a urgencias/emergencias, y han realizado menos formación de postgrado en MUE. Los profesionales hospitalarios, respecto a los extrahospitalarios, tienen mayor proporción de contratos fijos y vinculados al propio servicio, han realizado menos formación de postgrado, y la proporción de especialistas en medicina interna es mayor y en medicina familiar y comunitaria menor. Existe la percepción generalizada de plantillas insuficientes. La transferencia de pacientes es considerada mayoritariamente buena o correcta, pero es peor percibida por extrahospitalaria. El 13,5% refiere una conciliación familiar imposible, más frecuentemente en el ámbito hospitalario. El 88,2% ha sufrido algún tipo de agresión, el 60% lo comunico a sus superiores (enfermeros más que médicos) y el 10,1% lo denuncio judicialmente. Conclusión. Para los socios de la SoCMUE, en la práctica de la MUE en Cataluña, existen algunas condiciones laborales mejorables y la relación entre colectivos de profesionales es poco optima en algunos aspectos (AU)

Objective. To gather information on the contracting and training of members of the Catalan Society of Emergency Medicine (SoCMUE) who work in emergency medicine and services in Catalonia. To survey their opinions on certain aspects of resource availability and working conditions. Methods. Cross-sectional descriptive study based on a survey sent to SoCMUE members. We studied the opinions of 5 types of respondent: hospital physicians, out-of-hospital physicians, hospital nurses, out-of-hospital nurses, and emergency medical technicians. Responses were grouped to compare the opinions of physicians and nurses and workers in hospital and prehospital settings. Results. We received 616 responses from 1273 members (48.4% response rate). More physicians than nurses come from outside Catalonia and have contracts specifically linked to emergency care; in addition, physicians have done less postgraduate training in emergency medicine. More hospital staff than prehospital staff have permanent contracts linked to the department where they work. More hospital physicians are specialized in internal medicine than in family and community medicine. The opinion that emergency services are inadequately staffed was widespread. Most respondents believed that patient transport is good or adequate. However, respondents working in prehospital services expressed a lower opinion of transport. Great difficulty in combining work with family (life achieving work-life balance) was expressed by 13.5% overall, and more often by hospital staff. Some type of aggression was experienced by 88.2%; 60% reported the event to superiors. Nurses reported aggression more often than physicians. A police report was filed by 10.1%. Conclusion. Emergency medicine working conditions can be improved in Catalonia according to members of SoCMUE. Relations between groups of professionals are not optimum in some aspects (AU)

BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

BACKGROUND: Germline pathogenic variants in BRCA1 and BRCA2 (BRCA) are the main cause of Hereditary Breast and Ovarian Cancer syndrome (HBOC). METHODS: In this study we evaluated the mutational profile and prevalence of BRCA pathogenic/likely pathogenic variants among probands fulfilling the NCCN HBOC testing criteria. We characterized the clinical profile of these individuals and explored the performance of international testing criteria. RESULTS: A pathogenic/likely pathogenic variant was detected in 19.1% of 418 probands, including seven novel frameshift variants. Variants of uncertain significance were found in 5.7% of individuals. We evaluated 50 testing criteria and mutation probability algorithms. There was a significant odds-ratio (OR) for mutation prediction (p ≤ 0.05) for 25 criteria; 14 of these had p ≤ 0.001. Using a cutoff point of four criteria, the sensitivity is 83.8%, and the specificity is 53.5% for being a carrier. The prevalence of pathogenic/likely pathogenic variants for each criterion ranged from 22.1% to 55.6%, and criteria with the highest ORs were those related to triple-negative breast cancer or ovarian cancer. CONCLUSIONS: This is the largest study of comprehensive BRCA testing among Brazilians to date, and the first to analyze clinical criteria for genetic testing. Several criteria that are not included in the NCCN achieved a higher predictive value. Identification of the most informative criteria for each population will assist in the development of a rational approach to genetic testing, and will enable the prioritization of high-risk individuals as a first step towards offering testing in low-income countries.

Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by the development of multiple hamartomas in many organs and tissues. It occurs due to inactivating mutations in either of the two genes, TSC1 and TSC2, following a second hit in a tumor suppressor gene in most hamartomas. Comprehensive screening for mutations in both the TSC1 and TSC2 loci has been performed in several cohorts of patients and a broad spectrum of pathogenic mutations have been described. In Brazil, there is no data regarding incidence and prevalence of tuberous sclerosis and mutations in TSC1 and TSC2. We analyzed both genes in 53 patients with high suspicion of tuberous sclerosis using multiplex-ligation dependent probe amplification and a customized next generation sequencing panel. Confirmation of all variants was done by the Sanger method. We identified 50 distinct variants in 47 (89%) of the patients. Five were large rearrangements and 45 were point mutations. The symptoms presented by our series of patients were not different between male and female individuals, except for the more common occurrence of shagreen patch in women (p = 0.028). In our series, consistent with other studies, TSC2 mutations were associated with a more severe phenotypic spectrum than TSC1 mutations. This is the first study that sought to characterize the molecular spectrum of Brazilian individuals with tuberous sclerosis.