BRCA1 and BRCA2 mutations in a population-based study of male breast cancer

Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk. Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives. Conclusion: These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found

Implementation of nutritional guidelines in a university hospital monitored by repeated point prevalence surveys

Background/Objectives: Malnutrition is present in 20–50% of hospitalized patients, and nutritional care is a challenge. The aim was to evaluate whether the implementation of a nutritional strategy would influence nutritional care performance in a university hospital. Subjects/Methods: This was a prospective quality improvement program implementing guidelines for nutritional care, with the aim of improving nutritional practice. The Nutrition Risk Screening (NRS) 2002 was used. Point prevalence surveys over 2 years to determine whether nutritional practice had improved. Results: In total, 3604 (70%) of 5183 eligible patients were screened and 1230 (34%) were at nutritional risk. Only 53% of the at-risk patients got nutritional treatment and 5% were seen by a dietician. The proportion of patients screened increased from the first to the eighth point prevalence survey (P=0.012), but not the proportion of patients treated (P=0.66). The four initial screening questions in NRS 2002 identified 92% of the patients not at nutritional risk. Conclusions: Implementation of nutritional guidelines improved the screening performance, but did not increase the proportion of patients who received nutritional treatment. Point prevalence surveys were useful to evaluate nutritional practice in this university hospital. In order to improve practice, we suggest using only the four initial screening questions in NRS 2002 to identify patients not at risk, better education in nutritional care for physicians and nurses, and more dieticians employed. Audit of implementation of guidelines, performed by health authorities, and specific reimbursement for managing nutrition may also improve practice.publishedVersio

Increased somatic mutation burdens in normal human cells due to defective DNA polymerases.

Funder: Wellcome PhD StudentshipFunder: Jean Shank/Pathological Society Intermediate FellowshipFunder: Wellcome Clinical PhD fellowshipMutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life

In vivo performance of hierarchical HRP-crosslinked silk fibroin/β-TCP scaffolds for osteochondral tissue regeneration

Background: Osteochondral defects (OCD) can affect the articular cartilage and subchondral bone tissues, which requires superior therapies for the simultaneous and full restoration of such structurally and biologically different tissues. Methods: Tissue engineered OC grafts were prepared using a horseradish peroxidase (HRP) approach to crosslink silk fibroin (HRP-SF) as the articular cartilage-like layer and an underlying HRP-SF/ZnSrTCP subchondral bone-like layer (HRP-SF/dTCP), through salt-leaching/freeze-drying methodologies. In vivo OC regeneration was assessed by implantating the hierarchical scaffolds in rabbit critical size OC defects, during 8 weeks. A comparative analysis was performed using hierarchical OC grafts made of pure β-TCP (HRP-SF/TCP). Results: The hierarchical scaffolds showed good integration into the host tissue and no signs of acute inflammatory reaction, after 8 weeks of implantation. The histological analyses revealed positive collagen type II and glycosaminoglycansâ formation in the articular cartilage-like layer. New bone ingrowthâ s and blood vessels infiltration were detected in the subchondral bone-like layers. Conclusions: The proposed hierarchical scaffolds presented an adequate in vivo response with cartilage tissue regeneration and calcified tissue formation specially promoted by the ionic incorporation into the subchondral bone layer, confirming the hierarchical structures as suitable for OCD regeneration.Portuguese Foundation for Science and Technology for the Hierarchitech project (M-era-Net/0001/2014), for the fellowships (SFRH/BD/99555/2014) and (SFRH/BPD/101952/2014), and for the distinctions attributed to JMO (IF/01285/2015) and SP (CEECIND/03673/2017). Also, financial support from FCT/MCTES (Fundação para a Ciência e a Tecnologia/ Ministério Da Ciência, Tecnologia, e Ensino Superior) and fundo social europeu através do programa operacional do capital humano (FSE/POCH), PD/59/2013, PD/BD/113806/201

The landscape of somatic mutation in normal colorectal epithelial cells.

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer

Risk of malnutrition and health-related quality of life in community-living elderly men and women: The Tromsø study

Purpose To explore the association between risk of malnutrition as well as current body mass index (BMI) and health-related quality of life (HRQoL) in elderly men and women from the general population. Methods In a cross-sectional population survey including 1,632 men and 1,654 women aged 65 to 87 years from the municipality of Tromsø, Norway, we assessed HRQoL by using the EuroQol (EQ-5D) instrument in three risk groups of malnutrition and in different categories of BMI. The Malnutrition Universal Screening Tool (‘MUST’) was used to evaluate the risk of malnutrition. Results We found a significant reduction in HRQoL with an increasing risk of malnutrition, and this was more pronounced in men than in women. The relationship between BMI and HRQoL was dome shaped, with the highest score values in the BMI category being 25–27.5 kg/m2. Conclusions HRQoL was significantly reduced in elderly men and women at risk of malnutrition. The highest HRQoL was seen in moderately overweight individuals

If I Were You: Perceptual Illusion of Body Swapping

The concept of an individual swapping his or her body with that of another person has captured the imagination of writers and artists for decades. Although this topic has not been the subject of investigation in science, it exemplifies the fundamental question of why we have an ongoing experience of being located inside our bodies. Here we report a perceptual illusion of body-swapping that addresses directly this issue. Manipulation of the visual perspective, in combination with the receipt of correlated multisensory information from the body was sufficient to trigger the illusion that another person's body or an artificial body was one's own. This effect was so strong that people could experience being in another person's body when facing their own body and shaking hands with it. Our results are of fundamental importance because they identify the perceptual processes that produce the feeling of ownership of one's body

Child and Family Therapy Process: Concordance of Therapist and Observational Perspectives

The objective of this study is to examine the characteristics of outpatient mental health services delivered in community-based outpatient clinics, comparing information obtained from two different sources, therapists serving children and families, and observational coders viewing tapes of the same treatment sessions. Videotaped therapy sessions were rated by therapists and independent coders regarding goals and strategies pursued during each session. Sixty-three sessions were taped of outpatient care provided to 18 children and their caregivers by 11 therapists. Children were 4–13 years old and families were receiving services at least in part due to reported child behavior problems, confirmed by ratings from the Child Behavior Checklist and Conners Parent Rating Scale—Revised. Analyses assessed the frequency, type, and intensity of goals and strategies pursued in therapy sessions from both therapist and observational coders’ perspectives. Reliability of observer ratings and correspondence between therapist and observer reports were also examined. The reliability of observational coding of goals and strategies was moderate to good, with 76% of 39 codes having ICCs of .5 or greater. Therapists reported pursuing 2.5 times more goals and strategies per session, on average, than identified by observational coders. Correspondence between therapists and coders about the occurrence of specific goals and strategies in treatment sessions was low, with 20.5% of codes having a Kappa of .4 or higher. Substantial differences exist in what therapists and independent coders report as occurring in outpatient treatment sessions. Both perspectives suggest major differences between the content of services provided in community-based outpatient clinics and the structure of evidence-based programs, which emphasize intense pursuit of a small number of goals and strategies in each treatment session. Implications of the findings for quality improvement efforts in community-based mental health care settings are discussed