Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions

Loss-of-function mutations in the BRCA1 and BRCA2 genes increase the risk of cancer. Owing to their function in homologous recombination repair, much research has focused on the unstable genomic phenotype of BRCA1/2 mutant cells manifest mainly as large-scale rearrangements. We used whole-genome sequencing of multiple isogenic chicken DT40 cell clones to precisely determine the consequences of BRCA1/2 loss on all types of genomic mutagenesis. Spontaneous base substitution mutation rates increased sevenfold upon the disruption of either BRCA1 or BRCA2, and the arising mutation spectra showed strong and specific correlation with a mutation signature associated with BRCA1/2 mutant tumours. To model endogenous alkylating damage, we determined the mutation spectrum caused by methyl methanesulfonate (MMS), and showed that MMS also induces more base substitution mutations in BRCA1/2-deficient cells. Spontaneously arising and MMS-induced insertion/deletion mutations and large rearrangements were also more common in BRCA1/2 mutant cells compared with the wild-type control. A difference in the short deletion phenotypes of BRCA1 and BRCA2 suggested distinct roles for the two proteins in the processing of DNA lesions, as BRCA2 mutants contained more short deletions, with a wider size distribution, which frequently showed microhomology near the breakpoints resembling repair by non-homologous end joining. An increased and prolonged gamma-H2AX signal in MMS-treated BRCA1/2 cells suggested an aberrant processing of stalled replication forks as the cause of increased mutagenesis. The high rate of base substitution mutagenesis demonstrated by our experiments is likely to significantly contribute to the oncogenic effect of the inactivation of BRCA1 or BRCA2

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Trends in US home food preparation and consumption: analysis of national nutrition surveys and time use studies from 1965–1966 to 2007–2008

BACKGROUND: It has been well-documented that Americans have shifted towards eating out more and cooking at home less. However, little is known about whether these trends have continued into the 21(st) century, and whether these trends are consistent amongst low-income individuals, who are increasingly the target of public health programs that promote home cooking. The objective of this study is to examine how patterns of home cooking and home food consumption have changed from 1965 to 2008 by socio-demographic groups. METHODS: This is a cross-sectional analysis of data from 6 nationally representative US dietary surveys and 6 US time-use studies conducted between 1965 and 2008. Subjects are adults aged 19 to 60 years (n= 38,565 for dietary surveys and n=55,424 for time-use surveys). Weighted means of daily energy intake by food source, proportion who cooked, and time spent cooking were analyzed for trends from 1965–1966 to 2007–2008 by gender and income. T-tests were conducted to determine statistical differences over time. RESULTS: The percentage of daily energy consumed from home food sources and time spent in food preparation decreased significantly for all socioeconomic groups between 1965–1966 and 2007–2008 (p ≤ 0.001), with the largest declines occurring between 1965 and 1992. In 2007–2008, foods from the home supply accounted for 65 to 72% of total daily energy, with 54 to 57% reporting cooking activities. The low income group showed the greatest decline in the proportion cooking, but consumed more daily energy from home sources and spent more time cooking than high income individuals in 2007–2008 (p ≤ 0.001). CONCLUSIONS: US adults have decreased consumption of foods from the home supply and reduced time spent cooking since 1965, but this trend appears to have leveled off, with no substantial decrease occurring after the mid-1990’s. Across socioeconomic groups, people consume the majority of daily energy from the home food supply, yet only slightly more than half spend any time cooking on a given day. Efforts to boost the healthfulness of the US diet should focus on promoting the preparation of healthy foods at home while incorporating limits on time available for cooking

Rationale, design, methodology and sample characteristics for the family partners for health study: a cluster randomized controlled study

<p>Abstract</p> <p>Background</p> <p>Young children who are overweight are at increased risk of becoming obese and developing type 2 diabetes and cardiovascular disease later in life. Therefore, early intervention is critical. This paper describes the rationale, design, methodology, and sample characteristics of a 5-year cluster randomized controlled trial being conducted in eight elementary schools in rural North Carolina, United States.</p> <p>Methods/Design</p> <p>The first aim of the trial is to examine the effects of a two-phased intervention on weight status, adiposity, nutrition and exercise health behaviors, and self-efficacy in overweight or obese 2nd, 3 rd, and 4th grade children and their overweight or obese parents. The primary outcome in children is stabilization of BMI percentile trajectory from baseline to 18 months. The primary outcome in parents is a decrease in BMI from baseline to 18 months. Secondary outcomes for both children and parents include adiposity, nutrition and exercise health behaviors, and self-efficacy from baseline to 18 months. A secondary aim of the trial is to examine in the experimental group, the relationships between parents and children's changes in weight status, adiposity, nutrition and exercise health behaviors, and self-efficacy. An exploratory aim is to determine whether African American, Hispanic, and non-Hispanic white children and parents in the experimental group benefit differently from the intervention in weight status, adiposity, health behaviors, and self-efficacy.</p> <p>A total of 358 African American, non-Hispanic white, and bilingual Hispanic children with a BMI ≥ 85th percentile and 358 parents with a BMI ≥ 25 kg/m²have been inducted over 3 1/2 years and randomized by cohort to either an experimental or a wait-listed control group. The experimental group receives a 12-week intensive intervention of nutrition and exercise education, coping skills training and exercise (Phase I), 9 months of continued monthly contact (Phase II) and then 6 months (follow-up) on their own. Safety endpoints include adverse event reporting. Intention-to-treat analysis will be applied to all data.</p> <p>Discussion</p> <p>Findings from this trial may lead to an effective intervention to assist children and parents to work together to improve nutrition and exercise patterns by making small lifestyle pattern changes.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01378806">NCT01378806</a>.</p

Level of agreement between objectively determined body composition and perceived body image in 6- To 8-year-old South African children- To Body Composition-Isotope Technique study

To assess the level of agreement between body size self-perception and actual body size determined by body mass index (BMI) z-score and body fatness measured by the deuterium dilution method (DDM) in South African children aged 6-8 years. A cross-sectional sample of 202 children (83 boys and 119 girls) aged 6-8 years from the Body Composition-Isotope Technique study (BC-IT) was taken. Subjective measures of body image (silhouettes) were compared with the objective measures of BMI z-score and body fatness measured by the DDM. The World Health Organization BMI z-scores were used to classify the children as underweight, normal, overweight, or obese. DDM-measured fatness was classified based on the McCarthy centile curves set at 2nd, 85th and 95th in conjunction with fatness cut-off points of 25% in boys and 30% in girls. Data were analyzed using SPSS v26. Of 202 children, 32.2%, 55.1%, 8.8%, and 2.4% perceived their body size as underweight, normal, overweight, and obese, respectively. Based on BMI z-score, 18.8%, 72.8%, 6.9%, and 1.5% were classified as underweight, normal, overweight, and obese, respectively. Body fatness measurement showed that 2.5%, 48.0%, 21.8%, and 29.7% were underweight, normal weight, overweight, and obese, respectively

Emerging disparities in dietary sodium intake from snacking in the US population

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. Background: The US population consumes dietary sodium well in excess of recommended levels. It is unknown how the contribution of snack foods to sodium intake has changed over time, and whether disparities exist within specific subgroups of the US population. Objective: To examine short and long term trends in the contribution of snack food sources to dietary sodium intake for US adults and children over a 37-year period from 1977 to 2014. Methods: We used data collected from eight nationally representative surveys of food intake in 50, 052 US children aged 2-18 years, and 73, 179 adults aged 19+ years between 1977 and 2014. Overall, patterns of snack food consumption, trends in sodium intake from snack food sources and trends in food and beverage sources of sodium from snack foods across race-ethnic, age, gender, body mass index, household education and income groups were examined. Results: In all socio-demographic subgroups there was a significant increase in both per capita sodium intake, and the proportion of sodium intake derived from snacks from 1977-1978 to 2011-2014 (p < 0.01). Those with the lowest household education, Non-Hispanic Black race-ethnicity, and the lowest income had the largest increase in sodium intake from snacks. While in 1977-1978 Non-Hispanic Blacks had a lower sodium intake from snacks compared to Non-Hispanic Whites (p < 0.01), in 2011-2014 they had a significantly higher intake. Conclusions: Important disparities are emerging in dietary sodium intake from snack sources in Non-Hispanic Blacks. Our findings have implications for future policy interventions targeting specific US population subgroups