High-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection.

Eukaryotic gene expression regulation involves thousands of distal regulatory elements. Understanding the quantitative contribution of individual enhancers to gene expression is critical for assessing the role of disease-associated genetic risk variants. Yet, we lack the ability to accurately link genes with their distal regulatory elements. To address this, we used 3D enhancer-promoter (E-P) associations identified using split-pool recognition of interactions by tag extension (SPRITE) to build a predictive model of gene expression. Our model dramatically outperforms models using genomic proximity and can be used to determine the quantitative impact of enhancer loss on gene expression in different genetic backgrounds. We show that genes that form stable E-P hubs have less cell-to-cell variability in gene expression. Finally, we identified transcription factors that regulate stimulation-dependent E-P interactions. Together, our results provide a framework for understanding quantitative contributions of E-P interactions and associated genetic variants to gene expression.

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

A systematic scoping review of peer support interventions in integrated primary youth mental health care.

Peer support, defined as the social and emotional support offered and received by individuals with a shared experience of mental health difficulties, is gaining popularity in youth mental health settings. This systematic scoping review aimed to collate and synthesise the evidence on key aspects of peer support interventions within integrated youth services and educational settings. Specifically, it synthesised evidence on the (1) assessed mental health outcomes in peer support interventions, (2) key characteristics and associated roles of peer support workers (PSWs) and (3) barriers and facilitators to implementation. A search of peer reviewed articles from January 2005 to June 2022 across five electronic databases (PsychINFO, Pubmed, Scopus, ERIC and CINAHL) was conducted. A total of 15 studies retrieved in the search met the inclusion criteria and were included in the review. This review supports previous research indicating that peer support has potential for improving recovery related outcomes. While a variety of interventions and PSW roles were reported, studies could be strengthened by providing more in-depth information on intervention content. Examples of barriers to implementation included staff concerns around confidentiality of peer support relationships as well as PSWs' confidence in their roles. Facilitators included positive support from staff members and role clarity.

A comparison of patient-reported outcomes among Canadian women having hysterectomies.

PURPOSE: Many indications for hysterectomy can negatively affect patients' quality of life. This study uses patient-reported outcomes to measure changes in self-reported health among hysterectomy patients. METHOD: A prospective cohort of 294 hysterectomy patients completed patient-reported outcomes preoperatively and six months postoperatively in Vancouver, Canada. Patient-reported outcomes measured pelvic health, sexual function, pain, and depression. Changes in health were compared with paired t-tests, and multi-variable regression analysis measured associations between patient and clinical factors with postoperative outcomes RESULTS: Many patients reported improvements in health. Unadjusted analysis found that 65% of participants reported less pelvic distress, 55% reported less pain, and 47% reported less depression symptoms postoperatively. Multivariable regression analysis found that poorer preoperative health was associated with poorer postoperative outcomes in all domains of health measured (p-value < 0.01). Postoperative pain scores were lower (less pain) by 0.78 among residents of the most affluent neighborhoods (p-value = 0.02) compared to those in less affluent neighborhoods. Postoperative depression scores were 1.58 points worse among participants with endometriosis (p-value = 0.03) and 1.02 points worse among participants having abdominal surgery (p-value = 0.02). CONCLUSION: Many participants reported improvements in pelvic symptoms, pain, and depression after hysterectomy. Lower socioeconomic status patients may be at risk for reporting higher pain after surgery, and endometriosis patients may report higher depression. Further investigation is needed to determine effective interventions for the higher postoperative pain observed in this study for residents of less affluent neighborhoods.

Daily Affect and Daily Prospective Memory in People after Stroke and Their Partners: The Moderating Role of Resting Heart Rate.

INTRODUCTION: Experimental research suggests that affect may influence prospective memory performance, but real-life evidence on affect-prospective memory associations is limited. Moreover, most studies have examined the valence dimension of affect in understanding the influence of affect on cognitive performance in daily life, with insufficient consideration of the arousal dimension. To maximize ecological validity, the current study examined the relationships between daily affect and daily prospective memory using repeated daily assessments and the role of resting heart rate on these relationships. We examined both valence and arousal of daily affect by categorizing affect into four dimensions: high-arousal positive affect, low-arousal positive affect, high-arousal negative affect, and low-arousal negative affect. METHOD: We examined existing data collected from community-dwelling couples, of which at least one partner had a stroke history. The analytic sample included 111 adults (Mage = 67.46 years, SD = 9.64; 50% women) who provided 1,274 days of data. Among the participants, 58 were living with the effects of a stroke and 53 were partners. Participants completed daily event-based prospective memory tasks (in morning and/or evening questionnaires), reported daily affect in the evening, and wore a wrist-based Fitbit device to monitor resting heart rate over 14 consecutive days. RESULTS: Results from multilevel models show that, within persons, elevated high-arousal negative affect was associated with worse daily prospective memory performance. In addition, lower resting heart rate attenuated the inverse association between high-arousal negative affect and lowered prospective memory performance. We did not find significant associations of high- or low-arousal positive affect and low-arousal negative affect with daily prospective memory. DISCUSSION: Our findings are in line with the resource allocation model and the cue-utilization hypothesis in that high-arousal negative affect is detrimental to daily prospective memory performance. Lower resting heart rate may buffer individuals' prospective memory performance from the influence of high-arousal negative affect. These findings are consistent with the neurovisceral integration model on heart-brain connections, highlighting the possibility that cardiovascular fitness may help maintain prospective memory into older adulthood.

The Social Determinants of Mental Illness: A Rapid Review of Systematic Reviews.

Previous research agendas have prioritised the role of biological determinants in mental illness aetiology. This is of particular concern, as endorsing biological determinants has been shown to promote negative attitudes towards people with mental illness. The aim of this review was to provide an overview of high-quality evidence of the social determinants of mental illness. A rapid review of systematic reviews was conducted. Five databases were searched: Embase, Medline, Academic Search Complete, CINAHL Plus, and PsycINFO. Systematic reviews or meta-analyses that described any social determinant of mental illness, were published in peer-review journals in English, and focussed on human participants were included. The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines were applied for the selection procedure. Thirty-seven systematic reviews were deemed eligible for review and narrative synthesis. Determinants identified included conflict, violence and maltreatment, life events and experiences, racism and discrimination, culture and migration, social interaction and support, structural policies and inequality, financial factors, employment factors, housing and living conditions, and demographic factors. We recommend that mental health nurses ensure adequate support be provided to those affected by the evidenced social determinants of mental illness.

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci.

BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Anti-hypertensive medications and risk of colorectal cancer: a systematic review and meta-analysis.

PURPOSE: Antihypertensive medications may impact colorectal cancer risk. We conducted a systematic review and meta-analysis of associations, with colorectal cancer risk, of five classes of antihypertensive medications: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and diuretics. METHODS: A systematic search was conducted in MEDLINE, Embase, Web of Science, and the Cochrane library to identify relevant studies evaluating associations of ACEIs, ARBs, BBs, CCBs, and diuretics with colorectal cancer risk. Meta-analytic risk ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were calculated using the inverse variance method. RESULTS: No overall significant associations with colorectal cancer risk were observed; ACEIs (5 studies) RR 1.05, 95% CI 0.91-1.23, ARBs (5 studies) RR 0.94, 95% CI 0.80-1.11, BBs (4 studies) RR 1.00, 95% CI 0.92-1.08, CCBs (4 studies) RR 1.02, 95% CI 0.88-1.18, and diuretics (6 studies) RR 1.02, 95% CI 0.90-1.17. There was considerable heterogeneity across studies, partly explained by differences in study design and location. When stratified by study location, there was significantly reduced colorectal cancer risk for ARB use in Asian populations (2 studies, RR 0.69, 95% CI 0.58-0.83). CONCLUSION: No significant colorectal cancer risk with ACEIs, BBs, CCBs, or diuretics was observed. ARB use may be associated with decreased risk of colorectal cancer in Asian populations, although additional studies in diverse populations are needed to confirm associations and help understand possible reasons for geographical differences.

Lifestyle factors and lung cancer risk among never smokers in the Canadian Partnership for Tomorrow's Health (CanPath).

BACKGROUND: Although smoking is the primary risk factor for lung cancer, 15-25% of lung cancers occur in never smokers. Emerging evidence suggests lifestyle factors are associated with lung cancer risk, but few studies among never smokers exist. METHODS: A case-control study of never smokers within the Canadian Partnership for Tomorrow's Health was conducted. At recruitment, participants provided data on lifestyle, health history and sociodemographic factors. Incident lung cancers were identified through linkage with administrative health records. Cases (n = 190) were matched to controls (n = 760) on age, sex, and follow-up time. Logistic regression analyses, adjusted for matching factors and annual income, were used to identify associations between lifestyle factors and lung cancer risk. RESULTS: Consumption of < 5 servings of fruits and vegetables/day was associated with higher risk of lung cancer (OR 1.50, 95% CI 1.03-2.17). Short or long sleep (≤ 6 or > 9 h/night) was also associated with increased risk of lung cancer (OR 1.52, 95% CI 1.01-2.29). No associations were observed for obesity measures, alcohol consumption, or physical activity. CONCLUSION: Our findings provide evidence of a potential role between sleep, fruits and vegetable consumption, and lung cancer risk in a pan-Canadian, non-smoking population. However, the sample size is modest, and further investigation is needed.

Body Composition and Metabolomics in the Alberta Physical Activity and Breast Cancer Prevention Trial.

BACKGROUND: Obesity is correlated with many biomarkers, but the extent to which these correlate with underlying body composition is poorly understood. OBJECTIVES: Our objectives were to 1) describe/compare distinct contributions of fat/lean mass with BMI-metabolite correlations and 2) identify novel metabolite biomarkers of fat/lean mass. METHODS: The Alberta Physical Activity and Breast Cancer Prevention Trial was a 2-center randomized trial of healthy, inactive, postmenopausal women (n = 304). BMI (in kg/m2) was calculated using weight and height, whereas DXA estimated fat/lean mass. Ultra-performance liquid chromatography and mass spectrometry measured relative concentrations of serum metabolite concentrations. We estimated partial Pearson correlations between 1052 metabolites and BMI, adjusting for age, smoking, and site. Fat mass index (FMI; kg/m2) and lean mass index (LMI; kg/m2) correlations were estimated similarly, with mutual adjustment to evaluate independent effects. RESULTS: Using a Bonferroni-corrected α level <4.75 × 10-5,  we observed 53 BMI-correlated metabolites (|r| = 0.24-0.42). Of those, 21 were robustly correlated with FMI (|r| > 0.20), 25 modestly (0.10 ≤ |r| ≤ 0.20), and 7 virtually null (|r| < 0.10). Ten of 53 were more strongly correlated with LMI than with FMI. Examining non-BMI-correlated metabolites, 6 robustly correlated with FMI (|r| = 0.24-0.31) and 2 with LMI (r = 0.25-0.26). For these, correlations for fat and lean mass were in opposing directions compared with BMI-correlated metabolites, in which correlations were mostly in the same direction. CONCLUSIONS: Our results demonstrate how a thorough evaluation of the components of fat and lean mass, along with BMI, provides a more accurate assessment of the associations between body composition and metabolites than BMI alone. Such an assessment makes evident that some metabolites correlated with BMI predominantly reflect lean mass rather than fat, and some metabolites related to body composition are not correlated with BMI. Correctly characterizing these relations is important for an accurate understanding of how and why obesity is associated with disease.

Measuring the impact of a training intervention for early childhood centre staff on child development outcomes: Findings from a cluster randomized control field trial in rural Malawi.

BACKGROUND: Evidence from low-income settings around early education interventions that can improve young children's development is sparse, particularly with regard to the most marginalized children. This study used a two-arm parallel cluster randomized control design to evaluate the impact of an adapted staff training programme on the developmental outcomes of children attending community-based early learning centres in Thyolo district, rural Malawi. METHODS: At baseline we randomly selected 48 centres, from each of which 20 children were randomly selected, although data from one centre was incomplete resulting in 932 children from 47 centres. Centres were randomly allocated to either the intervention or control arm. Twelve months later, follow-up data were collected from 44 centres. At baseline and endline, community-based childcare centre (CBCC) managers provided information about the centre, and parents/guardians provided information on the children, including the primary outcomes of age-standardized development scores in the language and social domains, measured using the Malawi Developmental Assessment Tool. Children in the bottom 2.5 percentile of either domain were considered to have a delay; a third outcome variable, Any Delay, was developed to indicate children with a delay in either or both domains. Centre-level mean scores were calculated, and linear regression models were constructed to assess differences between baseline and endline and between allocation groups. RESULTS: Analysis of the difference between baseline and endline measures in the allocation groups shows a non-significant reduction in delay associated with the study intervention across all domains. Adjustment for baseline characteristics within the CBCCs showed little impact on the magnitude of the observed effect, and the difference remained non-significant. CONCLUSIONS: Despite no observed differences between allocation groups, the data did indicate a positive change in the intervention groups in both domains, particularly language. Community-based early learning in Malawi holds tremendous potential for promoting inclusive development and learning.

METHOD COMPARISON FOR MEASUREMENT OF SYMMETRIC DIMETHYLARGININE IN TIGERS (PANTHERA TIGRIS).

Renal disease is well documented in nondomestic felids and is monitored and diagnosed by serum concentration of blood urea nitrogen, creatinine, and phosphorous. Symmetric dimethylarginine (SDMA) has proven to be an earlier and more sensitive biomarker for the assessment of glomerular filtration rate. Although SDMA is commonly measured in nondomestic felids, information concerning the validity of the assay is lacking. The purpose of the study was to perform a method comparison between high-throughput immunoassay and the reference method, liquid chromatography-tandem mass spectrometry (LC-MS/MS), to quantify SDMA concentrations in tiger blood samples. Concentrations of SDMA were measured for 81 individual tiger samples. The SDMA immunoassay demonstrated excellent correlation to the LC-MS/MS reference method. A Passing and Bablok linear regression analysis had a slope of 1.03 (95% CI, 0.99-1.11), an intercept of 1.64 (95% CI, 0.46-2.34), and a Pearson R= 0.99. The mean bias was 1.53 µg/dl (95% CI, 0.63-2.42 µg/dl), and the limit of agreement was ±7.96 µg/dl. The degree of bias is within established acceptance criteria of 1-3 µg/dl for the immunoassay. Although this study provides good evidence of the utility of the immunoassay to measure SDMA in tiger serum and plasma, further assay validation is recommended.

Home visits in rural general practice: what does the future hold?

INTRODUCTION: Declining house-call rates have been documented worldwide; however, up-to-date data on current rates are lacking, particularly in rural settings. Systematic reviews in this area are inconsistent; however, other work, principally qualitative research, demonstrates benefits for both doctors and patients. The aim of this study was to establish the current rate of, and reasons for, home visits in a rural general practice setting. METHODS: This was a descriptive observational study in the north-west of Ireland. Fourteen general practice training practices with approximately 30 000 patients were recruited. Data on house calls done in each practice were collected during May and June 2019. Anonymised data were analysed using Microsoft Excel and GraphPad. RESULTS: Data were received on 547 house calls. The rate of house calls done within normal working hours (443) was calculated at 87 house calls/1000 patients/year (raw proportion 1.44%). Using the N-1 χ2 test, this rate was compared to that calculated in a similar 2009 study (143/1000/year; raw proportion 2.43%), giving a difference of 0.991% (95% confidence interval 0.759-1.22%; p<0.001). This is a statistically significant reduction of 40% over 10 years. Most (86.2%) house calls were to patients aged over 65 years. House calls were commonly done for respiratory infection (17%), other infections (12%), palliative care (11%) and pain (11%). Most patients were managed solely within the community (88.3%), with 45.8% of those requiring a prescription, and only 11.7% of house calls being referred to hospital. CONCLUSION: There are documented benefits to home visits and yet the rate of house calls has been declining worldwide. With no recent literature on the rate or reasons for home visits in rural general practice, this research has demonstrated that the house call rate in the north-west of Ireland is falling, mirroring the decline seen in other parts of Europe, Australia and the USA. These house calls are mainly for elderly patients to address infection or palliative care, and the majority can be managed successfully by general practitioners in the community. With an ageing population with increasing multi-morbidity, planning for care delivery to these patients is important for clinicians going forward. We now need to decide if house calls are a service worth saving.

Associations of ω-3 Fatty Acids With Interstitial Lung Disease and Lung Imaging Abnormalities Among Adults.

Docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, attenuates interstitial lung disease (ILD) in experimental models, but human studies are lacking. We examined associations of circulating levels of DHA and other polyunsaturated fatty acids with hospitalization and death due to ILD over 12 years in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6,573). We examined cross-sectional associations with CT lung abnormalities in MESA (2000-2012; n = 6,541), the Framingham Heart Study (2005-2011; n = 3,917), and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) (2002-2006; n = 1,106). Polyunsaturated fatty acid levels were determined from fasting blood samples and extracted from plasma phospholipids (MESA and AGES-Reykjavik) or red blood cell membranes (Framingham Heart Study). Higher DHA levels were associated with a lower risk of hospitalization due to ILD (per standard-deviation increment, adjusted rate ratio = 0.69, 95% confidence interval (CI): 0.48, 0.99) and a lower rate of death due to ILD (per standard-deviation increment, adjusted hazard ratio = 0.68, 95% CI: 0.47, 0.98). Higher DHA was associated with fewer interstitial lung abnormalities on computed tomography (per natural log increment, pooled adjusted odds ratio = 0.65, 95% CI: 0.46, 0.91). Higher DHA levels were associated with a lower risk of hospitalization and death due to ILD and fewer lung abnormalities on computed tomography in a meta-analysis of data from population-based cohort studies.

Examining the etiology of early-onset breast cancer in the Canadian Partnership for Tomorrow's Health (CanPath).

PURPOSE: Breast cancer incidence among younger women (under age 50) has increased over the past 25 years, yet little is known about the etiology among this age group. The objective of this study was to investigate relationships between modifiable and non-modifiable risk factors and early-onset breast cancer among three prospective Canadian cohorts. METHODS: A matched case-control study was conducted using data from Alberta's Tomorrow Project, BC Generations Project, and the Ontario Health Study. Participants diagnosed with breast cancer before age 50 were identified through provincial registries and matched to three control participants of similar age and follow-up. Conditional logistic regression was used to examine the association between factors and risk of early-onset breast cancer. RESULTS: In total, 609 cases and 1,827 controls were included. A body mass index ≥ 30 kg/m2 was associated with a lower risk of early-onset breast cancer (OR 0.65; 95% CI 0.47-0.90), while a waist circumference ≥ 88 cm was associated with an increased risk (OR 1.58; 95% CI 1.18-2.11). A reduced risk was found for women with ≥ 2 pregnancies (OR 0.76; 95% CI 0.59-0.99) and a first-degree family history of breast cancer was associated with an increased risk (OR 1.95; 95% CI 1.47-2.57). CONCLUSIONS: In this study, measures of adiposity, pregnancy history, and familial history of breast cancer are important risk factors for early-onset breast cancer. Evidence was insufficient to conclude if smoking, alcohol intake, fruit and vegetable consumption, and physical activity are meaningful risk factors. The results of this study could inform targeted primary and secondary prevention for early-onset breast cancer.

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality.

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.

BACKGROUND: De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). METHODS AND FINDINGS: Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. CONCLUSIONS: Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.

Dietary patterns in the healthy oldest old in the healthy aging study and the Canadian longitudinal study of aging: a cohort study.

BACKGROUND: Very few people live to eighty-five years and older (the 'oldest old'), and even fewer live to this age without developing chronic diseases. It is important to understand the relationship, if any, of modifiable factors such as diet on healthy aging. However, there are few studies of diet among healthy oldest old, especially in North American populations. We aimed to characterize dietary patterns among 'super-seniors' (SS) within the Canadian Healthy Aging Study. METHODS: 122 SS aged 85 years or older and free of cancer, cardiovascular or pulmonary disease, dementia and diabetes were recruited. Comparisons were made to 12,626 participants aged 65-86 in the Canadian Longitudinal Study of Aging who completed the same 36-item food frequency questionnaire that queried consumption over the prior 12 months of nutrients and foods thought to be important for aging. Dietary patterns were identified with principal component analysis. The odds of being a SS were determined for quartiles of each dietary pattern with logistic regression. RESULTS: Two dietary patterns were identified; a western diet characterized by french fries, red meat, processed meat and a nutrient-rich diet which included fruits, vegetables, whole grains, nuts and seeds among other healthy food choices. Higher scores for both dietary patterns were associated with increased odds of being a SS, however, only the western dietary pattern remained associated with adjustment for covariates (Quartile 4: OR = 3.21, 95% CI 1.91-5.51). CONCLUSIONS: Our finding adds to the limited evidence on dietary intake among the healthiest oldest old but it is unclear whether assocations reflect generational differences between groups or possible contributions to longevity.