Citations

Abstract BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

We previously reported that augmented skeletal muscle vasodilation during mild hypoxic forearm exercise includes beta‐adrenergic mechanisms. Furthermore, hypoxic vasodilation at rest is known to include beta‐adrenergic mediated nitric oxide (NO) production. Therefore, we tested the hypothesis that NO contributes to augmented vasodilation with hypoxic exercise. Twelve subjects (6M/6F; 26 ± 2 years) breathed hypoxic gas to titrate arterial O 2 saturation to 80% while remaining normocapnic via a rebreath system. Subjects performed incremental forearm exercise (10% and 20% of maximum) during saline infusion (control) and NO synthase inhibition ( N G ‐monomethyl‐L‐arginine; L‐NMMA) under normoxic and hypoxic conditions. Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from blood flow (ml/min) and blood pressure (mmHg). During the control condition, the rise in FVC (Δfrom normoxic baseline) due to hypoxic exercise was 211 ± 23 and 367 ± 34 (10% and 20% respectively). Infusion of L‐NMMA during hypoxic exercise attenuated ΔFVC at 10% (174 ± 20; P < 0.001) and 20% (317 ± 32; P < 0.01) compared to control condition. Our data indicate that NO contributes to the augmented vasodilation observed during hypoxic exercise. Supported by NIH HL‐46493 (MJJ) and AR‐55819 (DPC) and by CTSA RR‐024150.

Abstract Background Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. Methods Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. Results Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P &lt; .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers. Conclusion Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

Cardiovascular reactivity to stress may be predictive of cardiovascular disease. Sympathoexcitatory responses to mental stress (MS), cold pressor test (CPT), isometric handgrip (HG) and head‐up tilt (HUT) target different physiological mechanisms, but the correlation between response variables is unclear. Our purpose was to test the hypothesis that pressor and catecholamine responses between these stressors would be correlated within subjects. Healthy, normotensive young adults (n=76) underwent MS, CPT, HUT and HG to fatigue. Arterial pressure and HR were monitored, and arterial Epi and NE were sampled during the final 30 sec of each stressor. Percent change from baseline was averaged during MS, CPT, HUT and the final 20% time segment of HG. MAP and SBP were positively correlated between CPT and HG (r = 0.46, 0.52, resp, p < 0.001) but not among other tests. Interestingly, the % increase in NE response to all 4 maneuvers showed robust correlations (MS v CPT r = 0.65; MS v HG r = 0.74; MS v HUT r = 0.53; CPT v HG r = 0.72; CPT v HUT r = 0.68; HG v HUT r = 0.59; p < 0.001 for all). Similar correlations were present for Epi except for comparisons with HUT. This suggests that among the 4 tests, HR and BP responses are generally variable, but NE and Epi responses are remarkably consistent (except Epi for HUT), implying that lab stressors may evoke sympathoexcitation more similarly than previously thought. Support: K23‐RR17520, HL 46493.

The complex forearm vasodilator response during mental stress (MS) is mediated in part by unchanged or decreased forearm muscle sympathetic nerve activity. However, immediately after MS, nerve activity is increased. To determine the effect of chronic sympathetic denervation on forearm blood flow (FBF, [ml/100ml forearm volume/min]) response to MS, we studied patients pre and post sympathotomy (ETS) for palmar hyperhidrosis. 15 healthy subjects (11 F; 19‐32 yr) with a mean BMI of 23 ± 5 kg/m2 were studied 1 day‐6 mo before ETS and 1‐6 mo after ETS. FBF (plethysmography) was recorded during baseline, 3 min Stroop test, and 2 min post‐MS recovery. ETS did not affect resting HR, BP or FBF. However, resting forearm vascular resistance (FVR, [MAP/FBF]) was reduced after ETS (50 ± 20 vs 33 ± 14, p < 0.01) and forearm vascular conductance (FVC, [(FBF/MAP)*100]) was increased (3 ± 2 vs 4 ± 2, p < 0.05). MS caused significant increases in FBF and FVC, and a decrease in FVR, and these responses were unaffected by ETS. However during post‐MS recovery, ETS caused a significant increase in FBF (2 ± 1 vs 3 ± 1), FVC (3 ± 1 vs 4 ± 2), and a decrease in FVR (52 ± 22 vs 32 ± 16) (p < 0.01). Chronic sympathetic denervation influences post‐MS forearm vasoconstriction, which likely has minor hemodynamic consequences but confirms a greater role for sympathetic control of FBF in the post‐MS period as opposed to during MS. NIH HL‐089331, NS‐32352

Background: Guidelines recommend involvement of palliative care (PC) for patients with cardiovascular (CV) disease and their families. Little is known about the current integration of PC and CV services. Research Objectives: Our national survey aimed to describe current practices and to identify benefits, challenges, and barriers with collaboration. Methods: Qualitative content analysis of open-response questions in an investigator-developed electronic survey study of CV and PC providers (MDs, NPs, PAs, and other allied health) using email listservs, social media, and crowdsourcing. Frequencies were tabulated using SAS statistical software. Results: Of 134 respondents, most were physicians (n=56, 57%) or advanced practice RNs or PAs (n=37, 28%), from 52 U.S. institutions, representing 33 states. The most common care for which PC was integrated were mechanical circulatory support, advanced heart failure, and heart transplantation; the least common care for which PC was integrated were TAVR, ECMO, and pulmonary hypertension. Integrated practice (n=80, 61%), PC identification of goals of care (n=20, 15%) and PC aid in patient/family communication (n=15, 11%) were the most commonly identified as positives in current practice. PC provider workforce (n=22, 16%), underutilization of PC referrals (n=20, 15%), late disease PC referral (n=19, 14%), and fundamental knowledge deficit of specialty scope (n=18, 14%) were most frequently identified as challenges. Other barriers specifically noted were underdeveloped health infrastructure and limited allocated resources (n=23,17%) and mis-/negative perception of services (n=15, 11%). Conclusion: PC and CV collaboration occurs for a high proportion of CV patients and is viewed as overwhelming positive, despite the challenges of limited PC specialists availability, underdeveloped healthcare infrastructure, limited understanding of specialty practice, and late referrals. Priorities includes increasing PC provider availability, expanding knowledge of PC services, educating providers on models of collaboration, and improving institutional support.

Persons with metabolic syndrome could benefit from improved fruit consumption and reduced caloric intake. A cranberry fruit containing reduced titratable acidity was developed and used to create a 27% reduced calorie cranberry juice (RCCBJ) containing less added sugar (74 Cal/240 ml) relative to the 110 Cal/240 ml industry standard cranberry juice (CBJ). Subjects were recruited for metabolic syndrome (n=18; 53 16 years; BMI=34.4 ± 3.9) and their metabolic response to CBJ and RCCBJ was evaluated in single cross‐over fashion. Plasma glucose for CBJ at 0‐, 30‐, 60‐, and 120‐min was 105.6±12.3, 149.5±22.6, 127.9±30.3, and 98.6±14.6 (mg/dl). Plasma glucose for RCCBJ was 104.6±13.3, 140.3±22.5, 116.0±27.23, and 100.4±13. Plasma insulin for CBJ at 0‐, 30‐, 60‐, and 120‐ min was 10.21±5.1, 41.5±22.6, 30.3±19.7, and 12.0± (µIU/ml). Plasma insulin for RCCBJ was 12.2±8.4, 34.8±21.6, 20.7±13.9, and 12.3±9.8. For CBJ and RCCBJ plasma glucose and insulin significantly increased relative to baseline at 30‐ and 60‐min. At 60 min RCCBJ glucose and insulin were significantly less than CBJ. Plasma adiponectin and glucagon like peptide‐1 responses were also measured for CBJ and RCCBJ at 0‐, 30‐, 60‐, and 120‐min. Reduced acidity cranberry fruit was associated with RCCBJ containing 33% fewer calories and a beneficial metabolic response in persons with metabolic syndrome.

Background: Inflammatory myofibroblastic tumor is a rare, poorly understood tumor that has been found to occur in almost every organ tissue. Its location within the central nervous system is uncommon, and patients tend to present with nonspecific symptoms. Case Description: A female in her eighth decade presented to neurosurgery clinic with complaints of headache and dizziness. Initial imaging was consistent with a low-grade, benign brain lesion in the region of the left choroidal fissure. She was recommended for observation but returned 1 month later with progressive symptoms and doubling of the lesion size. She underwent surgical resection and was found to have an IMT arising from the wall of the left anterior choroidal artery. Conclusion: Intracranial IMT remains a rare and poorly understood entity. The present case demonstrates a novel presentation of IMT in an adult patient and exemplifies the heterogeneity of the disease presentation.

For several years, medical schools in the United States have been urged to integrate public health and population science into their curricula. The first‐year Gross Anatomy course at Mayo Clinic serves as a teaching platform for many non‐technical skills that include professionalism, patient communication and near‐peer teaching that aim to meet core ACGME requirements. As part of the standard Gross Anatomy curriculum, students are assessed on a laboratory based learning activity referred to as a “bedside presentation,” where each small group is assigned a clinical condition and asked to present a hypothetical case as it relates to the anatomy and radiology on their cadaver. The objective of this study is to assess whether first‐year medical students’ knowledge of global health disparities and national population health improved after a longitudinal curriculum revision that combined public health concepts with the bedside presentation. Students first learned to examine a major cause of morbidity and/or mortality on a global/population level following which each team was asked to present a hypothetical patient (relating to their assigned cadaver) with an acute condition associated with the disease or behavior that they had researched earlier. Teams focused on associated anatomic and radiographic findings and used full‐body CT scans and corresponding anatomic parts to illustrate the effects of the disease. Pre‐course data indicate that students have a 50% understanding of population health trends. We anticipate that first‐year medical students will have an improved awareness of public health problems globally and in the United States after completing this activity in Gross Anatomy.

We tested the hypothesis that dietary Na + intake alters the hemodynamic response to mental stress (MS) in normotensive subjects, which could be mediated by β‐adrenergic receptors (ADRB). As part of an ongoing ADRB2 phenotyping protocol, 12 subjects (age 23±5 year) completed 5 days of low (10 mmol day −1 ), normal (150) and high (400) dietary Na + intake. We measured heart rate (ECG), mean arterial pressure (MAP, Finometer), and calculated stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) responses to arithmetic MS, before and after administration of propranolol. The high Na + diet decreased CO (6.3±0.3 vs. 5.7±0.3 l min −1 , p<0.01) and increased SVR (1187±47 vs. 1311±68 dynes s −1 cm −1 , p<0.01) at rest, but MAP was unchanged (92±2 vs. 93±3 mmHg, p=0.37). During MS, the increase in HR, CO, and MAP was not affected by diet, nor was the decrease in SVR. However, on the high Na + diet β‐blockade increased resting MAP (93±3 vs. 97±2 mmHg, p<0.01), while the absolute MAP response to MS was unchanged, the ΔMAP was blunted (7.3 vs. 4.3 %, p=0.03) and ΔSV was decreased (1.7±3.5 vs. −5.3±2.0 %, p=0.03). In conclusion, reactivity to MS was not influenced by dietary Na + , but systemic β‐blockade after high Na + blunted the SV response during MS. This may be suggestive of augmented ADRB function or blunted non‐ADRB mechanisms of ventricular function during MS after high Na + . Support: R‐01 HL‐089331 and CTSA RR‐024150.