J. Strait

The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 ×10−7), hip circumference (p = 3.4 × 10−8), and weight (p = 9.1 × 10−7). In Sardinia, homozygotes for the rare “G” allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common “A” allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 × 10−6). Homozygotes for the rare “A” allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common “G” allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare “A” allele were, on average, 1.0–3.0 BMI units heavier than homozygotes for the more common “G” allele. In summary, we have completed a whole genome–association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

Aging represents a convergence of declining cardioprotective systems and increasing disease processes that is fertile ground for the development of heart failure. Fifty percent of all heart failure diagnoses and 90% of all heart failure deaths occur in individuals older than 70. This article discusses the microscopic and macroscopic changes in cardiovascular structure, function, protective systems, and disease associated with aging. In addition to outlining important clinical considerations and conditions in older persons, the link between normal aging and the elevated risk for development of stage B heart failure is explained and potential therapeutic pathways are highlighted.

Carotid-femoral pulse wave velocity (PWV), a marker of arterial stiffness, is an established independent cardiovascular risk factor. Little information is available on the pattern and determinants of the longitudinal change in PWV with aging. Such information is crucial to elucidating mechanisms underlying arterial stiffness and the design of interventions to retard it. Between 1988 and 2013, we collected 2 to 9 serial measures of PWV in 354 men and 423 women of the Baltimore Longitudinal Study of Aging, who were 21 to 94 years of age and free of clinically significant cardiovascular disease. Rates of PWV increase accelerated with advancing age in men more than women, leading to sex differences in PWV after the age of 50 years. In both sexes, not only systolic blood pressure (SBP) ≥140 mm Hg but also SBP of 120 to 139 mm Hg was associated with steeper rates of PWV increase compared with SBP<120 mm Hg. Furthermore, there was a dose-dependent effect of SBP in men with marked acceleration in PWV rate of increase with age at SBP ≥140 mm Hg compared with SBP of 120 to 139 mm Hg. Except for waist circumference in women, no other traditional cardiovascular risk factors predicted longitudinal PWV increase. In conclusion, the steeper longitudinal increase of PWV in men than women led to the sex difference that expanded with advancing age. Age and SBP are the main longitudinal determinants of PWV, and the effect of SBP on PWV trajectories exists even in the prehypertensive range.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se - are associated with accelerated arterial ageing and with cardiovascular (CV) events. To investigate whether the distribution of clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA in the MARE (Metabolic syndrome and Arteries REsearch) Consortium.In accordance with the ATP III criteria, MetS was defined as an alteration three or more of the following five components: elevated glucose (G), fasting glucose ≥110 mg/dl; low HDL cholesterol, < 40mg/dl for men or <50 mg/dl for women; high triglycerides (T), ≥150 mg/dl; elevated blood pressure (B), ≥130/≥85 mmHg; abdominal obesity (W), waist circumference >102 cm for men or >88 cm for women.MetS had a 24.3% prevalence (8468 subjects: 23.9% in men vs. 24.6% in women, p < 0.001) with an age-associated increase in its prevalence in all the cohorts. The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p < 0.0001) and in men and women (p < 0.0001). In details, the cluster TBW was observed in 12% of the subjects with MetS, but was far more common in the cohorts from the UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and the USA (2.5%). The cluster GBW accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal: 31.4, 18.4, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania: 7.6, 9.4, and 9.6% respectively).The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries.

Important changes occur in the cardiovascular system with advancing age, even in apparently healthy individuals. Thickening and stiffening of the large arteries develop due to collagen and calcium deposition and loss of elastic fibers in the medial layer. These arterial changes cause systolic blood pressure to rise with age, while diastolic blood pressure generally declines after the sixth decade. In the left ventricle, modest concentric wall thickening occurs due to cellular hypertrophy, but cavity size does not change. Although left ventricular systolic function is preserved across the age span, early diastolic filling rate declines 30-50% between the third and ninth decades. Conversely, an age-associated increase in late diastolic filling due to atrial contraction preserves end-diastolic volume. Aerobic exercise capacity declines approximately 10% per decade in cross-sectional studies; in longitudinal studies, however, this decline is accelerated in the elderly. Reductions in peak heart rate and peripheral oxygen utilization but not stroke volume appear to mediate the age-associated decline in aerobic capacity. Deficits in both cardiac β-adrenergic receptor density and in the efficiency of postsynaptic β-adrenergic signaling contribute significantly to the reduced cardiovascular performance during exercise in older adults. Although these cardiovascular aging changes are considered "normative", they lower the threshold for the development of cardiovascular disease, which affects the majority of older adults.

Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.

The age-associated increase in arterial stiffness has long been considered to parallel or to cause the age-associated increase in blood pressure (BP). Yet, the rates at which pulse wave velocity (PWV), a measure of arterial stiffness, and BP trajectories change over time within individuals who differ by age and sex have not been assessed and compared. This study determined the evolution of BP and aortic PWV trajectories during a 9.4-year follow-up in &gt;4000 community-dwelling men and women of 20 to 100 years of age at entry into the SardiNIA Study. Linear mixed effects model analyses revealed that PWV accelerates with time during the observation period, at about the same rate over the entire age range in both men and women. In men, the longitudinal rate at which BP changed over time, however, did not generally parallel that of PWV acceleration: at ages &gt;40 years the rates of change in systolic BP (SBP) and pulse pressure (PP) increase plateaued and then declined so that SBP, itself, also declined at older ages, whereas PP plateaued. In women, SBP, diastolic BP, and mean BP increased at constant rates across all ages, producing an increasing rate of increase in PP. Therefore, increased aortic stiffness is implicated in the age-associated increase in SBP and PP. These findings indicate that PWV is not a surrogate for BP and that arterial properties other than arterial wall stiffness that vary by age and sex also modulate the BP trajectories during aging and lead to the dissociation of PWV, PP, and SBP trajectories in men.

<h2>Abstract</h2> Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in ≥3 of the 5 components: abdominal obesity (<i>W</i>), high triglycerides (<i>T</i>), low HDL cholesterol (<i>H</i>), elevated blood pressure (<i>B</i>), and elevated fasting glucose (<i>G</i>). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components – even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus – in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV).

Although vascular risk factors have been implicated in the development of all-cause dementia and Alzheimer disease (AD), few studies have examined the association between subclinical atherosclerosis and prospective risk of dementia.Participants from the Baltimore Longitudinal Study of Aging (n=364; age, 60-95 years; median age, 73; 60% male; 82% white) underwent initial carotid atherosclerosis assessment and subsequently were assessed for dementia and AD annually for up to 14 years (median, 7.0). Cox proportional hazards models predicting all-cause dementia and AD were adjusted for age, sex, race, education, blood pressure, cholesterol, cardiovascular disease, diabetes mellitus, and smoking.Sixty participants developed dementia, with 53 diagnosed as AD. Raw rates of future dementia and AD among individuals initially in the upper quintile of carotid intimal medial thickness or with bilateral carotid plaque were generally double the rates of individuals with intimal medial thickness in the lower quintiles or no plaque at baseline. Adjusted proportional hazards models revealed >2.5-fold increased risk of dementia and AD among individuals in the upper quintile of carotid intimal medial thickness, and approximately 2.0-fold increased risk of dementia among individuals with bilateral plaque.Multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid intimal medial thickness or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD.

Pulse wave velocity (PWV), a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Heritability and linkage studies have pointed toward a genetic component affecting PWV. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with PWV.The study cohort included participants from the SardiNIA study for whom PWV measures were available. Genotyping was performed in 4221 individuals, using either the Affymetrix 500K or the Affymetrix 10K mapping array sets (with imputation of the missing genotypes). Associations with PWV were evaluated using an additive genetic model that included age, age(2), and sex as covariates. The findings were tested for replication in an independent internal Sardinian cohort of 1828 individuals, using a custom chip designed to include the top 43 nonredundant SNPs associated with PWV. Of the loci that were tested for association with PWV, the nonsynonymous SNP rs3742207 in the COL4A1 gene on chromosome 13 and SNP rs1495448 in the MAGI1 gene on chromosome 3 were successfully replicated (P=7.08 x 10(-7) and P=1.06 x 10(-5), respectively, for the combined analyses). The association between rs3742207 and PWV was also successfully replicated (P=0.02) in an independent population, the Old-Order Amish, leading to an overall P=5.16 x 10(-8).A genome-wide association study identified a SNP in the COL4A1 gene that was significantly associated with PWV in 2 populations. Collagen type 4 is the major structural component of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness.

The importance of vitamin D for bone health has long been acknowledged. Recent evidence suggests that vitamin D can also play a role in reducing the risk of several other diseases, including cardiovascular disease. The aim of this study is to test the hypothesis that 25-hydroxyvitamin D (25-OH D) is an independent cross-sectional correlate of central arterial stiffness in a normative aging study population. We conducted a cross-sectional analysis. We studied 1228 healthy volunteers (50% males; age, 70 ± 12 yr) of the Baltimore Longitudinal Study of Aging. We measured carotid-femoral pulse wave velocity (PWV) and 25-OH D levels. We found a significant inverse association between PWV and 25-OH D levels (adjusted r2 = 0.27; β = −0.43; P = 0.001). After adjusting for age, gender, ethnicity, season of blood draw, estimated glomerular filtration rate, physical activity level, cardiovascular risk factors score (smoking, visceral obesity, hypercholesterolemia, hypertension, and diabetes), calcium/vitamin D supplementation, serum calcium, and PTH levels, the association between PWV and 25-OH D levels was only slightly reduced and remained statistically significant (adjusted r2 = 0.34; β = −0.34; P = 0.04). Vitamin D levels are inversely associated with increased arterial stiffness in a normative aging population, irrespective of traditional risk factor burden. Further research is needed to understand the mechanism of this association and to test the hypothesis that vitamin D supplementation can reduce arterial stiffness.

Fibroblast growth factor 21 (FGF21), a recently discovered endocrine factor, plays an important role in glucose and lipid metabolism and may contribute to the development of atherosclerosis and coronary heart disease. The present cross sectional study examined the relationship of FGF21 with hypertension in 744 community-dwelling adults who participated in the Baltimore Longitudinal Study of Aging.

A significant inter-arm difference in systolic blood pressure (IADSBP) has recently been associated with worse cardiovascular outcomes. The authors hypothesized that part of this association is mediated by arterial stiffness, and examined the relationship between significant IADSBP and carotid-femoral pulse wave velocity (CF-PWV) in a sample from the Baltimore Longitudinal Study of Aging. Of 1045 participants, 50 (4.8%) had an IADSBP ≥10 mm Hg at baseline, and 629 had completed data from ≥2 visits (for a total of 1704 visits during 8 years). CF-PWV was significantly higher in patients with an IADSBP ≥10 mm Hg (7.3±1.9 vs 8.2±2, P=.002). Compared with others, patients with IADSBP ≥10 mm Hg also had higher body mass index, waist circumference, and triglycerides; higher prevalence of diabetes; and lower high-density lipoprotein (HDL) cholesterol (P<.001 for all). A significant association with IADSBP ≥10 mm Hg was observed for CF-PWV in both cross-sectional (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.06-1.87; P=.01) and longitudinal (OR, 1.15; 95% CI, 1.03-1.29; P=.01) multivariate analyses. Female sex, Caucasian race, high body mass index (plus diabetes and low HDL cholesterol only cross-sectionally) were other independent correlates of IADSBP ≥10 mm Hg. Significant IADSBP is associated with increased arterial stiffness in community-dwelling older adults.

Serum uric acid (SUA) has long been associated with increased cardiovascular risk, with arterial stiffness proposed as a mediator. However, evidence on the association between SUA and arterial stiffness is limited to contradicting cross-sectional studies. In this analysis, we examined the longitudinal relationship between SUA and pulse wave velocity, a measure of arterial stiffness, in a community-dwelling population. We studied 446 women and 427 men participating in the BLSA (Baltimore Longitudinal Study of Aging), with 1409 and 1434 observations, respectively, over an average period of 6 years. At baseline, mean ages of women and men were 65±13 and 68±13 years; mean SUA, 4.6±1.1 and 5.7±1.3 mg/dL; mean pulse wave velocity, 8.1±1.7 and 8.6±1.9 m/s, respectively ( P &lt;0.0001). In gender-stratified models accounting for age, blood pressure, renal function, metabolic measures, and medications, there was a significant interaction between SUA and follow-up time in men (β=0.69; P =0.0002) but not in women. Men, but not women, in the highest gender-specific SUA tertile at baseline (SUA≥6.2 mg/dL in men and SUA≥4.9 mg/dL in women) had a greater rate of pulse wave velocity increase over time than those in the lowest tertiles (β=0.997; P =0.012). This gender difference was lost when the distribution of SUA in men and women was made comparable by excluding hyperuricemic men (SUA≥6.2 mg/dL). In conclusion, higher SUA was associated with greater increase in pulse wave velocity in men but not women; this association was lost when men with SUA≥6.2 mg/dL were not included, suggesting a threshold for SUA association with arterial stiffness, which is more frequently reached in men.

Abstract Colliders are essential research tools for particle physics. Numerous future collider proposal were discussed in the course of the US high energy physics community strategic planning exercise Snowmass'21 . The Implementation Task Force (ITF) has been established to evaluate the proposed future accelerator projects for performance, technology readiness, schedule, cost, and environmental impact. Corresponding metrics has been developed for uniform comparison of the proposals ranging from Higgs/EW factories to multi-TeV lepton, hadron and ep collider facilities, based on traditional and advanced acceleration technologies. This article describes the metrics and approaches, and presents evaluations of future colliders performed by the ITF.

Endothelin-1 (ET) produces neonatal rat ventricular myocyte (NRVM) hypertrophy and activates focal adhesion kinase (FAK) in other cell types. In the present study, we examined whether ET activated FAK in NRVM and whether FAK was necessary and/or sufficient for ET-induced NRVM hypertrophy. Chronic ET-1 stimulation (100 nM, 48 h) increased protein-to-DNA and myosin heavy chain (MHC)-to-DNA ratios and stimulated the assembly of newly synthesized MHC into sarcomeres. ET-1 also induced the assembly of focal adhesions and costameres, as evidenced by increased phosphotyrosine, FAK, and paxillin immunostaining. Acutely, ET treatment rapidly increased tyrosine phosphorylation of FAK and paxillin. FAK was also activated by phorbol 12-myristate 13-acetate (2 microM, 5 min). Pretreatment with chelerythrine (5 microM) or rottlerin (10 microM) completely blocked ET-induced FAK phosphorylation, indicating that protein kinase C activation was upstream of ET-induced FAK activation. In contrast, ET-induced FAK activation was not affected by blocking calcium influx via L-type voltage-gated calcium channels. Adenoviruses (Adv) containing FAK and FAK-related nonkinase (FRNK) were used to specifically define the role of FAK in ET-induced hypertrophy. ET stimulation failed to increase total protein-to-DNA or MHC-to-DNA ratios or to stimulate sarcomeric assembly in myocytes infected with Adv-FRNK. However, Adv-FAK alone did not increase total protein-to-DNA or MHC-to-DNA ratios and failed to increase the number or size of myofibrils as evidenced by double immunofluorescence labeling for MHC and FAK. Thus, although FAK is necessary for ET-induced NRVM hypertrophy, other ET-generated signals are also required to elicit the hypertrophic phenotype.

Obesity is independently associated with left ventricular (LV) hypertrophy and thus may be an important modifier of the hypertrophic cardiomyopathy (HC) phenotype. We examined if obesity modifies the clinical presentation, LV morphology, outflow hemodynamics, and exercise tolerance in HC. In this cross-sectional study, 88 obese (body mass index [BMI] ≥30 kg/m2) and 154 nonobese (BMI <30 kg/m2) patients from the Johns Hopkins HC clinic were compared with respect to a variety of clinical and LV echocardiographic measurements. Obese patients (36.4%) were more likely to report exertional dyspnea (p = 0.04) and chest pain (p = 0.002) and had greater prevalence of hypertension (p = 0.008). LV posterior wall thickness (p = 0.01) but not the septal wall (p ≥0.21) was significantly greater in obese patients, resulting in an increased LV mass index (p = 0.003). No significant differences in LV systolic and diastolic functions were observed, but obesity was associated with higher LV stroke volume (p = 0.03), inducible LV outflow tract gradients (p = 0.045), and chance of developing LV outflow tract obstruction during stress (p = 0.035). In multivariate analysis, BMI was associated with increased posterior (but not septal) wall thickness (β = 0.15, p = 0.02) and LV mass index (β = 0.18, p = 0.005), particularly in those with hypertension. Obesity was also associated with reduced exercise time and functional capacity, and BMI independently correlated with reduced exercise tolerance. In conclusion, obesity is associated with larger LV mass, worse symptoms, lower exercise tolerance, and labile obstructive hemodynamics in HC. The association with increased outflow tract gradients has particular importance as contribution of obesity to the pressure gradients may influence clinical decisions in labile obstructive HC. Obesity is independently associated with left ventricular (LV) hypertrophy and thus may be an important modifier of the hypertrophic cardiomyopathy (HC) phenotype. We examined if obesity modifies the clinical presentation, LV morphology, outflow hemodynamics, and exercise tolerance in HC. In this cross-sectional study, 88 obese (body mass index [BMI] ≥30 kg/m2) and 154 nonobese (BMI <30 kg/m2) patients from the Johns Hopkins HC clinic were compared with respect to a variety of clinical and LV echocardiographic measurements. Obese patients (36.4%) were more likely to report exertional dyspnea (p = 0.04) and chest pain (p = 0.002) and had greater prevalence of hypertension (p = 0.008). LV posterior wall thickness (p = 0.01) but not the septal wall (p ≥0.21) was significantly greater in obese patients, resulting in an increased LV mass index (p = 0.003). No significant differences in LV systolic and diastolic functions were observed, but obesity was associated with higher LV stroke volume (p = 0.03), inducible LV outflow tract gradients (p = 0.045), and chance of developing LV outflow tract obstruction during stress (p = 0.035). In multivariate analysis, BMI was associated with increased posterior (but not septal) wall thickness (β = 0.15, p = 0.02) and LV mass index (β = 0.18, p = 0.005), particularly in those with hypertension. Obesity was also associated with reduced exercise time and functional capacity, and BMI independently correlated with reduced exercise tolerance. In conclusion, obesity is associated with larger LV mass, worse symptoms, lower exercise tolerance, and labile obstructive hemodynamics in HC. The association with increased outflow tract gradients has particular importance as contribution of obesity to the pressure gradients may influence clinical decisions in labile obstructive HC.

We examined the relations of central adiposity with left ventricular (LV) diastolic dysfunction in men and women who participated in the Baltimore Longitudinal Study of Aging, a prospective community-based study of older persons. The sample for this cross-sectional analysis included 399 women and 370 men. Central adiposity was estimated using the waist circumference (WC) and global adiposity using the body mass index (BMI). Using data from a comprehensive echocardiographic study that included tissue Doppler imaging, diastolic function was graded according to 3 parameters (E/A ratio, E/Em ratio, and left atrial volume index). In the logistic regression models adjusted for age, gender, cardiovascular risk factors, and hemodynamic parameters, WC and BMI were both independently associated with LV diastolic dysfunction. However, when both WC and BMI were in the same model, only WC remained significantly associated with LV diastolic dysfunction (odds ratio 1.04, 95% confidence interval 1.01 to 1.08, p = 0.02). In the gender-stratified analyses, WC was significantly associated with LV diastolic dysfunction—independently of BMI—in women (odds ratio 1.08, 95% confidence interval 1.04 to 1.14, p <0.001) but not in men (odds ratio 1.00, 95% confidence interval 0.95 to 1.05, p = 0.91). Additional adjustment for LV mass index failed to modify these relations. In conclusion, the adverse effect of central adiposity on LV diastolic function was independent of general adiposity and more pronounced among women. The effect of visceral adiposity on LV diastolic dysfunction would benefit from confirmation in longitudinal studies. We examined the relations of central adiposity with left ventricular (LV) diastolic dysfunction in men and women who participated in the Baltimore Longitudinal Study of Aging, a prospective community-based study of older persons. The sample for this cross-sectional analysis included 399 women and 370 men. Central adiposity was estimated using the waist circumference (WC) and global adiposity using the body mass index (BMI). Using data from a comprehensive echocardiographic study that included tissue Doppler imaging, diastolic function was graded according to 3 parameters (E/A ratio, E/Em ratio, and left atrial volume index). In the logistic regression models adjusted for age, gender, cardiovascular risk factors, and hemodynamic parameters, WC and BMI were both independently associated with LV diastolic dysfunction. However, when both WC and BMI were in the same model, only WC remained significantly associated with LV diastolic dysfunction (odds ratio 1.04, 95% confidence interval 1.01 to 1.08, p = 0.02). In the gender-stratified analyses, WC was significantly associated with LV diastolic dysfunction—independently of BMI—in women (odds ratio 1.08, 95% confidence interval 1.04 to 1.14, p <0.001) but not in men (odds ratio 1.00, 95% confidence interval 0.95 to 1.05, p = 0.91). Additional adjustment for LV mass index failed to modify these relations. In conclusion, the adverse effect of central adiposity on LV diastolic function was independent of general adiposity and more pronounced among women. The effect of visceral adiposity on LV diastolic dysfunction would benefit from confirmation in longitudinal studies.

Abstract Objectives The effects of vitamin D on the heart have been studied in patients with cardiac disease, but not in healthy persons. We investigated the relation between vitamin D status and left ventricular ( LV ) structure and function in community‐dwelling subjects without heart disease. Design The relationship between concentrations of 25‐hydroxyvitamin D [25( OH )D], a marker of vitamin D reserve, and LV transthoracic echocardiography measures was analysed in 711 participants in the Baltimore Longitudinal Study of Aging who were without cardiac disease. Results Mean 25(OH)D in the study population was 32.3 ± 11.4 ng mL −1 ; only 15.5% of subjects had moderate or severe vitamin D deficiency [25(OH)D &lt; 20 ng mL −1 ]. Adjusting for age, body mass index, cardiovascular disease risk factors, physical activity, calcium and parathyroid hormone, 25(OH)D was positively correlated with LV thickness (β 0.095, SE 0.039, P &lt; 0.05) and LV mass index (β 7.5, SE 2.6, P &lt; 0.01). A significant nonlinear relation between 25(OH)D and LV concentric remodelling was observed. LV remodelling was more likely in participants with 25(OH)D levels &lt;30 ng mL −1 [odds ratio (OR) 1.24; 95% confidence interval (CI) 0.83–1.85] or ≥38 ng mL −1 (OR 1.73; 95% CI 1.13–2.65), compared with those with 30–37 ng mL −1 25(OH)D. Consistently, LV relative wall thickness was significantly lower ( P for trend=0.05), and LV diastolic internal diameter index ( P for trend&lt;0.05) and end‐diastolic volume index ( P for trend&lt;0.05) were significantly higher in subjects with 30–37 ng mL −1 25(OH)D compared to the rest of the study population. There was a significant interaction between 25(OH)D and hypertension on the risk of LV hypertrophy ( P &lt; 0.05). Conclusions In a population‐based sample of predominantly vitamin D‐sufficient subjects without heart disease, LV geometry was most favourable at intermediate 25( OH )D concentrations.

It is unclear whether subcutaneous and visceral fat are differentially correlated to the decline in left ventricular (LV) diastolic function with aging. This study sought to examine the hypothesis that age-related changes in the regional fat distribution account for changes in LV diastolic function and to explore potential mediators of this association.In this cross-sectional study, we evaluated 843 participants of the Baltimore Longitudinal Study of Aging with echocardiogram, dual-energy X-ray absorptiometry (DEXA), abdominal computed tomography (CT) and blood tests performed at the same visit. LV diastolic function was assessed by parameters of LV relaxation (E/A ratio, Em and Em/Am ratio) and LV filling pressures (E/Em ratio). Total body fat was computed by DEXA, while visceral and subcutaneous fat were determined from abdominal CT. In multivariate models adjusted for demographics, cardiovascular risk factors, antihypertensive medications, physical activity and LV mass, both visceral and subcutaneous fat were associated with LV diastolic dysfunction. When both measures of adiposity were simultaneously included in the same model, only visceral fat was significantly associated with LV diastolic dysfunction. Triglycerides and sex-hormone binding globulin, but not adiponectin and leptin, were found to be significant mediators of the relationship between visceral fat and LV diastolic function, explaining 28-47% of the association. Bootstrapping analyses confirmed the significance of these findings.Increased visceral adiposity is associated with LV diastolic dysfunction, possibly through a metabolic pathway involving blood lipids and ectopic fat accumulation rather than adipokines.

Studies have found that central obesity is associated with higher carotid–femoral pulse wave velocity (PWV). However, traveled distance (TD) measured over the body surface can be substantially overestimated with wider waist circumference (WC). We sought to investigate whether central obesity biases the estimation of PWV and whether this bias explains the association between PWV and different measures of adiposity. Seven hundred eleven participants (49.5% men) from the Baltimore Longitudinal Study of Aging with PWV, anthropometrics, and quantification of different fat depots by computed tomography and dual x-ray absorptiometry were included. TD and relative PWV were estimated with a tape measure over the body surface or linear distances taken from radiological images, unaffected by obesity. A significant association was found between wider WC and a greater difference between the 2 TD measurements and their respective PWV in both sexes (r ≥ 0.34; P < 0.001). This overestimation bias appeared to be generally higher in women than men (0.27 m/sec for each unit increase in WC; P < 0.0001). When TD estimated over the body surface was used to calculate PWV, greater WC, total body fat, subcutaneous fat, and visceral fat were all associated with higher PWV (P < 0.05 for all). However, when PWV was calculated using TD estimated from radiological images or body height, only the association with visceral fat held significant. When TD is measured over the body surface, the role of obesity on PWV is substantially overestimated. After accounting for this bias, PWV was still independently associated with visceral fat but not with other measures of adiposity, confirming its contribution to arterial stiffening.

Summary Objective Thyroid dysfunction may accelerate atherosclerosis. Aortic pulse wave velocity (PWV) is an early index of arterial stiffness and an important risk factor for cardiovascular disease and might therefore be linked to changes in thyroid activity. We investigated the relationship between thyroid function and carotid‐femoral PWV, as an index of arterial stiffness. Design Cross‐sectional cohort study. Patients Participants from the Sardi NIA study. Those being treated for thyroid diseases were excluded, yielding a sample of 5875 aged 14–102. Measurements Clinical parameters, blood tests including serum TSH and serum FT 4, and carotid‐femoral PWV were measured. Results After adjusting for confounders, a direct and linear association between FT 4 and PWV was shown (multiple regression analysis). The model containing age, mean blood pressure, body mass index, heart rate, FT 4, hypertension, diabetes and dyslipidaemia accounted for 55% of the variation in PWV. Conclusions Like several other known risk factors, serum FT 4 levels are associated with carotid‐femoral PWV, suggesting that high FT 4 levels have a detrimental effect on aortic stiffness and may contribute to ageing process of the vascular system. This finding may help to understand the pathogenesis of cardiovascular disease and contribute to improve prevention therapy.

We investigated the gender-specific control of cardiovascular (CV) risk factors and subclinical vascular lesions in a founder population in Italy.6148 subjects were enrolled (aged 14-102 years) from four towns. Hypertension (HT), diabetes mellitus (DM) and dyslipidemia (LIP) were defined in accordance with guidelines. A self-reported diagnosis defined awareness of these conditions, and the current use of specific medications as treatment. Prevalence was HT 29.2%, DM 4.8%, LIP 44.1% and was higher in men than in women. Disease prevalence increased with age for every CV risk factor. Men were less likely than women to take anti-HT drugs and to reach BP control (9.9% vs. 16%). Only 17.6% of HT > 65 years had a BP < or =140/90 mmHg, though 48.5% were treated. The use of statins was very low (<1/3 of eligible subjects > 65 years, those with the highest treatment rate). The ratio of control-to-treated HT was lower in subjects with, than in those without, thicker carotid arteries (31.5% vs. 38.8%, p < 0.05) or stiffer aortas (26.0% vs. 40.0%, p < 0.05) or carotid plaques (26.3% vs. 41.1%, p<0.05).A large number of subjects at high CV risk are not treated and the management of subclinical vascular lesions is far from optimal.

Objectives: Anxiety and other psychological dispositions are thought to be associated with blood pressure. This study tests whether personality traits have long-term associations with masked and white-coat effects. Methods: A community-based sample of 2838 adults from Sardinia (Italy) completed the Revised NEO Personality Inventory, and 7 years later, blood pressure was assessed in the clinic and with ambulatory monitoring. Logistic regressions were used to test whether anxiety, neuroticism, extraversion, openness, agreeableness, and conscientiousness predicted the white-coat and masked hypertension phenomena. Age, sex, and antihypertensive medication use were tested as moderators. Results: Significant interactions were found between personality traits and antihypertensive medications in predicting masked and white-coat effects. Only among those taking antihypertensive medication, higher anxiety was associated with a higher risk of pseudo-resistant hypertension due to white-coat effect (odds ratio 1.39, 95% confidence interval 1.01–1.91) and higher conscientiousness was associated with a lower risk of masked uncontrolled hypertension (odds ratio 0.70, 95% confidence interval 0.49–0.99). There were no significant interactions with age or sex. Conclusions: Among those on antihypertensive medications, anxious individuals were more likely to have pseudo-resistant hypertension due to white-coat effect and less conscientious individuals were at increased risk of masked uncontrolled hypertension. Particularly among anxious and less conscientious individuals, ambulatory monitoring may improve the tailoring of pharmacological treatments.

Using adenovirus (Adv)-mediated overexpression of constitutively active (ca) and dominant-negative (dn) mutants, we examined whether protein kinase C (PKC)-ε, the major novel PKC isoenzyme expressed in the adult heart, was necessary and/or sufficient to induce specific aspects of the hypertrophic phenotype in low-density, neonatal rat ventricular myocytes (NRVM) in serum-free culture. Adv-caPKC-ε did not increase cell surface area or the total protein-to-DNA ratio. However, cell shape was markedly affected, as evidenced by a 67% increase in the cell length-to-width ratio and a 17% increase in the perimeter-to-area ratio. Adv-caPKC-ε also increased atrial natriuretic factor (ANF) and β-myosin heavy chain (MHC) mRNA levels 2.5 ± 0.3- and 2.1 ± 0.2-fold, respectively, compared with NRVM infected with an empty, parent vector ( P &lt; 0.05 for both). Conversely, Adv-dnPKC-ε did not block endothelin-induced increases in cell surface area, the total protein-to-DNA ratio, or upregulation of β-MHC and ANF gene expression. However, the dominant-negative inhibitor markedly suppressed endothelin-induced extracellular signal-regulated kinase (ERK) 1/2 activation. Taken together, these results indicate that caPKC-ε overexpression alters cell geometry, producing cellular elongation and remodeling without a significant, overall increase in cell surface area or total protein accumulation. Furthermore, PKC-ε activation and downstream signaling via the ERK cascade may not be necessary for cell growth, protein accumulation, and gene expression changes induced by endothelin.

Fermilab is developing and investigating different high-field magnets (HFM) for present and future accelerators. The HFM R&D program focused on the 10-12 T magnets based on Nb/sub 3/Sn superconductor and explored both basic magnet technologies for brittle superconductors-wind-and-react and react-and-wind. Magnet design studies in support of LHC upgrades and VLHC were conducted. A series of 1-m long cos-theta dipole models based on the wind-and-react technique was fabricated and tested. Three 1-m long flat racetracks and the common coil dipole model, based on a single-layer coil and react-and-wind technique, were also fabricated and tested. Extensive theoretical and experimental studies of electro-magnetic instabilities in Nb/sub 3/Sn strands, cables and magnets were performed and led to a successful 10 T dipole model. This paper presents the details of Fermilab's HFM program, reports its status and major results, and formulates the next steps for the program.

HomeJournal of the American Heart AssociationVol. 8, No. 10New Strategies for the Conduct of Clinical Trials in Pediatric Pulmonary Arterial Hypertension: Outcome of a Multistakeholder Meeting With Patients, Academia, Industry, and Regulators, Held at the European Medicines Agency on Monday, June 12, 2017 Open AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialOpen AccessResearch ArticlePDF/EPUBNew Strategies for the Conduct of Clinical Trials in Pediatric Pulmonary Arterial Hypertension: Outcome of a Multistakeholder Meeting With Patients, Academia, Industry, and Regulators, Held at the European Medicines Agency on Monday, June 12, 2017 Cécile Ollivier, MS, Haihao Sun, MD, PhD, Wayne Amchin, RAC, Maurice Beghetti, MD, Rolf M. F. Berger, MD, PhD, Stefanie Breitenstein, MD, Christine Garnett, PharmD, Ninna Gullberg, MD, PhD, Patrik Hassel, Dunbar Ivy, MD, Steven M. Kawut, MD, Agnes Klein, MD, DPH, Catherine Lesage, MD, Marek Migdal, MD, PhD, Barbara Nije, Michal Odermarsky, MD, PhD, James Strait, MD, Pieter A. de Graeff, MD, PhD and Norman Stockbridge, MD, PhD Cécile OllivierCécile Ollivier European Medicines Agency, London, United Kingdom , Haihao SunHaihao Sun Food and Drug Administration, Silver Spring, MD , Wayne AmchinWayne Amchin Food and Drug Administration, Silver Spring, MD , Maurice BeghettiMaurice Beghetti Pediatric Cardiology Unit, Centre Universitaire de Cardiologie et Chirurgie Cardiaque Pédiatrique, University Hospitals of Geneva, City of Geneva, Switzerland , Rolf M. F. BergerRolf M. F. Berger Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, the Netherlands , Stefanie BreitensteinStefanie Breitenstein Bayer AG, Pharmaceuticals, Research and Development, Wuppertal, Germany , Christine GarnettChristine Garnett Food and Drug Administration, Silver Spring, MD , Ninna GullbergNinna Gullberg European Medicines Agency, London, United Kingdom , Patrik HasselPatrik Hassel PH Sweden, Göteborg, Sweden , Dunbar IvyDunbar Ivy Heart Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO , Steven M. KawutSteven M. Kawut Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA , Agnes KleinAgnes Klein Health Canada, Ottawa, Ontario, Canada , Catherine LesageCatherine Lesage Actelion Pharmaceuticals Ltd, Allscwil, Switzerland , Marek MigdalMarek Migdal Childrens Memorial Health Institute, Warsaw, Poland , Barbara NijeBarbara Nije Health Canada, Ottawa, Ontario, Canada , Michal OdermarskyMichal Odermarsky Department of Paediatric Cardiology, Paediatric Heart Center, Lund University and Skåne University Hospital, Lund, Sweden , James StraitJames Strait MSD, Lucerne, Switzerland , Pieter A. de GraeffPieter A. de Graeff Medicines Evaluation Board, Utrecht, the Netherlands and Norman StockbridgeNorman Stockbridge Food and Drug Administration, Silver Spring, MD Originally published15 May 2019https://doi.org/10.1161/JAHA.118.011306Journal of the American Heart Association. 2019;8:e011306The Pediatric Regulation (EC) 1901/2006 in the European Union (EU) and the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act in the United States aim to ensure that medicines for use in children are of high quality, are ethically researched, and are authorized appropriately. Such an assessment requires clinically robust and relevant data. However, the conduct of pediatric clinical trials has proved difficult because of the rarity of the diseases and gaps in knowledge in younger populations, leading to a general concern internationally that, depending on the disease and age of the child, 50% to 80% of children are still treated off label.1, 2, 3 Over the years, this gap in available evidence has led to serious unintended harms. For example, the off‐label pediatric use of paroxetine was associated with an increased risk of suicidal ideation and hostility, resulting in warnings by regulators that the medicine should not be used in children and adolescents.4 In addition, local differences related to regulatory requirements, operational practicalities, standards of care, or cultural expectations are creating hurdles to conduct multiregional pediatric drug studies and develop pediatric clinical trials networks required when developing drugs for rare diseases.Many efforts have been taken among the regulatory agencies in recent years to achieve global regulatory harmonization, which have been helpful to mitigate these challenges in other areas.5, 6 Over the past 3 years, international experts convened to revise the ICH (International Council for Harmonisation) E11 guideline on clinical investigations of medicinal products in pediatric populations to harmonize approaches to pediatric extrapolation, striving to reduce substantial differences between regions in the acceptance of data for global pediatric medicine development programs.7, 8 In addition, there are other activities aiming at a more targeted harmonization at the product or therapeutic level. For example, there are monthly teleconferences among the US Food and Drug Administration, European Medicines Agency, Health Canada, Pharmaceuticals and Medical Devices Agency in Japan, and Therapeutic Goods Administration in Australia to exchange evolving science and discuss the current regulatory approaches for specific product applications in pediatrics.9 We have harmonized some regulatory approaches for certain pediatric indications, such as pediatric inflammatory bowel disease and Gaucher disease.5, 6These concerns and challenges apply also to the treatment of children with pulmonary arterial hypertension (PAH). Pediatric PAH is a rare and complex condition associated with diverse cardiac, pulmonary, and systemic diseases, with significant morbidity and mortality. It shares some similarities with adult PAH, but there are important known differences in vascular function, fetal origins of disease, growth and development, genetics, natural history, underlying disease, responses of the right ventricle, responsiveness to PAH‐specific therapies, and gaps in knowledge, particularly in the youngest age groups.10Because of the limitations in conducting pediatric studies, therapeutic strategies used for adult PAH have not been studied sufficiently in children to allow the definition of potential toxicities or optimal dosing. Hence, the lack of randomized clinical trials in pediatrics makes it difficult to deliver strong guidelines. On the basis of uncontrolled studies and one randomized controlled trial for sildenafil, STARTS‐1 (Sildenafil in Treatment‐Naïve Children, Aged 1–17 Years, With Pulmonary Arterial Hypertension), and experts' consensus, recommendations for extrapolating a pharmacological treatment algorithm to pediatric PAH were made at the fifth World Symposium for Pulmonary Hypertension held in Nice, France, in 2013.11Therefore, the European Medicines Agency, the US Food and Drug Administration, and Health Canada coorganized a workshop12 to discuss the requirements for the development of medicines for pediatric PAH that could address the high unmet medical needs of children.This report summarizes the main ideas and solutions proposed during the meeting. Ultimately, the goal is to provide a framework to further global development of successful strategies and alternative end points for pediatric drug development in PAH.The data that support the findings of the survey are provided in Data S1. The workshop brought together leading experts in PAH and PAH stakeholders across the globe, including regulators, researchers, clinicians, healthcare professionals, patients, and pharmaceutical industry representatives. The objectives of the workshop were to analyze the problems related to the conduct of clinical trials in children with PAH, to refine end points and study designs to address the challenges identified, and to set priorities for future research and development aspects of specific medicines as well as provide medicine developers with more advice specific to global pediatric drug development.Current Status of Drug Development in Pediatric PAHRandomized controlled trials have shaped advances in the care of adults with cardiovascular disease and are regarded as the gold standard design to provide evidence for regulatory approval for cardiovascular medicines. However, there are many challenges to relying exclusively on randomized clinical drug trials in adults to address the unique needs of children. Such studies cannot always be conducted in rare pediatric diseases, such as PAH. Because of these challenges, of the 9 products authorized for adults with PAH in the EU and Canada, and 11 in the United States, only 2 of these products, sildenafil and bosentan, are authorized for children in the EU and United States, respectively (Table 1). The complexity is increased in the case of the pediatric PAH population because of the many associated conditions that fragment the classification of pediatric PAH, which leaves only a relatively small number of patients with PAH at each center, facing a high number of competing medicinal products.Table 1. Overview of Medicines Available for Use in PAH for Adults and ChildrenClass of ProductsProductAuthorization for AdultsAuthorization for ChildrenEUUnited StatesCanadaEUUnited StatesCanadaProstacyclin analogueTreprostinilNoYesYesNoNoNoSelexipagYesYesYesNoNoNoTreprostinil diethanolamineNoYesNoNoNoNoIloprostYesYesNoNoNoNoEpoprostenolYesYesYesNoNoNoEndothelin receptors AntagonistBosentanYesYesYesPharmacokinetics dataYesPharmacokinetics dataAmbrisentanYesYesYesNoNoNoMacitentanYesYesYesNoNoNoPhosphodiesterase type 5 inhibitorSildenafilYesYesYesYesNoNoTadalafilYesYesYesNoNoNoGuanylate cyclase stimulatorsRiociguatYesYesYesNoNoNoJohn Wiley & Sons, LtdPediatric indications have not been granted; however, results of pharmacokinetic studies in the different pediatric age groups are summarized in the Summary of Product Characteristics, with a comparison to adults. Uncertainties caused by limited experience are also stated. EU indicates European Union; PAH, pulmonary arterial hypertension.The lack of suitable clinical end points is another important challenge for conducting pediatric clinical trials. End points used in adults, such as the use of the 6‐Minute Walking Distance (6MWD) Test, cannot be used in all pediatric age subsets. Furthermore, there is a lack of consensus about the use of right‐sided heart catheterization to obtain hemodynamic end points in pediatric clinical trials. This is confounded by a lack of adequate alternative end points because of gaps in knowledge related to methods to evaluate how a child and adolescent feel and function across the age spectrum in response to therapy. These challenges have limited the use of methods commonly used in pediatric development, such as extrapolation. Methodological tools, such as extrapolation, can optimize obtaining information about children involved in clinical studies by predicting how a medicine may work in children and adolescents on the basis of studies conducted in adults.13, 14, 15This situation has resulted in a lack of equipoise after marketing authorization for new investigational drugs in adults, making it even more difficult to enroll children, and contributes to off‐label use, which can increase the risk of inadequate dosing and results in lack of pediatric safety data. The main points of tension are related to finding the adequate balance between early access and sufficient exposure of children during pediatric trials for safety and adequate dosing; considerations should also be given about ethical and medical aspects, particularly related to end points.Premeeting Survey of Patients and Their Families, Healthcare Professionals, and Drug Developers on Pediatric PAH Drug DevelopmentAn online survey was conducted ahead of the workshop among all interested stakeholders to gather as much information as possible and facilitate an informed discussion. Healthcare professionals and patients in the EU, United States, and Canada were contacted as well as one expert in Japan. Survey questions were related to pathophysiological features, pharmacological behavior, mechanism of action, extrapolation, end points, quality of life, and clinical trials. Respondents included 22 healthcare professionals treating adults and children with PAH, 4 industry participants involved in PAH drug development, 26 parents of children with PAH, and 1 adolescent patient with PAH.For the healthcare professionals, specific points considered central to the discussion were related to the lack of sufficient outcome measures that are applicable to young children with PAH, including the lack of established biomarkers that can predict disease risk, severity, and disease progression. Experts welcomed the opportunity to investigate the use of activity measurement for the pediatric population and acknowledged the possibility of using noninvasive techniques and candidate surrogate markers, such as selected imaging (echocardiography or cardiac magnetic resonance imaging) parameters or NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide).With regard to patients, major topics for discussion were related to off‐label use, end points, daily monitoring, and participation in clinical trials. Most of the patients who participated in the survey and the workshop were not concerned about the off‐label use of drugs because they trust their physicians. Also, only a couple of medicinal products are licensed for children in their respective countries, leaving patients with no other choice than to accept the available therapy(‐ies) even when used off label. In addition, for medicinal products already licensed for adults, patients in many countries do not have an incentive to enroll in clinical studies because they can access these medicinal products for pediatric use outside of a clinical trial.Parents expressed concerns about the use of invasive procedures, such as right‐sided heart catheterization, to obtain hemodynamic end points in clinical trials and the use of the 6MWD Test, which was not considered a good indicator of the child's health status on its own. Parents take many other variables into account to monitor the child's health status, and many are regularly monitoring oxygen saturation. The most important signs for parents that their child's health is deteriorating are an observed increase in fatigue and change in physical appearance. In addition, most of the parents were supportive of the idea to self‐report specific symptoms and welcomed the possibility to gather and report data on quality of life and other important information through technologies, such as smartphone applications.Representatives from the pharmaceutical industry acknowledged the challenges of conducting studies in pediatric PAH, but also welcomed clarifications about assumptions and method (eg, knowledge on appropriate end points and applicability of extrapolation) to minimize the risk of inconclusive study results. More important, the level of evidence required for licensing should not differ substantially between the different regulatory regions and stakeholders. Streamlined clinical development programs that would meet global requirements would help optimize the use of resources and achieve success in a reasonable time.At the meeting, it was agreed that because of these various perceptions by stakeholders, pediatric development programs are disconnected from their respective adult programs. Such disconnections impede the design, recruitment, and conduct of studies in children, leading to significant delays. It is important to help ensure that the data generated in adults and children will address the scientific questions that are important for licensing for children in a timely manner.Trial Design in Pediatric PAH: Points to Consider and Paradigm ShiftTransfer of information from the adult to the pediatric population and use of existing knowledgeDrugs approved to treat PAH in adults are typically based on a single, well‐controlled clinical trial showing statistically significant improvement in exercise capacity or, more recently, improvements in a composite of mortality and morbidity end points (Table 2). The pivotal efficacy trial is usually supported by a smaller phase 2 study that relies on pharmacodynamic end points (eg, hemodynamic biomarkers obtained by right‐sided heart catheterization) to show dose‐response and guide selection of dosing regimens. On the basis of global requirements for the use of extrapolation,8, 15 the use of a drug in the pediatric population can be supported by adult efficacy data in 2 ways: The data from the adult population support the use in pediatrics for the PAH indication. The efficacy is established in pediatric populations on the basis of an adequate and well‐controlled clinical efficacy and safety trial. Efficacy in the pediatric population is assessed using an appropriate clinical end point.The efficacy in the pediatric population is extrapolated from adult data. Evidence for effectiveness is based on adequate and well‐controlled clinical trials in adults, with additional supporting data in the specific pediatric population, typically guided by biomarker and pharmacokinetic data. In this scenario, the pathophysiological features of some forms of PAH are proved sufficiently similar in adults and children, and there is a clear understanding of the basis for the drug's benefit (mechanism of action, ontogeny of the drug target, and disease in adults and children) and a biomarker with which to assess the drug effects in the pediatric population.Table 2. Summary of Efficacy End Points Used to Obtain Regulatory Approval of Medicines for Use in PAH for Adults and ChildrenEnd Points UsedStudy Population and Numbers of StudiesProducts ApprovedLimitations if Used in Pediatric TrialsIncrease in 6‐min walking distance16, 17, 18, 19, 20Adults (8 studies)BosentanAmbrisentanSildenafilTadalafilTreprostinilIloprostEpoprostenolRiociguatNeed large sample size because of variabilityNot reliable in children less than 7 yA composite of time to the first morbidity or mortality event21, 22Adults (2 studies)MacitentanSelexipagTo further optimize and define relevant components of clinical worsening in pediatric patients with PAHNeed relatively large sample sizeIncrease in O2 consumption at peak exercise via CPET23Pediatrics (1 study)Sildenafil (EU)a51% of children were developmentally unable to perform CPET in this trial∆PVR/∆PVRi assessed by RHC24Pediatrics (1 study)Bosentan (United States and Health Canada)End points collected by invasive RHC are not supported for the purpose of pediatric trials because of ethical concerns about the risk of death and severe adverse events related to the procedureJohn Wiley & Sons, LtdCPET indicates cardiopulmonary exercise testing; EU, European Union; PAH, pulmonary arterial hypertension; ∆PVR, change in pulmonary vascular resistance; ∆PVRi, ∆PVR index; RHC, right‐sided heart catheterization.aSildenafil is approved in the EU, but not in the United States and Canada, on the basis of the evidence that long‐term mortality showed a dose‐related adverse trend on mortality.Pharmacokinetic and safety data cannot be extrapolated from adults and would need to be assessed in the pediatric population.On the basis of the data presented at the meeting and existing knowledge at the time of the workshop, there was consensus among stakeholders that our understanding of the pathophysiological features of various PAH subgroups is still insufficient to draw detailed comparison between those seen in the adult versus the child, and consequently to extrapolate efficacy as a general rule.A positive example in which progress has been made through adequate data collection over the past years and in which existing knowledge can translate in facilitating regulatory requirements is idiopathic PAH and some forms of associated PAH in adults and children, making progress toward extrapolation of efficacy possible. Such progress has been integrated by the Committee for Medicinal Products for Human Use, which is the European Medicines Agency's committee responsible for human medicines in the pediatric addendum to its guideline on the clinical investigations of medicinal products for the treatment of PAH. Such an agreement means that there would no longer always be the necessity to run studies in which the main aim is to confirm clinical benefits, and it might not necessarily be required to conduct placebo‐controlled trials. Placebo control can lead to recruitment issues, even for short‐term placebo withdrawal studies, as particularly highlighted by the patient's representatives. The use of extrapolation of efficacy from adults to children could allow pediatric licensing on the basis of studies evaluating pharmacokinetics, pharmacodynamics, and safety in the pediatric population.25 For classes of products already authorized, and with appropriate end points, adult and pediatric PAH clinical programs may proceed simultaneously, leading to timely access for children. To date, only bosentan has obtained a claim for use in the pediatric population on the basis of an extrapolation approach in the United States. During the meeting, stakeholders agreed that pharmacokinetics data alone (ie, matching blood concentrations in pediatric patients with PAH to those achieved in adult patients with PAH) would not be sufficient for extrapolation. There is the need to confirm the adequate doses with pharmacodynamics end points. Studies focusing on pharmacokinetics/pharmacodynamics may not need a control arm of another medicinal compound or placebo, but could be dose controlled with at least 3 doses to characterize the dose‐response curve. Further considerations to the pharmacokinetics/pharmacodynamics study design will need to be developed, particularly paying careful attention to pediatric clinical pharmacological features early in study design, which can also help to optimize initial dose selection and data sampling.In addition, although extrapolation might allow a reduction in the number of pediatric trial participants, it was acknowledged that extrapolation in pediatric PAH is still at a learning stage and there is a need for further data to enhance our current knowledge, specifically with respect to how developmental growth and maturation would impact pharmacokinetics/pharmacodynamics outcomes. Furthermore, efficacy data may have some residual uncertainties stemming from the limited populations and feasibility reasons at the time of initial approval. To address uncertainties at the time of marketing authorization, postauthorization studies that are performed in patient registries in which patients are recruited on the basis of a disease (ie, disease registry) rather than on the basis of a specific drug exposure can be a useful tool as they may provide robust data on disease epidemiological characteristics, patients' characteristics, and current standard of care. Conversely, experience shows that when there is the need for collaboration between registries, it is contingent on agreement on data ownership and sharing, timelines, established protocols and statistical analysis plans, consideration of methodological differences between data sources because of consideration of adequate sample size, and provision of operational and scientific support (ie, for programming and statistical analyses).26 These pediatric‐specific disease registries, such as the TOPP (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) registry, and, in the future, databases that accurately reflect the phenotype and genotype of neonatal and childhood PAH may prove of particular relevance to elucidate the natural history of PAH; these are critical factors that modulate outcomes and responses to therapies and related research questions. To address the need to better characterize pediatric PAH, the TOPP registry was initiated in January 2008 and is a global, prospective study designed to provide information about demographics, treatment, and outcomes in pediatric pulmonary hypertension. Furthermore, one of the tools to be considered is the model of real‐world data that can help to overcome some of the challenges. However, the planning for collection of structured data is particularly important to be set up a priori with a view to be successfully implemented.Consequently, it was agreed that the identification of the evidence necessary to inform the pediatric drug development program in pediatric PAH may require considerations for additional longitudinal systematic collection of data across developments in both adults and children, during these learning stages. The pharmaceutical industry participants considered the use of data pooling for validation of a pharmacodynamics parameter to enable extrapolation as a potential solution. For example, working across industry and sharing available placebo data or using available supportive data (eg, from other products with a similar mechanism of action, registries, or open‐label data) could contribute to end point evaluation and validation.Evidence‐based medicine for pediatric PAH and end pointsRegulatory approval of a drug traditionally requires demonstration that it improves a clinical outcome (ie, how a patient feels, functions, or survives) or a validated surrogate for such an outcome. Improving survival, improving exercise capacity, preventing hospitalization, and improving quality of life are all important treatment goals and have a direct impact on patients with PAH and their families. A surrogate end point is defined as an end point that is used in clinical trials as a substitute for a direct measure of how a patient feels, functions, or survives. A surrogate end point does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict that clinical benefit or harm on the basis of epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.27, 28 At present, there are no validated surrogate end points that can substitute for clinical end points to support traditional or accelerated approval of new therapies for pediatric PAH.Despite emerging recent data on clinical course, prognosticators, treatment strategies, the definition of treatment targets and the potential of (surrogate) end points in pediatric PAH, clinical research in pediatric PAH has a lack of age‐appropriate clinical end points, including the lack of established biomarkers that can predict disease risk, severity, and disease progression. A summary of potential useful noninvasive clinical end points is presented in Table 3. The applicability of each end point in pediatric clinical trials is described below in more detail.Table 3. Noninvasive End Points With Potential Use as End Points in Clinical Trials in ChildrenEnd Point ModalityPotential Treatment Goals to be ConsideredStrengthsLimitationsWHO‐FCWHO‐FC improvementConveniencePredictive of transplant‐free survival in pediatric PAHVariability in classifications among cliniciansDefinitions of symptoms may differ and not be reliable in childrenNT‐proBNPNT‐proBNP loweringSimple procedure (plasma)Likely predictive of transplant‐free survival in pediatric PAH prognosisNot a specific indicator for PAH onlyImpacted by cause of PAHThe normal value of NT‐proBNP in children can vary with ageEchocardiographyTAPSE improvement3‐Dimensional right ventricular functionFractional area changeWidely used for monitoring in patient population3‐Dimensional echocardiography offers new options with end pointsHigh operator variabilityLikely larger sample sizeNo consensus on which echocardiographic end point should be used as a primary outcomeActigraphyPhysical activity countHeart rate variabilityChildren friendlySimple and can continuously record physical activity for days and weeksCorrelates with 6MWD Test, mPAP, and PRViSensitive and, thus, potentially requires smaller sample sizeNeeds to be validated in an interventional trialNeeds to optimize the cutoff values for different levels of physical activities across different devicesSeasonal and school/holiday influencesPRONot studiedDirect measurement of how a patient feels, functions, and survivesNot being developedJohn Wiley & Sons, Ltd6MWD indicates 6‐Minute Walking Distance; mPAP, mean pulmonary arterial pressure; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PAH, pulmonary arterial hypertension; PRO, patient‐reported outcome; PVRi, pulmonary vascular resistance index; TAPSE, tricuspid annular plane systolic excursion; WHO‐FC, World Health Organization functional class.Interventional clinical trials in adults have commonly used the 6MWD Test to demonstrate efficacy for drug approval; therefore, this end point could be used in pediatric patients developmentally able to perform the test.29, 30, 31 Unfortunately, young children (aged <7 years) cannot reliably perform the test, making this a suboptimal primary end point in a study of the full age range of children. Likewise, cardiopulmonary exercise testing has failed as a primary end point in pediatric PAH sildenafil efficacy trials as 51% of children were unable to perform it.32Clinical worsening as a composite end point in adult trials in PAH has incorporated certain soft components, such as need for more therapy or reductions in exercise capacity, and poses challenges in terms of interpretability in PAH.33 Regulators have not considered the magnitude of drug effects on this end point to be of critical concern in granting such claims in adults. Thus, a program seeking such a cla

A localized hypertrophy of the subaortic segment of the ventricular septum-ventricular septal bulge (VSB)-has been frequently described in series of elderly population, but its prevalence with age, clinical correlates, and impact on cardiac function and exercise capacity remain uncertain. We explored these associations in a cross-sectional sample without known cardiac disease from the Baltimore Longitudinal Study of Aging. We randomly selected 700 participants (50% men, mean age 64 ± 15, range 26 to 95 years) and reviewed their echocardiograms. We identified 28 men and 21 women with VSB (7% overall prevalence). The prevalence of VSB significantly increased with age in both genders (p <0.0001). In multivariate logistic regression including hypertension and other cardiovascular risk factors, only age displayed a significant independent association with VSB (OR 1.06 per year, 95% confidence interval 1.03 to 1.10, p = 0.0001). After multiple adjustments, participants with VSB compared with those without had enhanced global left ventricular contractility (fractional shortening 41 ± 1.3 vs 38 ± 0.3%, p = 0.04; ejection fraction 71 ± 1.6 vs 67 ± 0.4%, p = 0.06; systolic velocity of the mitral annulus 8.4 ± 0.1 vs 8.9 ± 0.3, p = 0.06), and larger aortic root diameters (3.3 ± 0.06 vs 3.1 ± 0.02 cm, p = 0.02). In subgroup of participants who completed a maximal treadmill test (177 women and 196 men), those with VSB (19, 5.1%) had significantly lower peak oxygen consumption than their counterparts (19.6 ± 3.8 vs 22.9 ± 6.6 ml/kg/min, p = 0.03). However, this association was no longer significant after multiple adjustments. In conclusion, the presence of VSB is independently associated with older age and determines enhanced left ventricular contractility, without any evident impact on exercise capacity.

Previous studies from our laboratory and others indicate that contraction-induced mechanical loading of cultured neonatal rat ventricular myocytes produces many of the phenotypic changes associated with cardiomyocyte hypertrophy in vivo, and that these changes occur via the activation of serine-threonine protein kinases. These may include the extracellular regulated protein kinases (ERK1 and ERK2), the c-Jun N-terminal kinases (JNK1, JNK2, and JNK3), and one or more isoenzymes of protein kinase C. In this study, we assessed whether one or more of these kinases are activated by stimulated contraction, and whether activation was isoenzyme-specific. Low-density, quiescent cultures of neonatal rat ventricular myocytes were maintained in serum-free medium, or electrically stimulated to contract (3 Hz) for up to 48 h. ERK and JNK activation was assessed by Western blotting with polyclonal antibodies specific for the phosphorylated forms of both kinases. PKC activation was analysed by subcellular fractionation, detergent extraction, and Western blotting using isoenzyme-specific monoclonal antibodies. Stimulated contractile activity produced myocyte hypertrophy, as indicated by increased cell size, a 15+/-5% increase in total protein/DNA ratio, and induction of ANF and beta MHC gene transcription. Electrical pacing did not cause ERK1/2 or JNK1 activation, but increased JNK2 and JNK3 phosphorylation by;two-fold. Subcellular fractionation revealed a time-dependent increase in PKC delta, and to a much lesser extent PKC xi, in a Triton X-100-soluble membrane fraction within 5 min of the onset of stimulated contraction. PKC alpha was not activated by electrical pacing. These results indicate that contraction-induced mechanical loading acutely activates some but not all of the specific isoenzymes of JNKs and PKCs in cardiomyocytes.

We examined the contribution of arterial wave reflection to early abnormalities in left ventricular relaxation, whether this association was modified by gender or hypertension and the role of reflected wave timing and amplitude. We studied a cohort of normotensive and untreated essential hypertensive Taiwanese participants (675 men, 601 women, mean age 52 years). Doppler flow and applanation tonometry were performed to assess carotid-femoral pulse wave velocity (PWV) and augmentation index (AI). Diastolic parameters including the ratio between the peak velocity of early and late diastolic mitral inflow (E/A), E-deceleration time and left atrial (LA) diameter were measured by echocardiography. In multivariate models predicting E/A, women were more likely to have lower E/A than men (β=-0.08, P<0.001). AI was significantly associated with lower E/A in both men (β=-0.09, P=0.005) and women (β=-0.12, P<0.001) independent of PWV. Inclusion of AI in the overall model reduced the gender difference in E/A by 61% and rendered it nonsignificant. There was a significant interaction between AI and hypertension (P=0.02). The inverse association between AI and E/A was significant only in normotensive men and women, and only for the amplitude but not timing of the reflected wave. In conclusion, the contribution of wave reflection to left ventricular diastolic dysfunction was independent of arterial stiffness, more pronounced in normotensive individuals and explained a significant portion of the gender difference in diastolic function.

A nighttime dip in blood pressure is associated with decreased risk of cardiovascular morbidity and mortality. We examined whether personality traits predict nighttime dipping blood pressure.A community-based sample of 2848 adults from Sardinia (Italy) completed the Revised NEO Personality Inventory and 7 years later were examined with 24-hour ambulatory blood pressure monitoring. The primary analyses examined the associations of personality traits with continuous and categorical measures of mean arterial, systolic, and diastolic blood pressure nighttime dipping.Agreeableness and conscientiousness were associated with more nocturnal blood pressure dipping (β = .05 [p = .025] and β = .07 [p < .001], respectively) and lower systolic blood pressure at night (β = -.05 [p = .018] and β = -.03 [p = .072], respectively). Nondippers were particularly more impulsive (p = .009), less trusting (p = .004), and less self-disciplined (p = .001), but there was no significant association between nocturnal dipping blood pressure and trait anxiety (p = .78) or depression (p = .59). The associations were stronger when comparing extreme dippers (nighttime drop ≥ 20%) to reverse dippers (nighttime increase in blood pressure). Indeed, scoring 1 standard deviation higher on conscientiousness was associated with approximately 40% reduced risk of reverse dipping (odds ratio = 1.43, confidence interval = 1.08-1.91).We found evidence that reduced nighttime blood pressure dipping is associated with antagonism and impulsivity-related traits but not with measures of emotional vulnerability. The strongest associations were found with conscientiousness, a trait that may have a broad impact on cardiovascular health.

Future high energy accelerators such as the Large Hadron Collider require accelerator magnets with the highest possible fields. For NbTi conductor magnets, this means operating at superfluid helium temperatures in the range of 1.8-1.9 K. As part of Fermilab's superconducting magnet R&D program, we have built a facility to test magnets in a vertical dewar of superfluid liquid helium. The dewar is designed for magnets up to 4 m length and 620 mm diameter, with a temperature range of 1.8 K to 4.4 K and 1 atmosphere helium. The power system consists of 10 kA and 8.8 kA power supplies operating in parallel, with a bus work and an extraction circuit that can accommodate up a 18 kA excitation current. A description of the facility as well as operational experience from the first magnet tests are presented.

After the LHC operates for several years at nominal parameters, it will be necessary to upgrade it for higher luminosity. Replacing the low-/spl beta/ insertions with a higher performance design based on advanced superconducting magnets is one of the most straightforward steps in this direction. Preliminary studies show that, with magnet technology that is expected to be developed by early in the next decade, a factor of 2 to 5 reduction in /spl beta/* could be achieved with new insertions, as part of an upgrade aimed at a factor of 10 luminosity increase. In this paper we survey several possible second generation LHC interaction regions designs, which address the expected limitations on LHC performance imposed by the baseline insertions.

Objective There is a J-shaped relationship between body mass index (BMI) and cardiovascular outcomes in elderly patients (obesity paradox). Whether low BMI correlates with aortic calcification (AC) and whether this association is accounted for by bone demineralization is uncertain. Methods Presence of AC was evaluated in 687 community-dwelling individuals (49% male, mean age 67 ± 13 years) using CT images of the thoracic, upper and lower abdominal aorta, and scored from 0 to 3 according to number of sites that showed any calcification. Whole-body bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry. Predictors of AC were assessed by logistic regression, and the role of BMD using mediation analysis. Results Age and cardiovascular risk factors were positively associated while both BMI (r = −0.11, p < 0.01) and BMD (r = −0.17, p < 0.0001) were negatively associated with AC severity. In multivariate models, lower BMI (OR 0.96, 95%CI 0.92–0.99, p = 0.01), older age, higher systolic blood pressure, use of lipid-lowering drugs and smoking were independent predictors of AC. A nonlinear relationship between BMI and AC was noticed (p = 0.03), with decreased AC severity among overweight participants. After adjusting for BMD, the coefficient relating BMI to AC was reduced by 14% and was no longer significant, whereas BMD remained negatively associated with AC (OR 0.82, 95%CI 0.069–0.96, p = 0.01), with a trend for a stronger relationship in older participants. Conclusion Low BMI is associated with increased AC, possibly through calcium mobilization from bone, resulting in low BMD. Prevention of weight loss and bone demineralization with aging may help reducing AC.

Background Common carotid intima medial thickness (IMT) increases with aging. However, the longitudinal association between IMT and other age‐associated hemodynamic alterations in men and in women are not fully explored. Methods and Results We analyzed repeated measures of IMT, blood pressure, and carotid‐femoral pulse wave velocity over a 20‐year period in 1067 men and women of the Baltimore Longitudinal Study on Aging; participants were ages 20 to 92 years at entry and free of overt cardiovascular disease. Linear mixed‐effects models were used to calculate the individual rates of change ( Change ) of IMT, pulse pressure, mean arterial pressure, and pulse wave velocity, among other covariates. Multivariate regression analysis was used to examine the association of IMT Change with baseline and rates of change of hemodynamic parameters and cardiovascular risk factors. IMT increased at accelerating rates from 0.02 mm/decade at age 50 years to 0.05 mm/decade at age 80 years greater rates in men than in women. IMT Change was positively associated with baseline low‐density lipoprotein, low‐density lipoprotein Change , and baseline systolic blood pressure and systolic blood pressure Change , but inversely with baseline diastolic blood pressure and diastolic blood pressure Change . When blood pressure was expressed as pulse pressure and MAP, IMT Change was positively associated with baseline pulse pressure and pulse pressure Change and inversely with baseline mean arterial pressure and mean arterial pressure Change . In sex‐specific analysis, these associations were observed in women, but not in men. Conclusions In summary, our analyses showed that IMT increases at accelerating rates with aging. Age‐associated changes in IMT were modulated by concurrent changes of low‐density lipoprotein in both sexes, and of pulsatile and mean blood pressure in women but not men.

A collaboration of Fermilab, Lawrence Berkeley National Laboratory and Brookhaven National Laboratory is engaged in the design of a high gradient quadrupole suitable for use in the LHC interaction regions. The cold iron design incorporates a two-layer, cos(2/spl theta/) coil geometry with a 70 mm aperture operating in superfluid helium. This paper summarizes the progress on a magnetic, mechanical and thermal design that meets the requirements of maximum gradient above 250 T/m, high field quality and provision for adequate cooling in a high radiation environment.

Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter Facebook Reddit LinkedIn Tools Icon Tools Reprints and Permissions Cite Icon Cite Search Site Citation A. Devred, T. Bush, R. Coombes, J. DiMarco, C. Goodzeit, J. Kuzminski, M. Puglisi, P. Radusewicz, P. Sanger, R. Schermer, G. Spigo, J. Thompkins, J. Turner, Z. Wolf, Y. Yu, H. Zheng, T. Ogitsu, M. Anerella, J. Cottingham, G. Ganetis, M. Garber, A. Ghosh, A. Greene, R. Gupta, J. Herrera, S. Kahn, E. Kelly, A. Meade, G. Morgan, J. Muratore, A. Prodell, M. Rehak, E. P. Rohrer, W. Sampson, R. Shutt, P. Thompson, P. Wanderer, E. Willen, M. Bleadon, R. Hanft, M. Kuchnir, P. Mantsch, P. O. Mazur, D. Orris, T. Peterson, J. Strait, J. Royet, R. Scanlan, C. Taylor; About the mechanics of SSC dipole magnet prototypes. AIP Conf. Proc. 11 March 1992; 249 (2): 1309–1374. https://doi.org/10.1063/1.41955 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAIP Publishing PortfolioAIP Conference Proceedings Search Advanced Search |Citation Search

Fermilab, in collaboration with LBNL and BNL, is developing a quadrupole for installation in the interaction region inner triplets of the LHC. This magnet is required to have an operating gradient of 215 T/m across a 70 mm coil bore, and operates in superfluid helium at 1.9 K. A 2 m magnet program addressing mechanical, magnetic, quench protection, and thermal issues associated with the design was completed earlier this year, and production of the first full length, cryostatted prototype magnet is underway. This paper summarizes the conclusions of the 2 m program, and the design and status of the first full-length prototype magnet.

Prior to the re-start of the Large Hadron Collider LHC in 2009 the protection system for superconducting magnets and bus-bars QPS will be substantially upgraded. The foreseen modifications will enhance the capability of the system in detecting problems related to the electrical interconnections between superconducting magnets as well as the detection of so-called aperture symmetric quenches in the LHC main magnets.

Cross section data from the HARP experiment for pion production by protons from a tantalum target have been convoluted with the acceptance of the front-end channel for the proposed neutrino factory or muon collider and integrated over the full phase space measured by HARP, to determine the beam-energy dependence of the muon yield. This permits a determination of the optimal beam energy for the proton driver for these projects. The cross section data are corrected for the beam-energy dependent amplification due to the development of hadronic showers in a thick target. The conclusion is that, for constant beam power, the yield is maximum for a beam energy of about 7 GeV, but it is within 10% of this maximum for $4&lt;{T}_{\mathrm{beam}}&lt;11\text{ }\text{ }\mathrm{GeV}$, and within 20% of the maximum for ${T}_{\mathrm{beam}}$ as low as 2 GeV. This result is insensitive to which of the two HARP groups' results are used, and to which pion generator is used to compute the thick target effects.

Carotid-femoral pulse wave velocity is considered the gold standard for measurements of central arterial stiffness obtained through noninvasive methods(1). Subjects are placed in the supine position and allowed to rest quietly for at least 10 min prior to the start of the exam. The proper cuff size is selected and a blood pressure is obtained using an oscillometric device. Once a resting blood pressure has been obtained, pressure waveforms are acquired from the right femoral and right common carotid arteries. The system then automatically calculates the pulse transit time between these two sites (using the carotid artery as a surrogate for the descending aorta). Body surface measurements are used to determine the distance traveled by the pulse wave between the two sampling sites. This distance is then divided by the pulse transit time resulting in the pulse wave velocity. The measurements are performed in triplicate and the average is used for analysis.

This volume of the LBNF/DUNE Conceptual Design Report covers the Long-Baseline Neutrino Facility for DUNE and describes the LBNF Project, which includes design and construction of the beamline at Fermilab, the conventional facilities at both Fermilab and SURF, and the cryostat and cryogenics infrastructure required for the DUNE far detector.

Conceptual designs of 90-mm aperture high-gradient quadrupoles based on the Nb/sub 3/Sn superconductor, are being developed at Fermilab for possible 2nd generation IRs with the similar optics as in the current low-beta insertions. Magnet designs and results of magnetic, mechanical, thermal and quench protection analysis for these magnets are presented and discussed.

This volume of the LBNF/DUNE Conceptual Design Report cover the Long-Baseline Neutrino Facility for DUNE and describes the LBNF Project, which includes design and construction of the beamline at Fermilab, the conventional facilities at both Fermilab and SURF, and the cryostat and cryogenics infrastructure required for the DUNE far detector.

Superconducting quadrupole magnets for the interaction regions of the Large Hadron Collider are being developed by the US-LHC Accelerator Project. These 70 mm bore quadrupole magnets are intended to operate in superfluid helium at 1.9 K with a nominal field gradient of 215 T/m. A series of 2 m model magnets has been built and cold tested at Fermilab to optimize their design and construction and to study the performance of the magnets. Field measurements of the 8 model magnets and comparisons with the required field quality are reported in this paper.

The authors describe the mechanical design of the two-dimensional cross section of the baseline collider dipole magnet for the Superconducting Super Collider. The components described are the collar and yoke laminations and the cold mass shell. The 50-mm-aperture collider dipole magnet uses stainless-steel collars to position the conductors at the locations specified by the magnetic design and to prestress the coil to prevent conductor motion under excitation. The collars are supported by the vertically split yoke and cold mass skin to reduce their deflection under excitation. The collar interior is designed to give the coil its required shape at the operating temperature, taking into account all deflections caused by assembly and cooldown.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Four full-scale SSC (Superconducting Super Collider) research and development dipole magnets, incorporating successive mechanical design improvements, have been quench-tested. Three of the magnets are heavily instrumented with sensors to measure their mechanical behavior and verify the effectiveness of the mechanical improvements and with multiple voltage taps to locate the origin of quenches. The last two magnets of this series reach the SSC design operating field of 6.6 T in two or fewer quenches. Load cells and motion sensors show that in these two magnets the azimuthal clamping stress is higher at zero current and drops more slowly with excitation that in previous long magnets, and that the axial motion of the coil upon excitation has been greatly reduced. Quenches are found to originate preferentially in several locations, suggesting other design improvements.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Fermilab, as part of the US-LHC Accelerator Project, is producing superconducting low-beta quadrupole magnets for the large hadron collider (LHC). These 5.5 m long magnets are designed to operate in superfluid helium at 1.9 K with a nominal gradient of 205 T/m in the 70 mm bore. Two quadrupoles separated by a dipole orbit corrector in a single cryogenic assembly comprise the Q2 optical elements of the final focus triplets in the LHC interaction regions. The field quality of the quadrupoles is measured at room temperature during construction of the cold masses as well as during cold testing of the cryogenic assembly. We summarize data from the series measurements of the magnets and discuss various topics of interest.

The Snowmass 2021 Implementation Task Force has been established to evaluate the proposed future accelerator projects for performance, technology readiness, schedule, cost, and environmental impact. Corresponding metrics has been developed for uniform comparison of the proposals ranging from Higgs/EW factories to multi-TeV lepton, hadron and ep collider facilities, based on traditional and advanced acceleration technologies. This report documents the metrics and processes, and presents evaluations of future colliders performed by Implementation Task Force.

Conceptual designs of large-aperture high-gradient Nb/sub 3/Sn quadrupoles, suitable for use in a second generation LHC interaction region, are presented. A quadrupole with a 90 mm coil aperture and the same 200 T/m gradient as in the current LHC IR is technically feasible and would allow /spl beta/*=0.25 in to be achieved, doubling the LHC luminosity.

Fermilab and LBNL are in the midst of superconducting magnet R&D program to test and optimize the design of quadrupoles to be used in the LHC Interaction Region inner triplets. The magnets are required to deliver a 215 T/m gradient across a 70 mm aperture. Five quadrupole short models have been fabricated and four of them have been tested. This paper describes the last model design details and reports the results of the magnet quench performance study.

The LHC performance depends critically on the low- beta triplets, located on either side of the four interaction points. Each triplet consists of four superconducting quadrupole magnets, which must operate reliably at up to 215 T/m, sustain extremely high heat loads and have an excellent field quality. A collaboration of CERN, Fermilab and KEK was formed in 1996 to design and build the triplet systems, and after nine years of joint effort the production will be completed in early 2006. We retrace the main events of the project and present the design features and performance of the low- beta quadrupoles, built by KEK and Fermilab, as well as of other vital elements of the triplet. The tunnel installation of the first triplet and plans for commissioning in the LHC are also presented. Apart from the excellent technical results, the construction of the LHC low- beta triplets has been a highly enriching experience combining harmoniously the different competences and approaches to engineering in a style reminiscent of high energy physics experiment collaborations

This volume of the LBNF/DUNE Conceptual Design Report cover the Long-Baseline Neutrino Facility for DUNE and describes the LBNF Project, which includes design and construction of the beamline at Fermilab, the conventional facilities at both Fermilab and SURF, and the cryostat and cryogenics infrastructure required for the DUNE far detector.

We present an overview of the CDF End Plug Upgrade Project. The structure of the upgraded calorimeter and the design of the optical readout system is discussed. We describe the production of scintillating tile/fiber multi-tile assemblies (megatiles) and present the quality control results of megatiles produced for the CDF End Plug Upgrade Hadron Calorimeter. The sample of megatiles presented in this analysis corresponds to approximately 16500 individual tile/fiber assemblies. We discuss the quality control requirements and present the distributions of the quantities measured during the QC process. The various contributions to the tile-to-tile light yield variations are isolated and discussed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Full-length SSC R&D dipole magnets instrumented with four voltage taps on each turn of the inner quarter coils have been tested. These voltage taps enable (1) accurate location of the point at which the quenches start and (2) detailed studies of quench development in the coil. Attention here is focused on localizing the quench source. After recalling the basic mechanism of a quench (why it occurs and how it propagates), the method of quench origin analysis is described: the quench propagation velocity on the turn where the quench occurs is calculated, and the quench location is then verified by reiterating the analysis on the adjacent turns. Last, the velocity value, which appears to be higher than previously measured, is discussed.

A novel technique for both online and offline computation is presented. With this technique, a reconstruction analysis in elementary particle physics, otherwise prohibitively long, has been accomplished. It will be used online in an upcoming Fermilab experiment to reconstruct more than 100000 events per second and to trigger on the basis of that information. The technique delivers 40 gigaoperations per second, has a bandwidth on the order of gigabytes per second, and has a modest cost. An overview of the program, details of the system, and performance measurements are presented.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Results are presented from tests of the third full-scale development dipole magnet for the Superconducting Super Collider (SSC) and from a retest of a 4.5-m model magnet of the same design mounted in an SSC cryostat. The 4.5-m magnet showed consistent quench performance between its original tests in boiling liquid helium in a vertical dewar and the current tests in forced-flow helium in a horizontal cryostat. Little or no retraining was observed over several thermal cycles. The full-length magnet required 12 quenches to train to its short-sample limit of 6800 A and displayed a reasonably stable quench plateau following training. Data are presented on quench behavior as a function of current and temperature, and on azimuthal and longitudinal loading of the coil by the support structure.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

The authors describe the mechanical design of the ends of Superconducting Super Collider (SSC) dipole magnets to be constructed and tested at Fermilab. Coil end clamps, end yoke configuration, and end plate design are discussed. Loading of the end plate by axial Lorentz forces is examined. Relevant data from 40 mm and 50 mm aperture model dipole magnets built and tested at Fermilab are presented. In particular, the apparent influence of end clamp design on the quench behavior of model SSC dipoles is described.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

As part of the US-LHC Accelerator Project, Fermilab is producing fully cryostated assemblies that will be installed as the Q1, Q2 and Q3 optical elements for the LHC Inner Triplets. The main quadrupole magnets in the Q1 (LQXA) and Q3 (LQXC) assemblies are MQXA elements designed and fabricated by KEK and Toshiba, while those in the Q2 (LQXB) assemblies are MQXB quadrupoles designed and fabricated by Fermilab. The cryostat assemblies for all magnets are designed by Fermilab, and final assembly of the optical elements occurs at Fermilab. This paper describes the production test results for the second LQXB cryostat assembly.

The US-LHC Accelerator Project is responsible for the production of the Q2 optical elements of the final focus triplets in the LHC interaction regions. As part of this program Fermilab is in the process of manufacturing and testing cryostat assemblies (LQXB) containing two identical quadrupoles (MQXB) with a dipole corrector between them. The 5.5 m long Fermilab designed MQXB have a 70 mm aperture and operate in superfluid helium at 1.9 K with a peak field gradient of 215 T/m. This paper summarizes the test results of several production MQXB quadrupoles with emphasis on quench performance and alignment studies. Quench localization studies using quench antenna signals are also presented.

Superconducting quadrupole magnets for the interaction regions of the Large Hadron Collider are being developed by the US-LHC Accelerator Project. These 70 mm bore quadrupole magnets are intended to operate in superfluid helium at 1.9 K with a nominal field gradient of 215 T/m. A series of 2 m model magnets are being built and tested at Fermilab to optimize design and construction parameters. Measurements of the field quality of the model magnets tested to date and comparisons with the required field quality are reported in this paper.

Aging is associated with a decline in heart function across the tissue, cellular, and molecular levels. The risk of cardiovascular disease grows significantly over time, and as developed countries continue to see an increase in lifespan, the cost of cardiovascular healthcare for the elderly will undoubtedly rise. The molecular basis for cardiac function deterioration with age is multifaceted and not entirely clear, and there is a limit to what investigations can be performed on human subjects or mammalian models. Drosophila melanogaster has emerged as a useful model organism for studying aging in a short timeframe, benefitting from a suite of molecular and genetic tools and displaying highly conserved traits of cardiac senescence. Here, we discuss recent advances in our understanding of cardiac aging and how the fruit fly has aided in these developments.

Results of tests of a redesigned quench protection heater for SSC (Superconducting Super Collider) dipole magnets are presented. It is shown that the redesigned heater has a performance similar to that of the existing heater in terms of its ability to protect a long 40-mm magnet. It meets the system requirements of increased resistance by using a smaller cross sectional area and a larger active length. This results in a larger area of heater, which has advantages but does not result in higher powers being required from the heater firing unit. The implication of increased cost is mitigated somewhat since lower-gauge connection cable is made possible. The magnet program for the 50-mm dipole is characterized by a higher operating margin and slower quench propagation velocities. >

As a part of the USLHC program, Fermilab is building half of the inner triplet quadrupole magnets for the LHC. Two identical quadrupoles (MQXB) with a dipole corrector between them in a single cryogenic unit (LQXB) comprise the Q2 optical element of the final focus triplets in the interaction regions. The 5.5 m long MQXB have a 70 mm aperture and operate in superfluid helium at 1.9 K with a peak field gradient of 215 T/m. Manufacturing of the 18 magnets is in an advanced stage. A program of magnetic field quality measurements of the magnets is performed at room temperature during magnet fabrication as well as at superfluid helium temperature during the cold qualification of each magnet. Results of the measurements are summarized in this paper.

Interaction region inner triplets are among the systems which may limit the LHC performance. An option for a new higher luminosity IR is a double-bore inner triplet with separation dipoles placed in front of the first quadrupole. The radiation load on the first dipole, resulting from pp-interactions, is a key parameter to determine the feasibility of this approach. Detailed energy deposition calculations were performed with the MARS 14 code for two Nb/sub 3/Sn dipole designs with no superconductor on the mid-plane. Comparison of peak power densities with those in the baseline LHC IR suggests that it may be possible to develop workable magnets for luminosities up to 10/sup 35/ cm/sup -2/ s/sup -1/.

The quench performance and ramp rate sensitivity of 18 5-cm-aperture, 15-m-long Superconducting Super Collider (SSC) dipole magnet prototypes are discussed. All the magnets appear to reach a quench plateau near their extrapolated short sample current limit and well in excess of the operating current with very little training. Most of the magnets, however, exhibit a dramatic degradation of their quench current as a function of ramp rate, which, for the most part, can be attributed to large cable eddy currents.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Tests have recently been performed at Fermilab in order to measure the energy losses due to eddy currents and iron and superconductor magnetization. These measurements were performed on six 1.5-m-long model magnets and eight 15-m-long full-scale collider dipole magnets. AC losses were measured as a function of ramp rate using sawtooth ramps from 500 to 5000 A for both types of magnets, while bipolar studies were additionally performed on some of the short magnets. The measured magnet voltage and current for a complete cycle were digitally integrated to yield the energy loss per cycle. Measurement reproducibility was typically 5%, with good agreement between long magnet measurements and extrapolations from short magnet measurement results. Magnetization loss measurements among similar magnet types agree to within experimental error, while eddy current losses correlate strongly with the observed dependence of quench current on ramp rate.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

This paper describes the system used to acquire cryogenic data for the testing of SSC magnets at the Fermilab Magnet Test Facility. An array of pressure transducers, resistance thermometers, vapor pressure thermometers, and signal conditioning circuits are used Readings with time resolution appropriate for quench recording are obtained with a waveform digitizer and steady-state measurements are obtained with higher accuracy using a digital voltmeter. The waveform digitizer is clocked at a 400 Hz sampling rate and these readings are stored in local ring buffers. The system is modular and can be expanded to add more channels. The software for the acquisition, control, logging, and display of cryogenic data consist of two programs which run as separate tasks. These programs (as well as a third program which acquires quench and magnetic data) communicate and pass data using shared global resources. The acquired data are available for analysis via a nationwide DECnetα network.

Superconducting low-beta quadrupole magnets for the interaction regions of the Large Hadron Collider have been developed by the US-LHC Accelerator Project. These 70 mm bore 5.5 m long quadrupoles are intended to operate in superfluid helium at 1.9 K with a nominal field gradient of 215 T/m. Following a series of 2 m long models, a full scale cryostated cold mass has been fabricated and cold tested at Fermilab. Magnetic field measurements of the prototype, including determination of the field axis using a single stretched wire, have been performed. These measurements and comparisons with results from the model magnets as well as field quality and alignment requirements are reported in this paper.

A series of 50-mm-diameter 1.5-m model magnets has been constructed. The tests of these magnets gave convincing results concerning the design of the 50-mm cross section of the Superconducting Super Collider dipoles. Although there are still difficulties in the detailed control of end shape, coil size, pressure and field, the basic design of the magnet is proved to be valid by this model magnet study. Results on quench characteristics, mechanical behavior, and field quality are presented.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

High gradient superconducting quadrupoles are an essential component of high energy hadron colliders, both in the arcs and in the insertions. The highest performance quadrupoles today are those for the Large Hadron Collider (LHC) at CERN. These 56 to 70 mm aperture magnets, developed in Europe, the United States, and Japan, reach gradients on the order of 250 T/m, which is near the limit for NbTi technology. Designs based on Nb/sub 3/Sn are now being developed, which are aimed at use in second generation LHC low-/spl beta/ insertions and in the next generation of very large hadron colliders (VLHC). These quadrupoles are planned to achieve gradients up to 300 T/m with the large aperture required for the LHC insertions or 450 T/m for smaller aperture arc quadrupoles for VLHC. Even higher gradients may be required for the VLHC final focus.

We consider a possible 2nd generation IR for the LHC that would be designed to achieve at least a factor of two increase in luminosity beyond that reached with the original IRs. We discuss the optics issues, in particular those associated with larger bore quadrupoles with Nb3Sn superconductor, field quality issues, energy deposition issues and the limitations imposed on energy and luminosity reach.

Focal adhesion kinase (FAK) and other protein tyrosine kinases (PTKs) found in focal adhesions regulate proliferation and cytoskeletal assembly of nonmuscle cells, but their role in hypertrophic growth of cardiac myocytes has not been investigated. Serum-free, primary cultures of spontaneously contracting and contractile-arrested neonatal rat ventricular myocytes (NRVMs) were used to determine the role of FAK and other PTKs in regulating cardiac gene expression and protein turnover associated with the hypertrophic phenotype. FAK was readily detected in focal adhesions and costameres of spontaneously contracting, hypertrophied myocytes, but was reduced in contractile-arrested cells. Chronic treatment of NRVMs with genistein (50µM), a relatively specific PTK inhibitor, prevented NRVM growth, as demonstrated by significant reductions (by 10–35%) in total protein, total protein/DNA ratio, and myofibrillar protein content. Genistein also significandy reduced myosin heavy chain (MHC) and actin synthesis, and increased MHC and actin degradation. Daidzein (50 µM), a weakly active analogue, had much less of an effect. Genistein also markedly reduced β-myosin heavy chain (β-MHC) and to a lesser extent atrial natriuretic factor (ANF) gene expression, thus reproducing many of the phenotypic features of cardiac myocyte atrophy produced by contractile arrest. Transient transfection of NRVMs with an expression vector containing the full-length coding sequence of chick FAK along with rat β-MHC and ANF promoter-luciferase constructs resulted in a 2–4-fold increase in luciferase activity, indicating that FAK stimulated transcription of fetal genes associated with the hypertrophic phenotype. Thus, FAK and/or other PTKs found in focal adhesions may play a role in both the transcriptional and posttranslational regulation of cardiac myocyte hypertrophy.

Eighteen 5-cm-aperture, 15-m-long Superconducting Super Collider (SSC) dipole magnet prototypes have been produced and cold tested. On each prototype, the dependence of harmonic field coefficients on magnetic current was measured as part of a study of the magnetic field quality. For most of the magnets, the observed behavior conforms to what can be expected from the effects of persistent magnetization currents and iron yoke saturation. A few prototypes, however, exhibited anomalies during current ramp at 4 A/s which can be attributed to large cable eddy currents.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Several short model SSC magnets have been built and tested at Fermilab. They establish a preliminary step toward the construction of SSC long models. Many aspects of magnet design and construction are involved. Experience includes coil winding, curing and measuring, coil end part design and fabrication, ground insulation, instrumentation, collaring and yoke assembly. Fabrication techniques are explained. Design of tooling and magnet components not previously incorporated into SSC magnets are described.

The performance of the LHC depends critically on the low-triplets, located on either side of the interaction points. Each triplet consists of four superconducting quadrupole magnets, which must operate reliably at up to 215 T/m, sustain high heat loads and have an excellent field quality. A collaboration between CERN, Fermilab and KEK was set up in 1996 to design and build the triplet systems, and after nine years of joint effort the production will be completed in 2005. We retrace the main events of the project and present the performance of the low-quadrupoles built by KEK and Fermilab and of other elements of the triplet. The assembly of the first triplet at CERN and plans for tunnel installation and commissioning in the LHC are also reported.

Eight 5-cm-aperture, 15-m-long dipole magnet prototypes have been produced and cold-tested at Brookhaven National Laboratory (BNL) and Fermi National Accelerator Laboratory (FNAL) under contract with the Superconducting Super Collider Laboratory (SSCL). These magnets are the last phase of an R&D program aimed at demonstrating the feasibility of the 5-cm-aperture designs developed by BNL and FNAL. They are also used as vehicles to transfer technology from the National Laboratories to the collider dipole magnet contractors. The BNL magnets, which rely on an horizontally-split yoke, and the FNAL magnets, which rely on a vertically-split yoke, perform according to their somewhat different mechanical designs and have equally successful quench performance.

In this paper we present results of quench testing of full length SSC dipole magnets at Fermilab. The data are from the first six of a series of thirteen 15 m long, 50 mm aperture SSC dipole magnets which are being built and tested at Fermilab. These magnets were designed jointly by Fermilab, Brookhaven Laboratory, Lawrence Berkeley Laboratory and the SSC Laboratory. Among the major goals for this series of magnets are to transfer magnet production technology to the lead vendor for the Collider Dipole Magnet, the General Dynamics Corporation, and to demonstrate industrial production by the vendor. The first magnet in the series, DCA311, was built by Fermilab technicians to establish assembly procedures. The second magnet, DCA312, was the “technology transfer magnet and was built jointly by Fermilab and General Dynamics technicians. The next seven, DCA313-319 are being built by General Dynamics personnel using Fermilab facilities and procedures. However, Fermilab personnel still operate the major tooling, provide the welders, perform assembly of items that would not be part of production magnets (e.g. voltage taps), and oversee the QA program. Five of these 7 GD-built magnets will be used in the Accelerator Systems String Test (ASST) to be carried out in Dallas later this year. The last four magnets, DCA320-323, are being built by Fermilab alone.”

The performance of the Large Hadron Collider (LHC) at collision energy is limited by the field quality of the interaction region (IR) quadrupoles and dipoles. In this paper we study the impact of the expected field errors of these magnets on the dynamic aperture (DA). Since the betatron phase advance is well defined for magnets that are located in regions of large beta functions, local corrections can be very effective and robust. We compare possible compensation schemes and propose a corrector layout to meet the required DA performance.

Results are presented from tests of the first full length prototype SSC dipole magnet. The cryogenic behavior of the magnet during a slow cooldown to 4.5K and a slow warmup to room temperature has been measured. Magnetic field quality was measured at currents up to 2000 A. Averaged over the body field all harmonics with the exception of b <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> and b <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8</inf> are at or within the tolerances specified by the SSC Central Design Group. (The values of b <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> and b <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8</inf> result from known design and construction defects which will be corrected in later magnets.) Using an NMR probe the average body field strength is measured to be 10.283 G/A with point to point variations on the order of one part in 1000. Data are presented on quench behavior of the magnet up to 3500 A (approximately 55% of full field) including longitudinal and transverse velocities for the first 250 msec of the quench.

Superconducting quadrupole magnets operating in superfluid helium at 1.9 K, with 70 mm bore and nominal field gradient of 205 T/m at collision optics, are being developed by the US LHC Accelerator Project for the Interaction Regions of the Large Hadron Collider (LHC). A magnet model program to validate and optimize the design is underway. This paper reports results of field quality measurements of four model magnets.

Fermilab, as part of the US-LHC Accelerator Project, has designed and is producing superconducting low-beta quadrupole magnets for the Large Hadron Collider (LHC). These 70 mm bore, 5.5 m long magnets operate in superfluid helium at 1.9 K with a maximum operating gradient of 214 T/m. Two quadrupoles, combined with a dipole orbit corrector, form a single LQXB cryogenic assembly, the Q2 optical element of the final focus triplets in the LHC interaction regions. Field quality was measured at room temperature during fabrication of the cold masses as well as at superfluid helium temperature in two thermal cycles for the first LQXB cryogenic assembly. Integral cold measurements were made with a 7.1 m long rotating coil and with a 0.8 m long rotating coil at 8 axial positions and in a range of currents. In addition to the magnetic measurements, this paper reports on the quench performance of the cold masses and on the measurements of their internal alignment.

Superconducting low-beta quadrupole magnets for the interaction regions of the Large Hadron Collider have been developed by the US-LHC Accelerator Project. These 70 mm bore 5.5 m quadrupole magnets are intended to operate in superfluid helium at 1.9 K with a nominal field gradient of 215 T/m. Fabrication and testing of these magnets has begun at Fermilab. Magnetic field measurements of the first magnets produced are described and compared with results from prototype magnets as well as with requirements set by machine performance studies.

Optimization of pion and muon production/collection for neutrino factories and muon colliders is described along with recent developments of the MARS15 code event generators and effects influencing the choice of the optimal beam energy.

As part of the US LHC Accelerator Project, Fermilab is nearing the completion of the Q2 optical elements for the LHC interaction region final focus. Each Q2 element (LQXB) consists of two identical high gradient quadrupoles (MQXB) with a dipole orbit corrector (MCBX). This paper summarizes the test results for the LQXB/MQXB program including quench performance, magnetic measurements and alignment, and gives the status of production and delivery of the LQXB magnets to the LHC.

Following the incident in sector 34, considerable effort has been made to improve the systems for detecting similar faults and to improve the safety systems to limit the damage if a similar incident should occur. Nevertheless, even after the consolidation and repairs are completed, other faults may still occur in the superconducting magnet systems, which could result in damage to the LHC. Such faults include both direct failures of a particular component or system, or an incorrect response to a “normal” upset condition, for example a quench. I will review a range of faults which could be reasonably expected to occur in the superconducting magnet systems, and which could result in substantial damage and down time to the LHC. I will evaluate the probability and the consequences of such faults, and suggest what mitigations, if any, are possible to protect against each.

The superconducting magnet R&D facility at Fermilab (Lab 2) has successfully tested superconducting dipole, quadrupole, and correction coil magnets less than 2 m in length for the Superconducting Super Collider (SSC) project and the Tevatron D0/B0 Low- beta Insertion. The authors describe the Lab 2 facility and the several upgrades which were developed to accomplish these successful test programs. Several improvements have been made to the facility that have greatly enhanced its magnet testing capabilities. Among the upgrades have been a new rotating coil and data acquisition system for measuring magnetic fields, a controlled flow liquid helium transfer line using an electronically actuated cryo valve, and stand-alone systems for measuring AC loss and training low current Tevatron correction coil packages. Tests are performed in vertical dewars of boiling liquid helium.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

The authors summarize the mechanical performance of the most recent 5-cm-aperture, 15-m-long SSC dipole magnet prototypes. The magnets were produced at Brookhaven National Laboratory (BNL) and Fermi National Accelerator Laboratory (FNAL) under contract with the Superconducting Super Collider Laboratory (SSCL). The BNL magnets rely on a horizontally split yoke with collared ends, while the FNAL magnets rely on a vertically split yoke with collet-style end clamps. Magnets of both designs are equipped with strain gauges enabling measurement of the azimuthal pressures exerted by the coils against the collar poles as well as the axial forces transmitted from the coil ends to the end plates. A comparison of the mechanical behaviors measured by the strain gauges is presented. How the behavior of the 5-cm-aperture magnets compares to that of the 4-cm-aperture prototypes is also discussed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>