Overweight children have a greater proportion of fat mass relative to muscle mass in the upper limbs than in the lower limbs: implications for bone strength at the distal forearm

BACKGROUND: The influence of adiposity on upper-limb bone strength has rarely been studied in children, despite the high incidence of forearm fractures in this population. OBJECTIVE: The objective was to compare the influence of muscle and fat tissues on bone strength between the upper and lower limbs in prepubertal children. DESIGN: Bone mineral content, total bone cross-sectional area, cortical bone area (CoA), cortical thickness (CoTh) at the radius and tibia (4% and 66%, respectively), trabecular density (TrD), bone strength index (4% sites), cortical density (CoD), stress-strain index, and muscle and fat areas (66% sites) were measured by using peripheral quantitative computed tomography in 427 children (206 boys) aged 7-10 y. RESULTS: Overweight children (n = 93) had greater values for bone variables (0.3-1.3 SD; P < 0.0001) than did their normal-weight peers, except for CoD 66% and CoTh 4%. The between-group differences were 21-87% greater at the tibia than at the radius. After adjustment for muscle cross-sectional area, TrD 4%, bone mineral content, CoA, and CoTh 66% at the tibia remained greater in overweight children, whereas at the distal radius total bone cross-sectional area and CoTh were smaller in overweight children (P < 0.05). Overweight children had a greater fat-muscle ratio than did normal-weight children, particularly in the forearm (92 +/- 28% compared with 57 +/- 17%). Fat-muscle ratio correlated negatively with all bone variables, except for TrD and CoD, after adjustment for body weight (r = -0.17 to -0.54; P < 0.0001). CONCLUSIONS: Overweight children had stronger bones than did their normal-weight peers, largely because of greater muscle size. However, the overweight children had a high proportion of fat relative to muscle in the forearm, which is associated with reduced bone strength.

The lifestyle of our kids (LOOK) project: outline of methods

This methods paper outlines the overall design of a community-based multidisciplinary longitudinal study with the intent to stimulate interest and communication from scientists and practitioners studying the role of physical activity in preventive medicine. In adults, lack of regular exercise is a major risk factor in the development of chronic degenerative diseases and is a major contributor to obesity, and now we have evidence that many of our children are not sufficiently active to prevent early symptoms of chronic disease. The lifestyle of our kids (LOOK) study investigates how early physical activity contributes to health and development, utilizing a longitudinal design and a cohort of eight hundred and thirty 7-8-year-old (grade 2) school children followed to age 11-12 years (grade 6), their average family income being very close to that of Australia. We will test two hypotheses, that (a) the quantity and quality of physical activity undertaken by primary school children will influence their psychological and physical health and development; (b) compared with existing practices in primary schools, a physical education program administered by visiting specialists will enhance health and development, and lead to a more positive perception of physical activity. To test the first hypothesis we will monitor all children longitudinally over the 4 years. To test the second we will involve an intervention group of 430 children who receive two 50min physical education classes every week from visiting specialists and a control group of 400 who continue with their usual primary school physical education with their class-room teachers. At the end of grades 2, 4, and 6 we will measure several areas of health and development including blood risk factors for chronic disease, cardiovascular structure and function, physical fitness, psychological characteristics and perceptions of physical activity, bone structure and strength, motor control, body composition, nutritional intake, influence of teachers and family, and academic performance.

Antigenic and genetic variations in European and North American equine influenza virus strains (H3N8) isolated from 2006 to 2007

Equine influenza virus (EIV) surveillance is important in the management of equine influenza. It provides data on circulating and newly emerging strains for vaccine strain selection. To this end, antigenic characterisation by haemaggluttination inhibition (HI) assay and phylogenetic analysis was carried out on 28 EIV strains isolated in North America and Europe during 2006 and 2007. In the UK, 20 viruses were isolated from 28 nasopharyngeal swabs that tested positive by enzyme-linked immunosorbent assay. All except two of the UK viruses were characterised as members of the Florida sublineage with similarity to A/eq/Newmarket/5/03 (clade 2). One isolate, A/eq/Cheshire/1/06, was characterised as an American lineage strain similar to viruses isolated up to 10 years earlier. A second isolate, A/eq/Lincolnshire/1/07 was characterised as a member of the Florida sublineage (clade 1) with similarity to A/eq/Wisconsin/03. Furthermore, A/eq/Lincolnshire/1/06 was a member of the Florida sublineage (clade 2) by haemagglutinin (HA) gene sequence, but appeared to be a member of the Eurasian lineage by the non-structural gene (NS) sequence suggesting that reassortment had occurred. A/eq/Switzerland/P112/07 was characterised as a member of the Eurasian lineage, the first time since 2005 that isolation of a virus from this lineage has been reported. Seven viruses from North America were classified as members of the Florida sublineage (clade 1), similar to A/eq/Wisconsin/03. In conclusion, a variety of antigenically distinct EIVs continue to circulate worldwide. Florida sublineage clade 1 viruses appear to predominate in North America, clade 2 viruses in Europe.

Endocardial Ablation to Eliminate Epicardial Arrhythmia Substrate in Scar-Related Ventricular Tachycardia

OBJECTIVES We evaluated the feasibility and safety of epicardial substrate elimination using endocardial radiofrequency (RF) delivery in patients with scar-related ventricular tachycardia (VT). BACKGROUND Epicardial RF delivery is limited by fat or associated with bleeding, extra-cardiac damages, coronary vessels and phrenic nerve injury. Alternative ablation approaches may be desirable. METHODS Forty-six patients (18 ischemic cardiomyopathy [ICM], 13 non-ischemic dilated cardiomyopathy [NICM], 15 arrhythmogenic right ventricular cardiomyopathy [ARVC]) with sustained VT underwent combined endo- and epicardial mapping. All patients received endocardial ablation targeting local abnormal ventricular activities in the endocardium (Endo-LAVA) and epicardium (Epi-LAVA), followed by epicardial ablation if needed. RESULTS From a total of 173 endocardial ablations targeting Epi-LAVA at the facing site, 48 (28%) applications (ICM: 20/71 [28%], NICM: 3/39 [8%], ARVC: 25/63 [40%]) successfully eliminated the Epi-LAVA. Presence of Endo-LAVA, most delayed and low bipolar amplitude of Epi-LAVA, low unipolar amplitude in the facing endocardium, and Epi-LAVA within a wall thinning area at CT scan were associated with successful ablation. Endocardial ablation could abolish all Epi-LAVA in 4 ICM and 2 ARVC patients, whereas all patients with NICM required epicardial ablation. Endocardial ablation was able to eliminate Epi-LAVA at least partially in 15 (83%) ICM, 2 (13%) NICM, and 11 (73%) ARVC patients, contributing to a potential reduction in epicardial RF applications. Pericardial bleeding occurred in 4 patients with epicardial ablation. CONCLUSIONS Elimination of Epi-LAVA using endocardial RF delivery is feasible and may be used first to reduce the risk of epicardial ablation.

Electrophysiologic characterization of local abnormal ventricular activities in postinfarction ventricular tachycardia with respect to their anatomic location.

BACKGROUND Local abnormal ventricular activities (LAVA) in patients with scar-related ventricular tachycardia (VT) may appear at any time during or after the far-field electrogram. Although they may be separated from the far-field signal by an isoelectric line and extend beyond the end of surface QRS, they may also appear fused or buried within the QRS. OBJECTIVE The purpose of this study was to characterize LAVA in postinfarction VT patients with respect to their anatomic locations. METHODS Thirty-one patients with postinfarction VT underwent mapping/ablation during sinus rhythm with a three-dimensional electroanatomic mapping system. From a total of 18,270 electrograms reviewed in all study subjects, 1104 LAVA (endocardium 839, epicardium 265) were identified and analyzed. RESULTS The interval from onset of QRS complex to ventricular electrogram (EGM onset) on the endocardium was significantly shorter than the epicardium (P < .001). EGM onset was shortest in the septal endocardium and longest in the inferior and lateral epicardium. There was a significant positive correlation between EGM onset and LAVA lateness as estimated by the interval from surface QRS onset to LAVA (r = 0.52, P < .001). LAVA were more frequently detected after the QRS complex in the epicardium (241/265 [91%]) than in the endocardium (551/839 [66%], P < .001). Only 43% of endocardial septal LAVA were detected after the QRS complex. CONCLUSION Lateness of LAVA is affected to a large extent by their locations. The chance of detecting late LAVA increases when electrogram onset is later. Substrate-based approach targeting delayed signals relative to the QRS complex may miss critical the arrhythmogenic substrate, particularly in the septum and other early-to-activate regions.

Pattern and timing of the coronary sinus activation to guide rapid diagnosis of atrial tachycardia after atrial fibrillation ablation

BACKGROUND Atrial tachycardias (AT) during or after ablation of atrial fibrillation frequently pose a diagnostic challenge. We hypothesized that both the patterns and the timing of coronary sinus (CS) activation could facilitate AT mapping. METHODS AND RESULTS A total of 140 consecutive postpersistent atrial fibrillation ablation patients with sustained AT were investigated by conventional mapping. CS activation pattern was defined as chevron or reverse chevron when the activations recorded on both the proximal and the distal CS dipoles were latest or earliest, respectively. The local activation of mid-CS was timed with reference to Ppeak-Ppeak (P-P) interval in lead V1. A ratio, mid-CS activation time to AT cycle length, was computed. Of 223 diagnosed ATs, 124 were macroreentrant (56%) and 99 were centrifugal (44%). When CS activation was chevron/reverse chevron (n=44; 20%), macroreentries were mostly roof dependent. With reference to P-P interval, mid-CS activation timing showed specific consistency for peritricuspid and perimitral AT. Proximal to distal CS activation pattern and mid-CS activation at 50% to 70% of the P-P interval (n=30; 13%) diagnosed peritricuspid AT with 81% sensitivity and 89% specificity. Distal to proximal CS activation and mid-CS activation at 10% to 40% of the P-P interval (n=44; 20%) diagnosed perimitral AT with 88% sensitivity and 75% specificity. CONCLUSIONS The analysis of the patterns and timing of CS activation provides a rapid stratification of most likely macroreentrant ATs and points toward the likely origin of centrifugal ATs. It can be included in a stepwise diagnostic approach to rapidly select the most critical mapping maneuvers.

Regional myocardial wall thinning at multidetector computed tomography correlates to arrhythmogenic substrate in postinfarction ventricular tachycardia: assessment of structural and electrical substrate

BACKGROUND A majority of patients undergoing ablation of ventricular tachycardia have implanted devices precluding substrate imaging with delayed-enhancement MRI. Contrast-enhanced multidetector computed tomography (MDCT) can depict myocardial wall thickness with submillimetric resolution. We evaluated the relationship between regional myocardial wall thinning (WT) imaged by MDCT and arrhythmogenic substrate in postinfarction ventricular tachycardia. METHODS AND RESULTS We studied 13 consecutive postinfarction patients undergoing MDCT before ablation. MDCT data were integrated with high-density 3-dimensional electroanatomic maps acquired during sinus rhythm (endocardium, 509±291 points/map; epicardium, 716±323 points/map). Low-voltage areas (<1.5 mV) and local abnormal ventricular activities (LAVA) during sinus rhythm were assessed with regard to the WT. A significant correlation was found between the areas of WT <5 mm and endocardial low voltage (correlation-R=0.82; P=0.001), but no such correlation was found in the epicardium. The WT <5 mm area was smaller than the endocardial low-voltage area (54 cm(2) [Q1-Q3, 46-92] versus 71 cm(2) [Q1-Q3, 59-124]; P=0.001). Among a total of 13 060 electrograms reviewed in the whole study population, 538 LAVA were detected and analyzed. LAVA were located within the WT <5 mm (469/538 [87%]) or at its border (100% within 23 mm). Very late LAVA (>100 ms after QRS complex) were almost exclusively detected within the thinnest area (93% in the WT<3 mm). CONCLUSIONS Regional myocardial WT correlates to low-voltage regions and distribution of LAVA critical for the generation and maintenance of postinfarction ventricular tachycardia. The integration of MDCT WT with 3-dimensional electroanatomic maps can help focus mapping and ablation on the culprit regions, even when MRI is precluded by the presence of implanted devices.

Cost-effectiveness of different strategies to monitor adults on antiretroviral treatment: a combined analysis of three mathematical models

Background: WHO's 2013 revisions to its Consolidated Guidelines on antiretroviral drugs recommend routine viral load monitoring, rather than clinical or immunological monitoring, as the preferred monitoring approach on the basis of clinical evidence. However, HIV programmes in resource-limited settings require guidance on the most cost-effective use of resources in view of other competing priorities such as expansion of antiretroviral therapy coverage. We assessed the cost-effectiveness of alternative patient monitoring strategies. Methods: We evaluated a range of monitoring strategies, including clinical, CD4 cell count, and viral load monitoring, alone and together, at different frequencies and with different criteria for switching to second-line therapies. We used three independently constructed and validated models simultaneously. We estimated costs on the basis of resource use projected in the models and associated unit costs; we quantified impact as disability-adjusted life years (DALYs) averted. We compared alternatives using incremental cost-effectiveness analysis. Findings: All models show that clinical monitoring delivers significant benefit compared with a hypothetical baseline scenario with no monitoring or switching. Regular CD4 cell count monitoring confers a benefit over clinical monitoring alone, at an incremental cost that makes it affordable in more settings than viral load monitoring, which is currently more expensive. Viral load monitoring without CD4 cell count every 6—12 months provides the greatest reductions in morbidity and mortality, but incurs a high cost per DALY averted, resulting in lost opportunities to generate health gains if implemented instead of increasing antiretroviral therapy coverage or expanding antiretroviral therapy eligibility. Interpretation: The priority for HIV programmes should be to expand antiretroviral therapy coverage, firstly at CD4 cell count lower than 350 cells per μL, and then at a CD4 cell count lower than 500 cells per μL, using lower-cost clinical or CD4 monitoring. At current costs, viral load monitoring should be considered only after high antiretroviral therapy coverage has been achieved. Point-of-care technologies and other factors reducing costs might make viral load monitoring more affordable in future. Funding: Bill & Melinda Gates Foundation, WHO.

Pulmonary veins to left atrium cycle length gradient predicts procedural and clinical outcomes of persistent atrial fibrillation ablation.

BACKGROUND Rapid pulmonary vein (PV) activity has been shown to maintain paroxysmal atrial fibrillation (AF). We evaluated in persistent AF the cycle length (CL) gradient between PVs and the left atrium (LA) in an attempt to identify the subset of patients where PVs play an important role. METHODS AND RESULTS Ninety-seven consecutive patients undergoing first ablation for persistent AF were studied. For each PV, the CL of the fastest activation was assessed over 1 minute (PVfast) using Lasso recordings. The PV to LA CL gradient was quantified by the ratio of PVfast to LA appendage (LAA) AF CL. Stepwise ablation terminated AF in 73 patients (75%). In the AF termination group, the PVfast CL was much shorter than the LAA CL resulting in lower PVfast/LAA ratios compared with the nontermination group (71±10% versus 92±7%; P<0.001). Within the termination group, PVfast/LAA ratios were notably lower if AF terminated after PV isolation or limited adjunctive substrate ablation compared with patients who required moderate or extensive ablation (63±6% versus 75±8%; P<0.001). PVfast/LAA ratio <69% predicted AF termination after PV isolation or limited substrate ablation with 74% positive predictive value and 95% negative predictive value. After a mean follow-up of 29±17 months, freedom from arrhythmia recurrence off-antiarrhythmic drugs was achieved in most patients with PVfast/LAA ratios <69% as opposed to the remaining population (80% versus 43%; P<0.001). CONCLUSIONS The PV to LA CL gradient may identify the subset of patients in whom persistent AF is likely to terminate after PV isolation or limited substrate ablation and better long-term outcomes are achieved.

Five-Year Outcome of Catheter Ablation of Persistent Atrial Fibrillation Using Termination of Atrial Fibrillation as a Procedural Endpoint.

BACKGROUND -This study aimed to determine five-year efficacy of catheter ablation for persistent atrial fibrillation (PsAF) using AF termination as a procedural endpoint. METHODS AND RESULTS -150 patients (57±10 years) underwent PsAF ablation using a stepwise ablation approach (pulmonary vein isolation, electrogram-guided and linear ablation) with the desired procedural endpoint being AF termination. Repeat ablation was performed for recurrent AF or atrial tachycardia (AT). AF was terminated by ablation in 120 patients (80%). Arrhythmia-free survival rates after a single procedure were 35.3±3.9%, 28.0±3.7%, and 16.8±3.2% at 1, 2, and 5 years, respectively. Arrhythmia-free survival rates after the last procedure (mean 2.1±1.0 procedures) were 89.7±2.5%, 79.8±3.4%, and 62.9±4.5%, at 1, 2, and 5 years, respectively. During a median follow-up of 58 (IQR 43-73) months following the last ablation procedure, 97 of 150 (64.7%) patients remained in sinus rhythm without antiarrhythmic drugs (AADs). Another 14 (9.3%) patients maintained sinus rhythm after re-initiation of AADs, and an additional 15 (10.0%) patients regressed to paroxysmal recurrences only. Failure to terminate AF during the index procedure (HR 3.831; 95%CI: 2.070-7.143; p<0.001), left atrial diameter ≥50mm (HR 2.083; 95%CI: 1.078-4.016; p=0.03), continuous AF duration ≥18 months (HR 1.984; 95%CI: 1.024-3.846; p<0.04) and structural heart disease (HR 1.874; 95% CI: 1.037-3.388; p=0.04) predicted arrhythmia recurrence. CONCLUSIONS -In patients with PsAF, an ablation strategy aiming at AF termination is associated with freedom from arrhythmia recurrence in the majority of patients over a 5-year follow up period.Procedural AF non-termination and specific baseline factors predict long-term outcome after ablation.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

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.

The Cost-Effectiveness of Monitoring Strategies for Antiretroviral Therapy of HIV Infected Patients in Resource-Limited Settings: Software Tool.

BACKGROUND The cost-effectiveness of routine viral load (VL) monitoring of HIV-infected patients on antiretroviral therapy (ART) depends on various factors that differ between settings and across time. Low-cost point-of-care (POC) tests for VL are in development and may make routine VL monitoring affordable in resource-limited settings. We developed a software tool to study the cost-effectiveness of switching to second-line ART with different monitoring strategies, and focused on POC-VL monitoring. METHODS We used a mathematical model to simulate cohorts of patients from start of ART until death. We modeled 13 strategies (no 2nd-line, clinical, CD4 (with or without targeted VL), POC-VL, and laboratory-based VL monitoring, with different frequencies). We included a scenario with identical failure rates across strategies, and one in which routine VL monitoring reduces the risk of failure. We compared lifetime costs and averted disability-adjusted life-years (DALYs). We calculated incremental cost-effectiveness ratios (ICER). We developed an Excel tool to update the results of the model for varying unit costs and cohort characteristics, and conducted several sensitivity analyses varying the input costs. RESULTS Introducing 2nd-line ART had an ICER of US$1651-1766/DALY averted. Compared with clinical monitoring, the ICER of CD4 monitoring was US$1896-US$5488/DALY averted and VL monitoring US$951-US$5813/DALY averted. We found no difference between POC- and laboratory-based VL monitoring, except for the highest measurement frequency (every 6 months), where laboratory-based testing was more effective. Targeted VL monitoring was on the cost-effectiveness frontier only if the difference between 1st- and 2nd-line costs remained large, and if we assumed that routine VL monitoring does not prevent failure. CONCLUSION Compared with the less expensive strategies, the cost-effectiveness of routine VL monitoring essentially depends on the cost of 2nd-line ART. Our Excel tool is useful for determining optimal monitoring strategies for specific settings, with specific sex-and age-distributions and unit costs.

Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.

BACKGROUND & AIMS Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. METHODS PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. RESULTS Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001). CONCLUSIONS Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.