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Supplementary Figures S1-S7 and Tables S1 and S2

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location.Significance:Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known.See related commentary by De Dominici and DeGregori, p. 227.This article is highlighted in the In This Issue feature, p. 211

Background Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253)

DOI: 10.19072/ijet.309372, The conceptual guideway structural designs for MAGLEV (magnetic-levitation) high-speed ground transportation system are discussed by considering four different guideway designs of Bechtel, Magneplane, Grumman and Foster-Miller. The important aspects of the conceptual designs as well as some of the apparent shortcomings that will need attention in the design studies are emphasized. In this context the technical assessments and design observations may be considered for the guideway conceptual designs are given in this study.

BACKGROUND The Long QT Syndrome (LQTS) is an infrequently occurring familial disorder in which affected individuals have electrocardiographic QT interval prolongation and a propensity to ventricular tachyarrhythmic syncope and sudden death. We prospectively investigated the clinical characteristics and the long-term course of 3,343 individuals from 328 families in which one or more members were identified as affected with LQTS (QTc greater than 0.44 sec1/2). METHODS AND RESULTS The first member of a family to be identified with LQTS, the proband, was usually brought to medical attention because of a syncopal episode during childhood or teenage years. Probands (n = 328) were younger at first contact (age 21 +/- 15 years), more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate less than 60 beats/min (31%), QTc greater than or equal to 0.50 sec1/2 (52%), and a history of ventricular tachyarrhythmia (47%) than other affected (n = 688) and unaffected (n = 1,004) family members. Arrhythmogenic syncope often occurred in association with acute physical, emotional, or auditory arousal. The syncopal episodes were frequently misinterpreted as a seizure disorder. By age 12 years, 50% of the probands had experienced at least one syncopal episode or death. The rates of postenrollment syncope (one or more episodes) and probable LQTS-related death (before age 50 years) for probands (n = 235; average follow-up 54 months per patient) were 5.0% per year and 0.9% per year, respectively; these event rates were considerably higher than those observed among affected and unaffected family members. CONCLUSIONS Among 232 probands and 1,264 family members with prospective follow-up, three factors made significant independent contributions to the risk of subsequent syncope or probable LQTS-related death before age 50 years, whichever occurred first (Cox hazard ratio; 95% confidence limits): 1) QTc (1.052; 1.017, 1.088), 2) history of cardiac event (3.1; 1.3, 7.2), and 3) heart rate (1.017; 1.004, 1.031). The findings from this prospective longitudinal study highlight the clinical features, risk factors, and course of LQTS.

The long QT syndrome is electrocardiographically characterized by a prolonged QT interval and by several other, more subtle, ST-T-U wave abnormalities, most of which have not been quantified. To determine the possible usefulness of several new electrocardiographic characteristics in identifying patients with known long QT syndrome, logistic regression models were applied to a data base of seven new, relatively independent, electrocardiographic repolarization variables. These were measured on digitized 12-lead electrocardiograms of 315 normal subjects and 37 patients with the long QT syndrome (members of well-identified long QT syndrome families, QTc greater than 0.44 second, 27% symptomatic), who ranged in age from 17 to 60 years. Electrocardiographic variables that independently differentiated (p less than 0.001) patients with long QT syndrome from normal subjects included quantitative measures of repolarization: early duration, rate, T wave symmetry, late phenomena, and heterogeneity. All selected repolarization variables except the early duration variable were essentially independent of the QTc (r2 less than 0.15), and all contributed significantly to the identification of patients with long QT syndrome. A classification model of five electrocardiographic predictor variables resulted in an estimated sensitivity (95% confidence interval) of 92.6% (81.6-100%) and an estimated specificity (95% confidence interval) of 95.8% (93.6-98.1%). This model performed significantly better than an alternative classification model that was based on the early duration variable as a single predictor variable. The symptomatic status of patients with long QT syndrome could not be predicted by any combination of the electrocardiographic variables in the investigated model.

A need to monitor on-site performance of solar-domestic water heaters has been universally identified throughout the solar industry. A low cost method for accomplishing this objective is described. This system utilizes a moderate amount of basic instrumentation for data acquisition and a manual data reduction technique. Comparative testing of the method using two separate configurations of commonly available instruments is reported. Results and observations noted in these tests are discussed in detail. Descriptions of the instrumentation and its installation and the equations applied in the data analyses are also included.

Daystar Corporation installed a solar/electric, domestic water heating system in the Borda Wing of the South County Hospital, Wakefield, Rhode Island, in 1975. THe primary purpose of this project was to study the feasibility of the use of Solar Energy in a commercial, healthcare institution. The thermal performance of this system was monitored from December 1976 through March 1978. The final stages of the development of the computerized monitoring system, and the system performance results for the 16 month monitoring period are described.