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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.

When combining estimates of a common parameter (of dimension d ⩾ 1 ) from independent data sets—as in stratified analyses and meta analyses—a weighted average, with weights ‘proportional’ to inverse variance matrices, is shown to have a minimal variance matrix (a standard fact when d = 1 )—minimal in the sense that all convex combinations of the coordinates of the combined estimate have minimal variances. Minimum variance for the estimation of a single coordinate of the parameter can therefore be achieved by joint estimation of all coordinates using matrix weights. Moreover, if each estimate is asymptotically efficient within its own data set, then this optimally weighted average, with consistently estimated weights, is shown to be asymptotically efficient in the combined data set and avoids the need to merge the data sets and estimate the parameter in question afresh. This is so whatever additional non-common nuisance parameters may be in the models for the various data sets. A special case of this appeared in Fisher [1925. Theory of statistical estimation. Proc. Cambridge Philos. Soc. 22, 700–725.]: Optimal weights are ‘proportional’ to information matrices, and he argued that sample information should be used as weights rather than expected information, to maintain second-order efficiency of maximum likelihood. A number of special cases have appeared in the literature; we review several of them and give additional special cases, including stratified regression analysis—proportional-hazards, logistic or linear—, combination of independent ROC curves, and meta analysis. A test for homogeneity of the parameter across the data sets is also given.

For testing the drift of Brownian motion with equal error probabilities. We provided an asymptotic solution, within the class of symmetric triangular stopping boundaries, to the Kiefer-Weiss problem of minimizing the maximum expected stopping time. The resulting asymptotic minimax triangular test (AMTT) is a slight improvement over Lordenś2-SPRT.

Receiver operating characteristic (ROC) curves are mapped out by the two types of errors that are generated by varying the decision threshold used to determine which subjects will be considered abnormal. Under the conventional binormal model for the ROC curve, two- sided and one-sided simultaneous confidence bands for an entire ROC curve, or for a portion of an ROC curve, are constructed by employing Working-Hotelling-type confidence bands for simple linear regression. Pointwise confidence bands are presented for comparison. The cases in which one has only asymptotically normally distributed estimates of the parameters of the ROC curve and consistent estimates of their variance-covariance matrix are em phasized. The methods extend beyond binormal models. Key words: confidence bands for linear regression; ROC curves. (Med Decis Making 1993;13:191-197)

In order to gain insight into the process of cardiac repolarization, the authors defined and studied the repolarization duration variability (RDV) on electrocardiograms. Spectrum techniques were used to evaluate the influence of the autonomic nervous system in the control of repolarization duration (RD). Coherence analysis was used to quantify common contributions between RDV and heart rate variability. The latter gave a reference of the sympathovagal balance. It was found that the autonomic nervous system acts tonically and directly to control RD. This action is mediated through both autonomic limbs. >

Ten morphological variables describing electrocardiographic ventricular repolarization were considered, an addition to the conventional QT interval, in order to have a more complete description of the phenomenon. The computer program QTNEW was developed in order to analyze the repolarization segment automatically and to measure the variables. A final list of seven variables was obtained after the application of dimensionality-reduction techniques and did not include the QT interval. Six variables were independent of the QT, six were heart-rate independent, and all were age and body surface-area independent. >

OSC/FD has successfully implemented unmodified PC Cards in military equipment. These implementations have been for memory only. In one instance PC Cards are being used in a new system (Bradley Fighting Vehicle Mass Memory Unit) and in another instance PC Cards are being used to cost effectively upgrade an existing system (the PC Card upgrade to the AN/ASQ-215 Navy standard data loader). OSC/FD is working on the application of PC Cards (or Credit Electronics) beyond memory. Both retrofit and new developments are being considered. Using PC Cards, with their limited processing and interface capabilities, in a complex, multi-processor military applications is significant challenge, but one OSC/FD will achieve.

This study was designed to assess the contribution of clinical, electrocardiographic and exercise hemodynamic variables to the prediction of normalization on resting reinjection scintigraphy of persistent thallium-201 (201Tl) myocardial perfusion defects seen with exercise and 2- to 4-hour delayed (redistribution) imaging. To evaluate this contribution, we studied 159 consecutive patients with persistent 201Tl myocardial perfusion defects on routine exercise and 2- to 4-hour-delayed scintigrams at the University of Rochester Medical Center who were classified as having moderate or greater ischemic normalization (group 1, n = 76) or minimal to no ischemic normalization (group 2, n = 83) by reinjection scintigraphy. Multiple logistic regression analysis with backward elimination was used to model the effects of clinical, electrocardiographic and exercise hemodynamic data on the odds ratio of a normalized defect. No difference was observed in the two groups with regard to gender, angina on exertion, rate-pressure product, exercise duration, resting or exertional ischemic ST changes on electrocardiogram, presence of Q waves or left ventricular hypertrophy on baseline electrocardiogram, or total number of stress thallium defects (2.8 +/- 1.5 segments). No single variable or combination of variables discriminated between groups 1 and 2 by logistic regression analysis. We conclude that defect normalization seen on resting 201Tl myocardial perfusion scintigraphy is prevalent in patients with persistent defects on routine exercise and delayed myocardial perfusion scintigraphy, and was not predictable from available clinical, electrocardiographic and exercise hemodynamic variables.

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.

1. 24 Na studies indicate that the ionic basis of the increase in SCC across isolated frog skin ( Rana temporaria ) following prostaglandin E 1 application, is an increase in gross sodium influx, with sodium efflux remaining unchanged. 2. In the first 15 min prostaglandin E 1 caused a decrease in net water inflow across frog skin. The time-course of this initial effect was similar to that observed for adrenaline, but it was unaffected by propranolol. In the second 15-min period net water inflow returned to the control level. In those skins where prostaglandin E 1 produced a substantial rise in SCC an increase in net water inflow was seen. 3. HTO studies revealed that prostaglandin E 1 also produced a significant increase in water influx across the skin. 4. It is concluded that the initial effect of prostaglandin E 1 on net water flow can be attributed to glandular secretion and the subsequent effect to stimulation of sodium transport.

Our replicate of a study by Takabayashi et al. (1981) Effects of pulse-wave ultrasonic irradiation on mouse embryo. Cho-Onpa Igaku (Supersonic Medicine) 8, 286-288 failed to show any effects of exposure in utero of mice to spatial average, temporal maximum intensities of 60 W/cm2. Fetuses were exposed at 8 days post fertilization and assessed at 18 days for fetal weight, resorptions, premature deaths, and malformations. Carrier frequency in the pulse was 2 MHz. Pulse lengths of 10 microseconds and pulse repetition frequencies of 1000 and 200 Hz yielded spatial average, temporal average intensities of 0.6 and 0.1 W/cm2. Total exposure time was 5 min. Our results provide no basis to conclude that conditions relevant to human fetal monitoring will cause developmental, externally visible anomalies in mice exposed as 8-day fetuses.

Consider a random sample from a statistical model with an unknown, and possibly infinite-dimensional, parameter - e.g., a nonparametric or semiparametric model - and a real-valued functional T of this parameter which is to be estimated. The objective is to develop bounds on the (negative) exponential rate at which consistent estimates converge in probability to T, or, equivalently, lower bounds for the asymptotic effective standard deviation of such estimates - that is, to extend work of R.R. Bahadur from parametric models to more general (semiparametric and nonparametric) models. The approach is to define a finite-dimensional submodel, determine Bahadur's bounds for a finite-dimensional model, and then ‘sup’ or ‘inf’ the bounds with respect to ways of defining the submodels; this can be construed as a ‘directional approach’, the submodels being in a specified ‘direction’ from a specific model. Extension is made to the estimation of vector-valued and infinite-dimensional functionals T, by expressing consistency in terms of a distance, or, alternatively, by treating classes of real functionals of T. Several examples are presented.

1. The effects of prostaglandin E1, vasopressin, ouabain and tetrodotoxin on the electrical excitability of isolated frog skin (Rana temporaria) were tested. The following variables were measured: the threshold voltage for excitation (Vt), threshold current (It), spike height (St), spike duration, total skin resistance (R) and SCC. 2. Prostaglandin E1 and vasopressin increased the SCC and caused a significant decrease in R, associated with an increase in It. 3. Ouabain did not alter excitability but blocked the effects of prostaglandin E1 and vasopressin. 4. The SCC, electrical excitability and the responses of the skin to prostaglandin E1 and vasopressin were insensitive to tetrodotoxin. 5. The duration of the calcium-prolonged spike was unaltered by prostaglandin treatment. 6. The actions of calcium on skin excitability are consistent with the hypothesis that calcium acts on the outer membrane. An effect of prostaglandin E1 or vasopressin at the same site cannot be postulated.

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.

Ultrasonographic assessment of ovarian follicular maturity was reportedly associated with atypically early ovulation in women; related studies reported reduced litter sizes in rats. To confirm these findings, mice which were midway between ovulatory gonadotropin (LH or human chorionic gonadotropin) stimulation and ovulation, were sham- or ultrasound-treated periovarially for 5 min. Exposure was at a spatial average, temporal maximum intensity of 60 W/cm2. Carrier frequency in the pulse was 2.2 MHz, pulse length was 10 microseconds, and pulse repetition frequency was 200 Hz. Spatial average, temporal average intensity was 0.12 W/cm2. At autopsy, ultrasound- and sham-treated groups responded similarly in proportions ovulating and in mean ova ovulated. Combined experiments had a 97% chance of detecting a significant (greater than 1 h) advance in ovulation time, had it occurred. Thus, our adequately sensitive mammalian ovulatory tests revealed no association of ultrasound with decrease in ovum number or acceleration in ovulation time (as reported in humans).

Factors affecting the evaluation of fracture tests receive general attention in this chapter. The discussion begins with observations on the philosophy of testing; this is followed by a brief description of 11 types of tests commonly employed for steel, with examples of the types of data obtained. For the most part, the discussion in this chapter centers about those types of tests associated with the transition temperature concept. The topic of fracture mechanics testing, of obvious importance, receives only limited attention because other chapters in this treatise are devoted solely to this complex topic. Brief comments are offered about factors that play an important role in testing and interpretation; namely, the effects of welding procedures, residual stress, flaws, and instrumentation. The last major section discusses techniques for interpreting the test results and factors that must be considered in such interpretation.