Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine

Genetic cardiomyopathies have been studied for decades, and it has become increasingly clear that these progressive diseases are more complex than originally thought. These complexities can be seen both in the molecular etiologies of these disorders and in the clinical phenotypes observed in patients. While these disorders can be caused by mutations in cardiac genes, including ones encoding sarcomeric proteins, the disease presentation varies depending on the patient mutation, where mutations even within the same gene can cause divergent phenotypes. Moreover, it is challenging to connect the mutation-induced molecular insult that drives the disease pathogenesis with the various compensatory and maladaptive pathways that are activated during the course of the subsequent progressive, pathogenic cardiac remodeling. These inherent complexities have frustrated our ability to understand and develop broadly effective treatments for these disorders. It has been proposed that it might be possible to improve patient outcomes by adopting a precision medicine approach. Here, we lay out a practical framework for such an approach, where patient subpopulations are binned based on common underlying biophysical mechanisms that drive the molecular disease pathogenesis, and we propose that this function-based approach will enable the development of targeted therapeutics that ameliorate these effects. We highlight several mutations to illustrate the need for mechanistic molecular experiments that span organizational and temporal scales, and we describe recent advances in the development of novel therapeutics based on functional targets. Finally, we describe many of the outstanding questions for the field and how fundamental mechanistic studies, informed by our more nuanced understanding of the clinical disorders, will play a central role in realizing the potential of precision medicine for genetic cardiomyopathies

Are Regulators Forward-Looking? The Market Price of Copper Versus the Regulated Price of Mandatory Access to Unbundled Local Loops in Telecommunications Networks

The Enduring Lessons of the Breakup of AT&T: A Twenty-Five Year Retrospective. \u27 Conference held at the University of Pennsylvania Law School on April 18-19, 2008. Around the world, since 1996, regulators have mandated that incumbent local exchange carriers (ILECs) offer competitors access to their network at regulated prices that reflect forward-looking cost. Regulated prices for unbundled network elements are based on total element long-run incremental cost (TELRIC), which in turn is calculated using engineering models that estimate the costs of a hypothetical carrier employing the most efficient telecommunications technology currently available and the lowest cost network configuration, given the existing location of the ILEC\u27s actual wire centers. These cost models require detailed estimates of the equipment and installation prices of the numerous components that are used in a telecommunications network. When there is uncertainty about how these prices will change over the period for which costs and prices are required, the resulting cost estimates used for setting the regulated prices of unbundled network elements can be very inaccurate. Similarly, when regulators in other jurisdictions are considering such rates as benchmarks, it is necessary to make adjustments to account for such large differences in critical input prices, so that the benchmark rates will be representative of the costs that actually will be incurred by efficient carriers offering unbundled elements in those jurisdictions. The precipitous rise in the price of copper since 2003 exemplifies this need to reevaluate the inputs used by regulators in their cost model, as well as the inferences drawn from those models. These increases differ from the type of constant annual expected input price growth (or decline) situation that some cost models used outside the United States have accommodated with tilted annuity methods. Rather than a gradual anticipated price increase, copper prices escalated rapidly and are likely to remain well above the levels that regulators used to set existing loop rates. Accounting for such evidence would change the forward-looking costs of a hypothetically efficient ILEC network that one of the most prominent U.S. state regulatory commissions--the California Public Utilities Commission (CPUC)--established in 2006. Similarly, in 2007, the Commerce Commission in New Zealand employed a benchmarking methodology for the pricing of unbundled loops that failed to account for the increased price of copper. A global trend may be emerging among telecommunications regulators to ignore the input requirements of their own forward-looking cost models. Such a trend would be consistent with a version of regulatory opportunism in which regulators are forward-looking only when doing so produces lower regulated prices over time. The risk of regulatory opportunism and the high price of copper together create a strong incentive for an ILEC to replace its copper loops with optical fiber. Although some CLECS could be adversely affected by such a decommissioning of copper loops, an ILEC has no duty under U.S. antitrust or telecommunications law to keep copper loops in service for the benefit of its competitors

Monitoring the health of transgender and other gender minority populations: Validity of natal sex and gender identity survey items in a U.S. national cohort of young adults

Background: A barrier to monitoring the health of gender minority (transgender) populations is the lack of brief, validated tools with which to identify participants in surveillance systems. Methods: We used the Growing Up Today Study (GUTS), a prospective cohort study of U.S. young adults (mean age = 20.7 years in 2005), to assess the validity of self-report measures and implement a two-step method to measure gender minority status (step 1: assigned sex at birth, step 2: current gender identity). A mixed-methods study was conducted in 2013. Construct validity was evaluated in secondary data analysis of the 2010 wave (n = 7,831). Cognitive testing interviews of close-ended measures were conducted with a subsample of participants (n = 39). Results: Compared to cisgender (non-transgender) participants, transgender participants had higher levels of recalled childhood gender nonconformity age < 11 years and current socially assigned gender nonconformity and were more likely to have ever identified as not completely heterosexual (p < 0.001). No problems with item comprehension were found for cisgender or gender minority participants. Assigned sex at birth was interpreted as sex designated on a birth certificate; transgender was understood to be a difference between a person’s natal sex and gender identity. Participants were correctly classified as male, female, or transgender. Conclusions: The survey items performed well in this sample and are recommended for further evaluation in languages other than English and with diverse samples in terms of age, race/ethnicity, and socioeconomic status

One-Particle Measurement of the Antiproton Magnetic Moment

\DeclareRobustCommand{\pbar}{\HepAntiParticle{p}{}{}\xspace} \DeclareRobustCommand{\p}{\HepParticle{p}{}{}\xspace} \DeclareRobustCommand{\mup}{$\mu_{p}${}{}\xspace} \DeclareRobustCommand{\mupbar}{\mu_{\pbar}{}{}\xspace} \DeclareRobustCommand{\muN}{$\mu_N${}{}\xspace For the first time a single trapped \pbar is used to measure the \pbar magnetic moment {\bm\mu}_{\pbar}. The moment {\bm\mu}_{\pbar} = \mu_{\pbar} {\bm S}/(\hbar/2) is given in terms of its spin ${\bm S}$ and the nuclear magneton (\muN) by \mu_{\pbar}/\mu_N = -2.792\,845 \pm 0.000\,012. The 4.4 parts per million (ppm) uncertainty is 680 times smaller than previously realized. Comparing to the proton moment measured using the same method and trap electrodes gives \mu_{\pbar}/\mu_p = -1.000\,000 \pm 0.000\,005 to 5 ppm, for a proton moment ${\bm{\mu}}_{p} = \mu_{p} {\bm S}/(\hbar/2)$, consistent with the prediction of the CPT theorem.Comment: 4 pages, 4 figures. arXiv admin note: substantial text overlap with arXiv:1201.303

Spatial analytic approaches to explaining the trends and patterns of drug overdose deaths

To effectively utilize and interpret spatial analyses, substance use researchers, public health practitioners and policy makers should be familiar with some of the available data analytic techniques, each of which comes with advantages and drawbacks. In this chapter we first discuss three cluster detection tools and their associated software applications. We then present a Bayesian hierarchical approach, briefly reviewing its theoretical underpinnings, commonly used models, and how inferences may be drawn a sample-based posterior distribution. We demonstrate the use of each approach on a set of substance abuse mortality data, comparing the results across the four tools. Our empiric illustration, considers the role of neighborhood-level socioeconomic status (SES) in explaining opiate-related overdose deaths in New York City. We end with a discussion of the implications of the choice of technique and software on interpreting spatial analyses of substance abuse and conclude that the choice of a method will be driven by the question to be answered, data and software availability and the intended audience or context in which the research is being conducted

New generalized fuzzy metrics and fixed point theorem in fuzzy metric space

In this paper, in fuzzy metric spaces (in the sense of Kramosil and Michalek (Kibernetika 11:336-344, 1957)) we introduce the concept of a generalized fuzzy metric which is the extension of a fuzzy metric. First, inspired by the ideas of Grabiec (Fuzzy Sets Syst. 125:385-389, 1989), we define a new G-contraction of Banach type with respect to this generalized fuzzy metric, which is a generalization of the contraction of Banach type (introduced by M Grabiec). Next, inspired by the ideas of Gregori and Sapena (Fuzzy Sets Syst. 125:245-252, 2002), we define a new GV-contraction of Banach type with respect to this generalized fuzzy metric, which is a generalization of the contraction of Banach type (introduced by V Gregori and A Sapena). Moreover, we provide the condition guaranteeing the existence of a fixed point for these single-valued contractions. Next, we show that the generalized pseudodistance J:X×X→[0,∞) (introduced by Włodarczyk and Plebaniak (Appl. Math. Lett. 24:325-328, 2011)) may generate some generalized fuzzy metric NJ on X. The paper includes also the comparison of our results with those existing in the literature

Predicting detection probabilities for gas mixtures over HSI backgrounds

Detecting and identifying weak gaseous plumes using thermal image data acquired by airborne detectors is an area of ongoing research. This contribution investigates the relative detectability of gas mixtures over different backgrounds and a range of plume temperatures that are warmer and cooler than the ground. The focus of this analysis to support mission planning. When the mission is intended to collect evidence of particular chemicals, the analysis presented is this report can be used to determine conditions under which useful data can be acquired. Initial analyses can be used to determine whether LWIR is useful for the anticipated gas, temperature, and background combination

High-Precision Measurement of the 19Ne Half-Life and Implications for Right-Handed Weak Currents

We report a precise determination of the 19Ne half-life to be $T_{1/2} = 17.262 \pm 0.007$ s. This result disagrees with the most recent precision measurements and is important for placing bounds on predicted right-handed interactions that are absent in the current Standard Model. We are able to identify and disentangle two competing systematic effects that influence the accuracy of such measurements. Our findings prompt a reassessment of results from previous high-precision lifetime measurements that used similar equipment and methods.Comment: 5 pages and 5 figures. Paper accepted for publication in Phys. Rev. Let