Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention

Discovery of an intermediate-luminosity red transient in M51 and its likely dust-obscured, infrared-variable progenitor

We present the discovery of an optical transient (OT) in Messier 51, designated M51 OT2019-1 (also ZTF19aadyppr, AT 2019abn, ATLAS19bzl), by the Zwicky Transient Facility (ZTF). The OT rose over 15 days to an observed luminosity of $M_r=-13$ (${\nu}L_{\nu}=9\times10^6~L_{\odot}$), in the luminosity gap between novae and typical supernovae (SNe). Spectra during the outburst show a red continuum, Balmer emission with a velocity width of $\approx400$ km s$^{-1}$, Ca II and [Ca II] emission, and absorption features characteristic of an F-type supergiant. The spectra and multiband light curves are similar to the so-called "SN impostors" and intermediate-luminosity red transients (ILRTs). We directly identify the likely progenitor in archival Spitzer Space Telescope imaging with a $4.5~\mu$m luminosity of $M_{[4.5]}\approx-12.2$ and a $[3.6]-[4.5]$ color redder than 0.74 mag, similar to those of the prototype ILRTs SN 2008S and NGC 300 OT2008-1. Intensive monitoring of M51 with Spitzer further reveals evidence for variability of the progenitor candidate at [4.5] in the years before the OT. The progenitor is not detected in pre-outburst Hubble Space Telescope optical and near-IR images. The optical colors during outburst combined with spectroscopic temperature constraints imply a higher reddening of $E(B-V)\approx0.7$ mag and higher intrinsic luminosity of $M_r\approx-14.9$ (${\nu}L_{\nu}=5.3\times10^7~L_{\odot}$) near peak than seen in previous ILRT candidates. Moreover, the extinction estimate is higher on the rise than on the plateau, suggestive of an extended phase of circumstellar dust destruction. These results, enabled by the early discovery of M51 OT2019-1 and extensive pre-outburst archival coverage, offer new clues about the debated origins of ILRTs and may challenge the hypothesis that they arise from the electron-capture induced collapse of extreme asymptotic giant branch stars.Comment: 21 pages, 5 figures, published in ApJ

Long-Term Functionality of Rural Water Services in Developing Countries: A System Dynamics Approach to Understanding the Dynamic Interaction of Causal Factors

Research has shown that sustainability of rural water infrastructure in developing countries is largely affected by the dynamic and systemic interactions of technical, social, financial, institutional, and environmental factors that can lead to premature water system failure. This research employs systems dynamic modeling, which uses feedback mechanisms to understand how these factors interact dynamically to influence long-term rural water system functionality. To do this, the research first identified and aggregated key factors from literature, then asked water sector experts to indicate the polarity and strength between factors through Delphi and cross impact survey questionnaires, and finally used system dynamics modeling to identify and prioritize feedback mechanisms. The resulting model identified 101 feedback mechanisms that were dominated primarily by three and four-factor loops that contained some combination of the factors: Water System Functionality, Community, Financial, Government, Management, and Technology. These feedback mechanisms were then scored and prioritized, with the most dominant feedback mechanism identified as Water System Functionality – Community – Finance – Management. This research offers insight into the dynamic interaction of factors impacting sustainability of rural water infrastructure through the identification of these feedback mechanisms and makes a compelling case for future research to longitudinally investigate the interaction of these factors in various contexts

Real-bogus classification for the Zwicky Transient Facility using deep learning

Efficient automated detection of flux-transient, re-occurring flux-variable, and moving objects is increasingly important for large-scale astronomical surveys. We present BRAAI, a convolutional-neural-network, deep-learning real/bogus classifier designed to separate genuine astrophysical events and objects from false positive, or bogus, detections in the data of the Zwicky Transient Facility (ZTF), a new robotic time-domain survey currently in operation at the Palomar Observatory in California, USA. BRAAI demonstrates a state-of-the-art performance as quantified by its low false negative and false positive rates. We describe the open-source software tools used internally at Caltech to archive and access ZTF’s alerts and light curves (KOWALSKI ), and to label the data (ZWICKYVERSE). We also report the initial results of the classifier deployment on the Edge Tensor Processing Units that show comparable performance in terms of accuracy, but in a much more (cost-) efficient manner, which has significant implications for current and future surveys

Motivations for the use and consumption of wildlife products

The dominant approach to combating the illegal wildlife trade has traditionally been to restrict the supply of wildlife products. Yet conservationists increasingly recognize the importance of implementing demand‐side interventions that target the end consumers in the trade chain. Their aim is to curb the consumption of wildlife or shift consumption to more sustainable alternatives. However, there are still considerable knowledge gaps in understanding of the diversity of consumer motivations in the context of illegal wildlife trade, which includes hundreds of thousands of species, different uses, and diverse contexts. Based on consultation with multiple experts from a diversity of backgrounds, nationalities, and focal taxa, we developed a typology of common motivations held by wildlife consumers that can be used to inform conservation interventions. We identified 5 main motivational categories for wildlife use: experiential, social, functional, financial, and spiritual, each containing subcategories. This framework is intended to facilitate the segmentation of consumers based on psychographics and allow the tailoring of interventions—whether behavior change campaigns, enforcement efforts, or incentive programs—to the specific context in which they will be used. Underlining the importance of consumer research and collaborating with local actors is an important step toward promoting a more systematic approach to the design of demand reduction interventions

Identifying invasive species threats, pathways, and impacts to improve biosecurity

Managing invasive species with prevention and early-detection strategies can avert severe ecological and economic impacts. Horizon scanning, an evidence-based process combining risk screening and consensus building to identify threats, has become a valuable tool for prioritizing invasive species management and prevention. We assembled a working group of experts from academic, government, and nonprofit agencies and organizations, and conducted a multi-taxa horizon scan for Florida, USA, the first of its kind in North America. Our primary objectives were to identify high-risk species and their introduction pathways, to detail the magnitude and mechanism of potential impacts, and, more broadly, to demonstrate the utility of horizon scanning. As a means to facilitate future horizon scans, we document the process used to generate the list of taxa for screening. We evaluated 460 taxa for their potential to arrive, establish, and cause negative ecological and socioeconomic impacts, and identified 40 potential invaders, including alewife, zebra mussel, crab-eating macaque, and red swamp crayfish. Vertebrates and aquatic invertebrates posed the greatest invasion threat, over half of the high-risk taxa were omnivores, and there was high confidence in the scoring of high-risk taxa. Common arrival pathways were ballast water, biofouling of vessels, and escape from the pet/aquarium/horticulture trade. Competition, predation, and damage to agriculture/forestry/aquaculture were common impact mechanisms. We recommend full risk analysis for the high-risk taxa; increased surveillance at Florida's ports, state borders, and high-risk pathways; and periodic review and revision of the list. Few horizon scans detail the comprehensive methodology (including list-building), certainty estimates for all scoring categories and the final score, detailed pathways, and the magnitude and mechanism of impact. Providing this information can further inform prevention efforts and can be efficiently replicated in other regions. Moreover, harmonizing methodology can facilitate data sharing and enhance interpretation of results for stakeholders and the general public.</p

Long-term functional health status and exercise test variables for patients with pulmonary atresia with intact ventricular septum: A Congenital Heart Surgeons Society study

Background: A bias favoring biventricular (BV) repair exists regarding choice of repair pathway for patients with pulmonary atresia with intact ventricular septum (PAIVS). We sought to determine the implications of moving borderline candidates down a BV route in terms of late functional health status (FHS) and exercise capacity (EC). Methods: Between 1987 and 1997, 448 neonates with PAIVS were enrolled in a multi-institutional study. Late EC and FHS were assessed following repair (mean 14 years) using standardized exercise testing and 3 validated FHS instruments. Relationships between FHS, EC, morphology, and 3 end states (ie, BV, univentricular [UV], or 1.5-ventricle repair [1.5V]) were evaluated. Results: One hundred two of 271 end state survivors participated (63 BV, 25 UV, and 14 1.5V). Participants had lower FHS scores in domains of physical functioning (P<.001) compared with age- and sex-matched normal controls, but scored significantly higher in nearly all psychosocial domains. EC was higher in 1.5V-repair patients (P ¼ .02), whereas discrete FHS measures were higher in BV-repair patients. Peak oxygen consumption was low across all groups, and was positively correlated with larger initial tricuspid valve z-score (P<.001), with an enhanced effect within the BV-repair group. Conclusions: Late patient-perceived physical FHS and measured EC are reduced, regardless of PAIVS repair pathway, with an important dichotomy whereby patients with PAIVS believe they are doing well despite important physical impediments. For those with smaller initial tricuspid valve z-score, achievement of survival with BV repair may be at a cost of late deficits in exercise capacity, emphasizing that better outcomes may be achieved for borderline patients with a 1.5V- or UV-repair strategy. (J Thorac Cardiovasc Surg 2013;145:1018-27

The equity dimension in evaluations of the quality and outcomes framework: A systematic review

<p>Abstract</p> <p>Background</p> <p>Pay-for-performance systems raise concerns regarding inequity in health care because providers might select patients for whom targets can easily be reached. This paper aims to describe the evolution of pre-existing (in)equity in health care in the period after the introduction of the Quality and Outcomes Framework (QOF) in the UK and to describe (in)equities in exception reporting. In this evaluation, a theory-based framework conceptualising equity in terms of equal access, equal treatment and equal treatment outcomes for people in equal need is used to guide the work.</p> <p>Methods</p> <p>A systematic MEDLINE and Econlit search identified 317 studies. Of these, 290 were excluded because they were not related to the evaluation of QOF, they lacked an equity dimension in the evaluation, their qualitative research focused on experiences or on the nature of the consultation, or unsuitable methodology was used to pronounce upon equity after the introduction of QOF.</p> <p>Results</p> <p>None of the publications (n = 27) assessed equity in access to health care. Concerning equity in treatment and (intermediate) treatment outcomes, overall quality scores generally improved. For the majority of the observed indicators, all citizens benefit from this improvement, yet the extent to which different patient groups benefit tends to vary and to be highly dependent on the type and complexity of the indicator(s) under study, the observed patient group(s) and the characteristics of the study. In general, the introduction of QOF was favourable for the aged and for males. Total QOF scores did not seem to vary according to ethnicity. For deprivation, small but significant residual differences were observed after the introduction of QOF favouring less deprived groups. These differences are mainly due to differences at the practice level. The variance in exception reporting according to gender and socio-economic position is low.</p> <p>Conclusions</p> <p>Although QOF seems not to be socially selective at first glance, this does not mean QOF does not contribute to the inverse care law. Introducing different targets for specific patient groups and including appropriate, non-disease specific and patient-centred indicators that grasp the complexity of primary care might refine the equity dimension of the evaluation of QOF. Also, information on the actual uptake of care, information at the patient level and monitoring of individuals' health care utilisation tracks could make large contributions to an in-depth evaluation. Finally, evaluating pay-for-quality initiatives in a broader health systems impact assessment strategy with equity as a full assessment criterion is of utmost importance.</p