A process-based approach to understanding and managing triggered seismicity.

There is growing concern about seismicity triggered by human activities, whereby small increases in stress bring tectonically loaded faults to failure. Examples of such activities include mining, impoundment of water, stimulation of geothermal fields, extraction of hydrocarbons and water, and the injection of water, CO2 and methane into subsurface reservoirs1. In the absence of sufficient information to understand and control the processes that trigger earthquakes, authorities have set up empirical regulatory monitoring-based frameworks with varying degrees of success2,3. Field experiments in the early 1970s at the Rangely, Colorado (USA) oil field4 suggested that seismicity might be turned on or off by cycling subsurface fluid pressure above or below a threshold. Here we report the development, testing and implementation of a multidisciplinary methodology for managing triggered seismicity using comprehensive and detailed information about the subsurface to calibrate geomechanical and earthquake source physics models. We then validate these models by comparing their predictions to subsequent observations made after calibration. We use our approach in the Val d'Agri oil field in seismically active southern Italy, demonstrating the successful management of triggered seismicity using a process-based method applied to a producing hydrocarbon field. Applying our approach elsewhere could help to manage and mitigate triggered seismicity.

Measured Oxygen Consumption During Pediatric Cardiac Catheterization is More Accurate than Assumed Oxygen Consumption.

When calculating cardiac index (C.I.) by the Fick method, oxygen consumption (VO2) is often unknown, so assumed values are typically used. This practice introduces a known source of inaccuracy into the calculation. Using a measured VO2 (mVO2) from the CARESCAPE E-sCAiOVX module provides an alternative that may improve accuracy of C.I. calculations. Our aim is to validate this measurement in a general pediatric catheterization population and compare its accuracy with assumed VO2 (aVO2). mVO2 was recorded for all patients undergoing cardiac catheterization with general anesthesia and controlled ventilation during the study period. mVO2 was compared to the reference VO2 (refVO2) determined by the reverse Fick method using cardiac MRI (cMRI) or thermodilution (TD) as a reference standard for measurement of C.I. when available. 193 VO2 measurements were obtained, including 71 with a corresponding cMRI or TD measure of cardiac index for validation. mVO2 demonstrated satisfactory concordance and correlation with the TD- or cMRI-derived refVO2 (ρc = 0.73, r2 = 0.63) with a mean bias of - 3.2% (SD ± 17.3%). Assumed VO2 demonstrated much weaker concordance and correlation with refVO2 (ρc = 0.28, r2 = 0.31) with a mean bias of + 27.5% (SD ± 30.0%). Subgroup analysis of patients < 36 months of age demonstrated that error in mVO2 was not significantly different from that observed in older patients. Many previously reported prediction models for assuming VO2 performed poorly in this younger age range. Measured oxygen consumption using the E-sCAiOVX module is significantly more accurate than assumed VO2 when compared to TD- or cMRI-derived VO2 in a pediatric catheterization lab.

Intrinsic DNA binding properties demonstrated for lineage-specifying basic helix-loop-helix transcription factors.

During development, transcription factors select distinct gene programs, providing the necessary regulatory complexity for temporal and tissue-specific gene expression. How related factors retain specificity, especially when they recognize the same DNA motifs, is not understood. We address this paradox using basic helix-loop-helix (bHLH) transcription factors ASCL1, ASCL2, and MYOD1, crucial mediators of lineage specification. In vivo, these factors recognize the same DNA motifs, yet bind largely different genomic sites and regulate distinct transcriptional programs. This suggests that their ability to identify regulatory targets is defined either by the cellular environment of the partially defined lineages in which they are endogenously expressed, or by intrinsic properties of the factors themselves. To distinguish between these mechanisms, we directly compared the chromatin binding properties of this subset of bHLH factors when ectopically expressed in embryonic stem cells, presenting them with a common chromatin landscape and cellular components. We find that these factors retain distinct binding sites; thus, specificity of binding is an intrinsic property not requiring a restricted landscape or lineage-specific cofactors. Although the ASCL factors and MYOD1 have some distinct DNA motif preference, it is not sufficient to explain the extent of the differential binding. All three factors can bind inaccessible chromatin and induce changes in chromatin accessibility and H3K27ac. A reiterated pattern of DNA binding motifs is uniquely enriched in inaccessible chromatin at sites bound by these bHLH factors. These combined properties define a subclass of lineage-specific bHLH factors and provide context for their central roles in development and disease.

Smek promotes corticogenesis through regulating Mbd3's stability and Mbd3/NuRD complex recruitment to genes associated with neurogenesis.

The fate of neural progenitor cells (NPCs) during corticogenesis is determined by a complex interplay of genetic or epigenetic components, but the underlying mechanism is incompletely understood. Here, we demonstrate that Suppressor of Mek null (Smek) interact with methyl-CpG-binding domain 3 (Mbd3) and the complex plays a critical role in self-renewal and neuronal differentiation of NPCs. We found that Smek promotes Mbd3 polyubiquitylation and degradation, blocking recruitment of the repressive Mbd3/nucleosome remodeling and deacetylase (NuRD) complex at the neurogenesis-associated gene loci, and, as a consequence, increasing acetyl histone H3 activity and cortical neurogenesis. Furthermore, overexpression of Mbd3 significantly blocked neuronal differentiation of NPCs, and Mbd3 depletion rescued neurogenesis defects seen in Smek1/2 knockout mice. These results reveal a novel molecular mechanism underlying Smek/Mbd3/NuRD axis-mediated control of NPCs' self-renewal and neuronal differentiation during mammalian corticogenesis.

International bull evaluations by genomic BLUP with a prediction population.

The purpose of this study was to determine whether multi-country genomic evaluation can be accomplished by multiple-trait genomic best linear unbiased predictor (GBLUP) without sharing genotypes of important animals. Phenotypes and genotypes with 40k SNP were simulated for 25,000 animals, each with 4 traits assuming the same genetic variance and 0.8 genetic correlations. The population was split into 4 subpopulations corresponding to 4 countries, one for each trait. Additionally, a prediction population was created from genotyped animals that were not present in the individual countries but were related to each country's population. Genomic estimated breeding values were computed for each country and subsequently converted to SNP effects. Phenotypes were reconstructed for the prediction population based on the SNP effects of a country and the prediction animals' genotypes. The prediction population was used as the basis for the international evaluation, enabling bull comparisons without sharing genotypes and only sharing SNP effects. The computations were such that SNP effects computed within-country or in the prediction population were the same. Genomic estimated breeding values were calculated by single-trait GBLUP for within-country and multiple-trait GBLUP for multi-country predictions. The true accuracy for the prediction population with reconstructed phenotypes was at most 0.02 less than the accuracy with the original data. The differences increased when countries were assumed unequally sized. However, accuracies by multiple-trait GBLUP with the prediction population were always greater than accuracies from any single within-country prediction. Multi-country genomic evaluations by multiple-trait GBLUP are possible without using original genotypes at a cost of lower accuracy compared with explicitly combining countries' data.

Modeling pedigree accuracy and uncertain parentage in single-step genomic evaluations of simulated and US Holstein datasets.

The objective of this study was to model differences in pedigree accuracy caused by selective genotyping. As genotypes are used to correct pedigree errors, some pedigree relationships are more accurate than others. These accuracy differences can be modeled with uncertain parentage models that distribute the paternal (maternal) contribution across multiple sires (dams). In our case, the parents were the parent on record and an unknown parent group to account for pedigree relationships that were not confirmed through genotypes. Pedigree accuracy was addressed through simulation and through North American Holstein data. Data were simulated to be representative of the dairy industry with heterogeneous pedigree depth, pedigree accuracy, and genotyping. Holstein data were obtained from the official evaluation for milk, fat, and protein. Two models were compared: the traditional approach, assuming accurate pedigrees, and uncertain parentage, assuming variable pedigree accuracy. The uncertain parentage model was used to add pedigree relationships for alternative parents when pedigree relationships were not certain. The uncertain parentage model included 2 possible sires (dams) when the sire (dam) could not be confirmed with genotypes. The 2 sires (dams) were the sire (dam) on record with probability 0.90 (0.95) and the unknown parent group for the birth year of the sire (dam) with probability 0.10 (0.05). An additional set of assumptions was tested in simulation to mimic an extensive dairy production system by using a sire probability of 0.75, a dam probability of 0.85, and the remainder attributed to the unknown parent groups. In the simulation, small bias differences occurred between models based on pedigree accuracy and genotype status. Rank correlations were strong between traditional and uncertain parentage models in simulation (≥0.99) and in Holstein (≥0.99). For Holsteins, the estimated breeding value differences between models were small for most animals. Thus, traditional models can continue to be used for dairy genomic prediction despite using genotypes to improve pedigree accuracy. Those genotypes can also be used to discover maternal parentage, specifically maternal grandsires and great grandsires when the dam is not known. More research is needed to understand how to use discovered maternal pedigrees in genetic prediction.

Modeling missing pedigree in single-step genomic BLUP.

The objective was to compare methods of modeling missing pedigree in single-step genomic BLUP (ssGBLUP). Options for modeling missing pedigree included ignoring the missing pedigree, unknown parent groups (UPG) based on A (the numerator relationship matrix) or H (the unified pedigree and genomic relationship matrix), and metafounders. The assumptions for the distribution of estimated breeding values changed with the different models. We simulated data with heritabilities of 0.3 and 0.1 for dairy cattle populations that had more missing pedigrees for animals of lesser genetic merit. Predictions for the youngest generation and UPG solutions were compared with the true values for validation. For both traits, ssGBLUP with metafounders provided accurate and unbiased predictions for young animals while also appropriately accounting for genetic trend. Accuracy was least and bias was greatest for ssGBLUP with UPG for H for the trait with heritability of 0.3 and with UPG for A for the trait with heritability of 0.1. For the trait with heritability of 0.1 and UPG for H, the UPG accuracy (SD) was -0.49 (0.12), suggesting poor estimates of genetic trend despite having little bias for validations on young, genotyped animals. Problems with UPG estimates were likely caused by the lesser amount of information available for the lower heritability trait. Hence, UPG need to be defined differently based on the trait and amount of information. More research is needed to investigate accounting for UPG in A22 to better account for missing pedigrees for genotyped animals.

Selection of core animals in the Algorithm for Proven and Young using a simulation model.

The Algorithm for Proven and Young (APY) enables the implementation of single-step genomic BLUP (ssGBLUP) in large, genotyped populations by separating genotyped animals into core and non-core subsets and creating a computationally efficient inverse for the genomic relationship matrix (G). As APY became the choice for large-scale genomic evaluations in BLUP-based methods, a common question is how to choose the animals in the core subset. We compared several core definitions to answer this question. Simulations comprised a moderately heritable trait for 95,010 animals and 50,000 genotypes for animals across five generations. Genotypes consisted of 25,500 SNP distributed across 15 chromosomes. Genotyping errors and missing pedigree were also mimicked. Core animals were defined based on individual generations, equal representation across generations, and at random. For a sufficiently large core size, core definitions had the same accuracies and biases, even if the core animals had imperfect genotypes. When genotyped animals had unknown parents, accuracy and bias were significantly better (p ≤ .05) for random and across generation core definitions.

Implications of SNP weighting on single-step genomic predictions for different reference population sizes.

We investigated the importance of SNP weighting in populations with 2,000 to 25,000 genotyped animals. Populations were simulated with two effective sizes (20 or 100) and three numbers of QTL (10, 50 or 500). Pedigree information was available for six generations; phenotypes were recorded for the four middle generations. Animals from the last three generations were genotyped for 45,000 SNP. Single-step genomic BLUP (ssGBLUP) and weighted ssGBLUP (WssGBLUP) were used to estimate genomic EBV using a genomic relationship matrix (G). The WssGBLUP performed better in small genotyped populations; however, any advantage for WssGBLUP was reduced or eliminated when more animals were genotyped. WssGBLUP had greater resolution for genome-wide association (GWA) as did increasing the number of genotyped animals. For few QTL, accuracy was greater for WssGBLUP than ssGBLUP; however, for many QTL, accuracy was the same for both methods. The largest genotyped set was used to assess the dimensionality of genomic information (number of effective SNP). The number of effective SNP was considerably less in weighted G than in unweighted G. Once the number of independent SNP is well represented in the genotyped population, the impact of SNP weighting becomes less important.

Bringing the Social Sciences to Health Policy: An Appreciation of David Mechanic.

David Mechanic has been a pioneering leader in the social and behavioral sciences of health, health services, and health and mental health policy for more than fifty years. One of David's most distinctive qualities has been his vision in identifying trends and defining new research areas and perspectives in health care policy. His early work on how methods of physician payment by capitation and fee-for-service in England and the United States affected physicians' responses to patients and patient care addressed present challenges and many ongoing studies of payment mechanisms. His papers on rationing of health care established a framework for examining alternative allocation mechanisms and just decision making. Influential papers dealt with risk selection, policy challenges in managed care, reducing racial disparities, trust relationships between patients, doctors, and the public and health institutions, and the predicaments of health reform. Focusing on the implementation of the Affordable Care Act, David explored its opportunities and challenges especially in providing comprehensive and effective behavioral health services. A hallmark of his work has been his redirecting our attention to the most severely ill and those in greatest need. Less visible is the leadership and institution building endeavors and the many honors David has received.

Incomplete Markets and Imperfect Institutions: Some Challenges Posed by Trust for Contemporary Health Care and Health Policy.

As contemporary health policy promotes evidence-based practices using targeted incentives, policy makers may lose track of vital aspects of care that are difficult to measure. For more than a half century, scholars have recognized that these latter aspects play a crucial role in high-quality care and equitable health system performance but depend on the potentially frail reed of providers' trustworthiness: that is, their commitment to facets and outcomes of care not easily assessed by external parties. More recently, early experience with pay for performance in health settings suggests that enhancing financial rewards for the measurable undermines providers' commitment to the unmeasurable, degrading the trustworthiness of their practices. Reformers have looked to revised professional norms or reorganized practice arrangements to bolster the intrinsic motivations required for trustworthiness. We suggest here that these responses are likely to prove inadequate. We propose that they be complemented by a renewed policy-making commitment to nonprofit ownership among health care providers, insurers, and integrated delivery systems. We identify some of the concerns raised in the past with ownership-based policies and propose a set of responses. If these are pursued in combination, they hold the promise of a sustainable ownership-based policy reform for the United States.

Health care for undocumented migrants: European approaches.

European countries have smaller shares of undocumented migrants than does the United States, but these individuals have substantial needs for medical care and present difficult policy challenges even in countries with universal health insurance systems. Recent European studies show that policies in most countries provide for no more than emergency services for undocumented migrants. Smaller numbers of countries provide more services or allow undocumented migrants who meet certain requirements access to the same range of services as nationals. These experiences show it is possible to improve access to care for undoc­umented migrants. Strategies vary along three dimensions: (1) focusing on segments of the population, like children or pregnant women; (2) focusing on types of services, like preventive services or treatment of infectious diseases; or (3) using specific funding policies, like allowing undocumented migrants to purchase insurance.

The Influence of Gender Categories and Gender Stereotypes on Young Children's Generalizations of Biological and Behavioral Characteristics.

We examined the influence of categorization and stereotyping on young children's (N = 96; 39 to 71 months of age) use of gender to make generalizations regarding novel biological and behavioral characteristics. Participants were asked to sort pictures of children according to either gender, common gender stereotypes, or shirt color. Then participants performed a triad inductive reasoning task. Children in the Stereotype condition consistently generalized on the basis of gender, but performance was inconsistent in the absence of stereotyping. Results are discussed in relation to variability in early gender cognition.

England's approach to improving end-of-life care: a strategy for honoring patients' choices.

In the U.S. health care system, and in those of many other countries, the care of dying patients is generally not performed well, with pain and other distress frequently undertreated and patients' preferences not respected. England's evidence-based End of Life Care Strategy could prove instructive. This issue brief discusses the origins, content, and implementation of the Strategy, as well as its potential impact. Both England and the United States struggle with similar challenges, including looking beyond the province of hospice and palliative-care specialists and initiating palliative services before the patient's final days. Aspects of the English approach that may be useful in the United States include strategies to help physicians recognize when patients are entering a trajectory that may end in death, the use of "death at home" as a metric for measuring progress, improving the skills of clinical and caregiving personnel through Web-based training, and developing a national improvement pathway.

Electronic health records: an international perspective on "meaningful use".

Research has shown that the United States lags many other countries in the adoption of electronic health records (EHRs). The U.S. has now embarked on a major effort to achieve "meaningful use" of health information technology by clinicians and hospitals. This issue brief describes the extent of meaningful use in three countries with very high levels of health information technology adoption­Denmark, New Zealand, and Sweden. While all three have achieved high levels of meaningful use, none has reached 100 percent in all categories. The brief find[sic] high levels of meaningful use for EHR items and substantial information-sharing with other organizations or health authorities, although less information is shared with patients. Insights that may prove useful to the United States include providing economic incentives to encourage adoption and designating an organization to take responsibility for standardization and interoperability.

Use of Virtual Reality for Pediatric Cardiac Critical Care Simulation.

Simulation is a key component of training in the pediatric cardiac intensive care unit (CICU), a complex environment that lends itself to virtual reality (VR)-based simulations. However, VR has not been previously described for this purpose. Two simulations were developed to test the use of VR in simulating pediatric CICU clinical scenarios, one simulating junctional ectopic tachycardia and low cardiac output syndrome, and the other simulating acute respiratory failure in a patient with suspected coronavirus disease 2019. Six attending pediatric cardiac critical care physicians were recruited to participate in the simulations as a pilot test of VR's feasibility for educational and practice improvement efforts in this highly specialized clinical environment. All participants successfully navigated the VR environment and met the critical endpoints of the two clinical scenarios. Qualitative feedback was overall positive with some specific critiques regarding limited realism in some mechanical aspects of the simulation. This is the first described use of VR in pediatric cardiac critical care simulation.

Age-related changes in children's and adults' explanations of interpersonal actions.

We investigated the content of children's and adults' explanations of interpersonal actions. Participants were 5-, 7-, and 9-year-old children, as well as adults, who were presented with 8 stories containing either prosocial or antisocial target actions, and asked to explain why each actor performed that action. In half of the stories, an interpersonal event preceded the action. Children and adults provided situational and mental-state explanations, but mental-state explanations were especially common for antisocial actions not preceded by an interpersonal event. With increasing age, participants explained prosocial actions by referring to the actor's goals, but referred to the actor's emotions and beliefs to explain antisocial actions. Finally, adults were most likely to mention psychological goals. These results suggest that (a) elementary school children provide a variety of explanations for interpersonal events; (b) children use different types of explanations flexibly, depending on the context and nature of the target action; (c) the frequency of different types of explanations for interpersonal actions changes during childhood; and (d) between middle childhood and adulthood, the recognition of psychological goals increases greatly.

Children's and adults' judgments of the certainty of deductive inferences, inductive inferences, and guesses.

Children and adults rated their own certainty following inductive inferences, deductive inferences, and guesses. Beginning in kindergarten, participants rated deductions as more certain than weak inductions or guesses. Deductions were rated as more certain than strong inductions beginning in Grade 3, and fourth-grade children and adults differentiated strong inductions, weak inductions, and informed guesses from pure guesses. By Grade 3, participants also gave different types of explanations for their deductions and inductions. These results are discussed in relation to children's concepts of cognitive processes, logical reasoning, and epistemological development.

Does it all add up?

Flaws in Schedule H community benefit reporting will affect systems.