York University

Stan is a probabilistic programming language for specifying statistical models. A Stan program imperatively defines a log probability function over parameters conditioned on specified data and constants. As of version 2.14.0, Stan provides full Bayesian inference for continuous-variable models through Markov chain Monte Carlo methods such as the No-U-Turn sampler, an adaptive form of Hamiltonian Monte Carlo sampling. Penalized maximum likelihood estimates are calculated using optimization methods such as the limited memory Broyden-Fletcher-Goldfarb-Shanno algorithm. Stan is also a platform for computing log densities and their gradients and Hessians, which can be used in alternative algorithms such as variational Bayes, expectation propagation, and marginal inference using approximate integration. To this end, Stan is set up so that the densities, gradients, and Hessians, along with intermediate quantities of the algorithm such as acceptance probabilities, are easily accessible. Stan can be called from the command line using the cmdstan package, through R using the rstan package, and through Python using the pystan package. All three interfaces support sampling and optimization-based inference with diagnostics and posterior analysis. rstan and pystan also provide access to log probabilities, gradients, Hessians, parameter transforms, and specialized plotting.

In 2008 we published the fi rst set of guidelines for standardiz- ing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the fi eld. Our knowledge base and relevant new tech- nologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in differ- ent organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between meas urements that monitor the num- bers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the com- plete process including the amoun t and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accu mulation must be differentiated from stimuli that increas e autophagic activity, de fi ned as increased autophagy induction coupled with in creased delivery to, and degra- dation within, lysosomes (in most higher eukaryotes and some pro- tists such as Dictyostelium ) or the vacuole (in plants and fungi). In otherwords,itisespeciallyimportantthatinvestigatorsnewtothe fi eld understand that the appearance of more autophagosomes does not necessarily equate with mo re autophagy. In fact, in many cases, autophagosomes accumu late because of a block in traf fi cking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may re fl ect a reductionindegradativeactivity .Itisworthemphasizingherethat lysosomal digestion is a stage of au tophagy and evaluating its com- petence is a crucial part of the evaluation of autophagic fl ux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appro- priate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no indi- vidual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy- related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a speci fi c marker for an autophagic process. In these guidelines, we con- sider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the fi eld

This paper describes the Seventh Data Release of the Sloan Digital Sky Survey (SDSS), marking the completion of the original goals of the SDSS and the end of the phase known as SDSS-II. It includes 11,663 deg 2 of imaging data, with most of the ∼2000 deg 2 increment over the previous data release lying in regions of low Galactic latitude. The catalog contains five-band photometry for 357 million distinct objects. The survey also includes repeat photometry on a 120° long, 2 5 wide stripe along the celestial equator in the Southern Galactic Cap, with some regions covered by as many as 90 individual imaging runs. We include a co-addition of the best of these data, going roughly 2 mag fainter than the main survey over 250 deg 2 . The survey has completed spectroscopy over 9380 deg 2 ; the spectroscopy is now complete over a large contiguous area of the Northern Galactic Cap, closing the gap that was present in previous data releases. There are over 1.6 million spectra in total, including 930,000 galaxies, 120,000 quasars, and 460,000 stars. The data release includes improved stellar photometry at low Galactic latitude. The astrometry has all been recalibrated with the second version of the USNO CCD Astrograph Catalog, reducing the rms statistical errors at the bright end to 45 milliarcseconds per coordinate. We further quantify a systematic error in bright galaxy photometry due to poor sky determination; this problem is less severe than previously reported for the majority of galaxies. Finally, we describe a series of improvements to the spectroscopic reductions, including better flat fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities.

MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. The majority of miRNAs are transcribed from DNA sequences into primary miRNAs and processed into precursor miRNAs, and finally mature miRNAs. In most cases, miRNAs interact with the 3' untranslated region (3' UTR) of target mRNAs to induce mRNA degradation and translational repression. However, interaction of miRNAs with other regions, including the 5' UTR, coding sequence, and gene promoters, have also been reported. Under certain conditions, miRNAs can also activate translation or regulate transcription. The interaction of miRNAs with their target genes is dynamic and dependent on many factors, such as subcellular location of miRNAs, the abundancy of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. miRNAs can be secreted into extracellular fluids and transported to target cells via vesicles, such as exosomes, or by binding to proteins, including Argonautes. Extracellular miRNAs function as chemical messengers to mediate cell-cell communication. In this review, we provide an update on canonical and non-canonical miRNA biogenesis pathways and various mechanisms underlying miRNA-mediated gene regulations. We also summarize the current knowledge of the dynamics of miRNA action and of the secretion, transfer, and uptake of extracellular miRNAs.

Firms compete for reputational status in institutional fields. Managers attempt to influence other stakeholders' assessments by signaling firms' salient advantages. Stakeholders gauge firms' relati...

BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

The development and validation of a new measure, the Eating Disorder Inventory (EDI) is described. The EDI is a 64 item, self-report, multiscale measure designed for the assessment of psychological and behavioral traits common in anorexia nervosa (AN) and bulimia. The EDI consists of eight sub-scales measuring: 1) Drive for Thinness, 2) Bulimia, 3) Body Dissatisfaction, 4) Ineffectiveness, 5) Perfectionism, 6) Interpersonal Distrust, 7) Interoceptive Awareness and 8) Maturity Fears. Reliability (internal consistency) is established for all subscales and several indices of validity are presented. First, AN patients (N = 113) are differentiated from female comparison (FC) subjects (N = 577) using a cross-validation procedure. Secondly, patient self-report subscale scores agree with clinician ratings of subscale traits. Thirdly, clinically recovered AN patients score similarly to FCs on all subscales. Finally, convergent and discriminate validity are established for subscales. The EDI was also administered to groups of normal weight bulimic women, obese, and normal weight but formerly obese women, as well as a male comparison group. Group differences are reported and the potential utility of the EDI is discussed.

Abstract Deliberate and emergent strategies may be conceived as two ends of a continuum along which real‐world strategies lie. This paper seeks to develop this notion, and some basic issues related to strategic choice, by elaborating along this continuum various types of strategies uncovered in research. These include strategies labelled planned, entrepreneurial, ideological, umbrella, process, unconnected, consensus and imposed.

The Kepler mission was designed to determine the frequency of Earth-sized planets in and near the habitable zone of Sun-like stars. The habitable zone is the region where planetary temperatures are suitable for water to exist on a planet's surface. During the first 6 weeks of observations, Kepler monitored 156,000 stars, and five new exoplanets with sizes between 0.37 and 1.6 Jupiter radii and orbital periods from 3.2 to 4.9 days were discovered. The density of the Neptune-sized Kepler-4b is similar to that of Neptune and GJ 436b, even though the irradiation level is 800,000 times higher. Kepler-7b is one of the lowest-density planets (approximately 0.17 gram per cubic centimeter) yet detected. Kepler-5b, -6b, and -8b confirm the existence of planets with densities lower than those predicted for gas giant planets.

BACKGROUND: Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity are not known. METHODS: In this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary end points were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population. RESULTS: At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was -15.0% (95% confidence interval [CI], -15.9 to -14.2) with 5-mg weekly doses of tirzepatide, -19.5% (95% CI, -20.4 to -18.5) with 10-mg doses, and -20.9% (95% CI, -21.8 to -19.9) with 15-mg doses and -3.1% (95% CI, -4.3 to -1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with tirzepatide. The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively. CONCLUSIONS: In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. (Supported by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).

The adoption and maintenance of physical activity are critical foci for blood glucose management and overall health in individuals with diabetes and prediabetes. Recommendations and precautions vary depending on individual characteristics and health status. In this Position Statement, we provide a clinically oriented review and evidence-based recommendations regarding physical activity and exercise in people with type 1 diabetes, type 2 diabetes, gestational diabetes mellitus, and prediabetes. Physical activity includes all movement that increases energy use, whereas exercise is planned, structured physical activity. Exercise improves blood glucose control in type 2 diabetes, reduces cardiovascular risk factors, contributes to weight loss, and improves well-being (1,2). Regular exercise may prevent or delay type 2 diabetes development (3). Regular exercise also has considerable health benefits for people with type 1 diabetes (e.g., improved cardiovascular fitness, muscle strength, insulin sensitivity, etc.) (4). The challenges related to blood glucose management vary with diabetes type, activity type, and presence of diabetes-related complications (5,6). Physical activity and exercise recommendations, therefore, should be tailored to meet the specific needs of each individual.

Academic conventions divide up the seamless web of the real social world into separate spheres, each with its own theorising; this is a necessary and practical way of gaining understanding. Subdivisions of social knowledge thus may roughly correspond to the ways in which human affairs are organised in particular times and places. E. H. Carr and Eric Hobsbawm have both been sensitive to the continuities between social forces, the changing nature of the state and global relationships. Critical theory is directed to the social and political complex as a whole rather than to the separate parts. Critical theory allows for a normative choice in favour of a social and political order different from the prevailing order, but it limits the range of choice to alternative orders which are feasible transformations of the existing world. The common rationality of neo-realism arises from its polemic with liberal internationalism.

This article suggests that the context and process of resource selection have an important influence on firm heterogeneity and sustainable competitive advantage. It is argued that a firm’s sustainable advantage depends on its ability to manage the institutional context of its resource decisions. A firm’s institutional context includes its internal culture as well as broader influences from the state, society, and interfirm relations that define socially acceptable economic behavior. A process model of firm heterogeneity is proposed that combines the insights of a resource-based view with the institutional perspective from organization theory. Normative rationality, institutional isolating mechanisms, and institutional sources of firm homogeneity are proposed as determinants of rent potential that complement and extend resource-based explanations of firm variation and sustainable competitive advantage. The article suggests that both resource capital and institutional capital are indispensable to sustainable competitive advantage. © 1997 John Wiley & Sons, Ltd.

BACKGROUND: Electronic health resources are helpful only when people are able to use them, yet there remain few tools available to assess consumers' capacity for engaging in eHealth. Over 40% of US and Canadian adults have low basic literacy levels, suggesting that eHealth resources are likely to be inaccessible to large segments of the population. Using information technology for health requires eHealth literacy-the ability to read, use computers, search for information, understand health information, and put it into context. The eHealth Literacy Scale (eHEALS) was designed (1) to assess consumers' perceived skills at using information technology for health and (2) to aid in determining the fit between eHealth programs and consumers. OBJECTIVES: The eHEALS is an 8-item measure of eHealth literacy developed to measure consumers' combined knowledge, comfort, and perceived skills at finding, evaluating, and applying electronic health information to health problems. The objective of the study was to psychometrically evaluate the properties of the eHEALS within a population context. A youth population was chosen as the focus for the initial development primarily because they have high levels of eHealth use and familiarity with information technology tools. METHODS: Data were collected at baseline, post-intervention, and 3- and 6-month follow-up using control group data as part of a single session, randomized intervention trial evaluating Web-based eHealth programs. Scale reliability was tested using item analysis for internal consistency (coefficient alpha) and test-retest reliability estimates. Principal components factor analysis was used to determine the theoretical fit of the measures with the data. RESULTS: A total of 664 participants (370 boys; 294 girls) aged 13 to 21 (mean = 14.95; SD = 1.24) completed the eHEALS at four time points over 6 months. Item analysis was performed on the 8-item scale at baseline, producing a tight fitting scale with alpha = .88. Item-scale correlations ranged from r = .51 to .76. Test-retest reliability showed modest stability over time from baseline to 6-month follow-up (r = .68 to .40). Principal components analysis produced a single factor solution (56% of variance). Factor loadings ranged from .60 to .84 among the 8 items. CONCLUSIONS: The eHEALS reliably and consistently captures the eHealth literacy concept in repeated administrations, showing promise as tool for assessing consumer comfort and skill in using information technology for health. Within a clinical environment, the eHEALS has the potential to serve as a means of identifying those who may or may not benefit from referrals to an eHealth intervention or resource. Further research needs to examine the applicability of the eHEALS to other populations and settings while exploring the relationship between eHealth literacy and health care outcomes.

Information systems researchers have a long tradition of drawing on theories from disciplines such as economics, computer science, psychology, and general management and using them in their own research. Because of this, the information systems field has become a rich tapestry of theoretical and conceptual foundations. As new theories are brought into the field, particularly theories that have become dominant in other areas, there may be a benefit in pausing to assess their use and contribution in an IS context. The purpose of this paper is to explore and critically evaluate use of the resource-based view of the firm (RBV) by IS researchers. The paper provides a brief review of resource-based theory and then suggests extensions to make the RBV more useful for empirical IS research. First, a typology of key IS resources is presented, and these are then described using six traditional resource attributes. Second, we emphasize the particular importance of looking at both resource complementarity and moderating factors when studying IS resource effects on firm performance. Finally, we discuss three considerations that IS researchers need to address when using the RBV empirically. Eight sets of propositions are advanced to help guide future research.

BACKGROUND: The magnitude, consistency, and manner of association between sedentary time and outcomes independent of physical activity remain unclear. PURPOSE: To quantify the association between sedentary time and hospitalizations, all-cause mortality, cardiovascular disease, diabetes, and cancer in adults independent of physical activity. DATA SOURCES: English-language studies in MEDLINE, PubMed, EMBASE, CINAHL, Cochrane Library, Web of Knowledge, and Google Scholar databases were searched through August 2014 with hand-searching of in-text citations and no publication date limitations. STUDY SELECTION: Studies assessing sedentary behavior in adults, adjusted for physical activity and correlated to at least 1 outcome. DATA EXTRACTION: Two independent reviewers performed data abstraction and quality assessment, and a third reviewer resolved inconsistencies. DATA SYNTHESIS: Forty-seven articles met our eligibility criteria. Meta-analyses were performed on outcomes for cardiovascular disease and diabetes (14 studies), cancer (14 studies), and all-cause mortality (13 studies). Prospective cohort designs were used in all but 3 studies; sedentary times were quantified using self-report in all but 1 study. Significant hazard ratio (HR) associations were found with all-cause mortality (HR, 1.240 [95% CI, 1.090 to 1.410]), cardiovascular disease mortality (HR, 1.179 [CI, 1.106 to 1.257]), cardiovascular disease incidence (HR, 1.143 [CI, 1.002 to 1.729]), cancer mortality (HR, 1.173 [CI, 1.108 to 1.242]), cancer incidence (HR, 1.130 [CI, 1.053 to 1.213]), and type 2 diabetes incidence (HR, 1.910 [CI, 1.642 to 2.222]). Hazard ratios associated with sedentary time and outcomes were generally more pronounced at lower levels of physical activity than at higher levels. LIMITATION: There was marked heterogeneity in research designs and the assessment of sedentary time and physical activity. CONCLUSION: Prolonged sedentary time was independently associated with deleterious health outcomes regardless of physical activity. PRIMARY FUNDING SOURCE: None.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Researchers are increasingly using the standardized difference to compare the distribution of baseline covariates between treatment groups in observational studies. Standardized differences were initially developed in the context of comparing the mean of continuous variables between two groups. However, in medical research, many baseline covariates are dichotomous. In this article, we explore the utility and interpretation of the standardized difference for comparing the prevalence of dichotomous variables between two groups. We examined the relationship between the standardized difference, and the maximal difference in the prevalence of the binary variable between two groups, the relative risk relating the prevalence of the binary variable in one group compared to the prevalence in the other group, and the phi coefficient for measuring correlation between the treatment group and the binary variable. We found that a standardized difference of 10% (or 0.1) is equivalent to having a phi coefficient of 0.05 (indicating negligible correlation) for the correlation between treatment group and the binary variable.

The neurocognitive literature on test performance in schizophrenia is reviewed quantitatively. The authors report 22 mean effect sizes from 204 studies to index schizophrenia versus control differences in global and selective verbal memory, nonverbal memory, bilateral and unilateral motor performance, visual and auditory attention, general intelligence, spatial ability, executive function, language, and interhemispheric tactile-transfer test performance. Moderate to large raw effect sizes (d > .60) were obtained for all 22 neurocognitive test variables, and none of the associated confidence intervals included zero. The results indicate that schizophrenia is characterized by a broadly based cognitive impairment, with varying degrees of deficit in all ability domains measured by standard clinical tests.

Recently, the hybrid deep neural network (DNN)-hidden Markov model (HMM) has been shown to significantly improve speech recognition performance over the conventional Gaussian mixture model (GMM)-HMM. The performance improvement is partially attributed to the ability of the DNN to model complex correlations in speech features. In this paper, we show that further error rate reduction can be obtained by using convolutional neural networks (CNNs). We first present a concise description of the basic CNN and explain how it can be used for speech recognition. We further propose a limited-weight-sharing scheme that can better model speech features. The special structure such as local connectivity, weight sharing, and pooling in CNNs exhibits some degree of invariance to small shifts of speech features along the frequency axis, which is important to deal with speaker and environment variations. Experimental results show that CNNs reduce the error rate by 6%-10% compared with DNNs on the TIMIT phone recognition and the voice search large vocabulary speech recognition tasks.