Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these ...patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown.
DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m
, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP.
Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304),
=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal
=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all
values for interaction=NS).
In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.
Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the ...mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD.
•Maternal deprivation (MD) did not affect AMPAR-mediated synaptic transmission in VTA DA neurons•MD induced both pre- and postsynaptic GABAergic LTD•MD induced GABAergic metaplasticity through disruption of AKAP150 signaling•GABAergic synaptic and AKAP signaling deficits were rescued by HDAC inhibition
Childhood adversities increase the risk of later psychopathology via dopamine dysregulation. Authement et al. demonstrate that early maternal deprivation induced GABAergic metaplasticity in ventral tegmental area dopamine neurons through reversible epigenetic mechanisms that involve the scaffolding A-kinase anchoring protein (AKAP79/150).
► Core design principles that increase the efficacy of common pool resource groups can be generalized to other kinds of groups. ► The core design principles follow from the evolutionary dynamics of ...cooperation in all species and the biocultural evolution of our own species. ► The generality of the core design principles enables them to be used as a practical framework for increasing the efficacy of many kinds of groups. ► Examples are provided for classroom groups and neighborhood groups.
This article generalizes a set of core design principles for the efficacy of groups that was originally derived for groups attempting to manage common-pool resources (CPRs) such as irrigation systems, forests, and fisheries. The dominant way of thinking until recently was that commons situations invariably result in the tragedy of overuse, requiring either privatization (when possible) or top-down regulation. Based on a worldwide database of CPR groups, Ostrom proposed a set of principles that broadly captured the essential aspects of the institutional arrangements that succeeded, as contrasted to groups whose efforts failed. These principles can be generalized in two respects: first, by showing how they follow from foundational evolutionary principles; and second, by showing how they apply to a wider range of groups. The generality of the core design principles enables them to be used as a practical guide for improving the efficacy of many kinds of groups.
In preview of the special issue on “Environmental Governance for Sustainability”, this manuscript examines three key themes on governance and sustainability. Governance for sustainability, by its ...nature, requires long-enduring institutional arrangements. Given the complex adaptive systems in which governance decision-making takes place, we explore three key characteristics of successful, long-term governance. The first of these is working across scale. This includes nested institutions as well as communication and coordination both horizontally and vertically between diverse governance groups. Second, we highlight the importance of collaboration. Building on the previous point, we draw on literature from collaborative governance and co-management to emphasize how collaboration can help to build more enduring governance structures. Third, we examine the importance of adaptation and evolution in the resolution of collective action dilemmas in complex systems filled with nonlinearities, unclear causal chains, and environments in which we have less than a full understanding of the ramifications of governance actions.
The ETS family of proteins consists of 28 transcription factors, many of which have been implicated in development and progression of a variety of cancers. While one family member, ERG, has been ...rigorously studied in the context of prostate cancer where it plays a critical role, other ETS factors keep emerging as potential hallmark oncodrivers. In recent years, numerous studies have reported initial discoveries of small molecule inhibitors of ETS proteins and opened novel avenues for ETS‐directed cancer therapies. This review summarizes the state of the art data on therapeutic targeting of ETS family members and highlights the corresponding drug discovery strategies.
The framework for analyzing sustainability of social-ecological systems (SES) framework of Elinor Ostrom is a multitier collection of concepts and variables that have proven to be relevant for ...understanding outcomes in diverse SES. The first tier of this framework includes the concepts resource system (RS) and resource units (RU), which are then further characterized through lower tier variables such as clarity of system boundaries and mobility. The long-term goal of framework development is to derive conclusions about which combinations of variables explain outcomes across diverse types of SES. This will only be possible if the concepts and variables of the framework can be made operational unambiguously for the different types of SES, which, however, remains a challenge. Reasons for this are that case studies examine other types of RS than those for which the framework has been developed or consider RS for which different actors obtain different kinds of RU. We explore these difficulties and relate them to antecedent work on common-pool resources and public goods. We propose a diagnostic procedure which resolves some of these difficulties by establishing a sequence of questions that facilitate the step-wise and unambiguous application of the SES framework to a given case. The questions relate to the actors benefiting from the SES, the collective goods involved in the generation of those benefits, and the action situations in which the collective goods are provided and appropriated. We illustrate the diagnostic procedure for four case studies in the context of irrigated agriculture in New Mexico, common property meadows in the Swiss Alps, recreational fishery in Germany, and energy regions in Austria. We conclude that the current SES framework has limitations when applied to complex, multiuse SES, because it does not sufficiently capture the actor interdependencies introduced through RS and RU characteristics and dynamics.
To date, genome-wide association studies (GWAS) have identified at least 32 novel loci for obesity and body mass-related traits. However, the causal genetic variant and molecular mechanisms of ...specific susceptibility genes in relation to obesity are yet to be fully confirmed and characterised. Here, we examined whether the candidate gene NEGR1 encoding the neuronal growth regulator 1, also termed neurotractin or Kilon, accounts for the obesity association. To characterise the function of NEGR1 for body weight control in vivo, we generated two novel mutant mouse lines, including a constitutive NEGR1-deficient mouse line as well as an ENU-mutagenised line carrying a loss-of-function mutation (Negr1-I87N) and performed metabolic phenotypic analyses. Ablation of NEGR1 results in a small but steady reduction of body mass in both mutant lines, accompanied with a small reduction in body length in the Negr1-I87N mutants. Magnetic resonance scanning reveals that the reduction of body mass in Negr1-I87N mice is due to a reduced proportion of lean mass. Negr1-I87N mutants display reduced food intake and physical activity while normalised energy expenditure remains unchanged. Expression analyses confirmed the brain-specific distribution of NEGR1 including strong expression in the hypothalamus. In vitro assays show that NEGR1 promotes cell-cell adhesion and neurite growth of hypothalamic neurons. Our results indicate a role of NEGR1 in the control of body weight and food intake. This study provides evidence that supports the link of the GWAS candidate gene NEGR1 with body weight control.
Moving beyond panaceas in fisheries governance Young, Oran R.; Webster, D. G.; Cox, Michael E. ...
Proceedings of the National Academy of Sciences - PNAS,
09/2018, Letnik:
115, Številka:
37
Journal Article
Recenzirano
Odprti dostop
In fisheries management—as in environmental governance more generally—regulatory arrangements that are thought to be helpful in some contexts frequently become panaceas or, in other words, simple ...formulaic policy prescriptions believed to solve a given problem in a wide range of contexts, regardless of their actual consequences. When this happens, management is likely to fail, and negative side effects are common. We focus on the case of individual transferable quotas to explore the panacea mindset, a set of factors that promote the spread and persistence of panaceas. These include conceptual narratives that make easy answers like panaceas seem plausible, power disconnects that create vested interests in panaceas, and heuristics and biases that prevent people from accurately assessing panaceas. Analysts have suggested many approaches to avoiding panaceas, but most fail to conquer the underlying panacea mindset. Here, we suggest the codevelopment of an institutional diagnostics toolkit to distill the vast amount of information on fisheries governance into an easily accessible, open, on-line database of checklists, case studies, and related resources. Toolkits like this could be used in many governance settings to challenge users’ understandings of a policy’s impacts and help them develop solutions better tailored to their particular context. They would not replace the more comprehensive approaches found in the literature but would rather be an intermediate step away from the problem of panaceas.
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