Environmental decision-makers and practitioners need and deserve high-quality environmental evidence for effective decision-making. We collate and share a suite of best practices for applied ...environmental researchers to support their capacity to inform such decision-making processes. This raises a number of important questions: What does “relevant” and informative evidence look like? How do we know when evidence has been applied? We assembled an experienced team of knowledge generators and users in Canada to identify insights that have emerged from their work and that could serve as guideposts for others who seek to apply environmental research to policy challenges. By reflecting on successes and failures, we define “success” in applied environmental science as respectfully conducted, partner-relevant research that is accessible, understandable, and shared and that can create opportunities for change (e.g., in policy, behaviour, management). Next, we generated a list of best practices for delivering “successful” applied environmental research. Our guidance emphasizes the importance of engaging early and often, in a respectful manner, with partners, generating high-quality, relevant research (which requires flexibility), having a plan for communicating and sharing outputs, and being transparent about uncertainties and limitations. Other important considerations include acknowledging partners for involvement and training early career researchers in applied partnership research. Finally, we generated a list of specific, measurable indicators for evaluating success, including quality and quantity of scientific outputs, the relationship with the partner(s), relevance and connectedness of the research, accessibility and availability of outputs to users, provision of outputs that are digestible and usable by different audiences,training and capacity building, and ultimate outcomes (e.g., including social, environmental, and economic outcomes, as well as partner satisfaction). We encourage those embarking on applied environmental research to consider embracing the strategies, to continuously reflect on progress toward shared research goals, and to be flexible. Doing so will increase the likelihood of delivering research that is “successful” and in doing so contribute to overcoming and addressing environmental issues and problems.
Les décideurs et les praticiens de l’environnement ont besoin de données environnementales de haute qualité pour prendre des décisions efficaces et ils le méritent. Les auteurs colligent et partagent un ensemble des meilleures pratiques à l’intention des personnes qui réalisent de la recherche appliquée en environnement afin de soutenir leur capacité à éclairer la prise de décisions. Cela soulève un certain nombre de questions importantes. À quoi ressemblent une preuve « pertinente » et informative? Quand savons-nous qu’une preuve a été appliquée? Ils ont réuni une équipe expérimentée de producteurs et d’utilisateurs de connaissances au Canada afin d’identifier les idées qui ont émané de leurs travaux et qui pourraient servir de guide à d’autres qui cherchent à appliquer la recherche environnementale aux enjeux politiques. En réfléchissant sur les succès et les échecs, les auteurs définissent la notion de « succès » en science environnementale appliquée comme étant une recherche respectueuse, pertinente pour les partenaires, accessible, compréhensible et partagée, et qui peut créer des occasions de changement (par exemple en matière de politique, de comportement, de gestion). Ils ont ensuite établi une liste des meilleures pratiques pour mener à bien une recherche environnementale appliquée « réussie ». Leurs orientations soulignent l’importance de s’engager tôt et souvent, de manière respectueuse, avec les partenaires, de générer une recherche de haute qualité et pertinente (ce qui nécessite de la flexibilité), d’avoir un plan de communication et de partage des résultats, et d’être transparent sur les incertitudes et les limites. D’autres considérations importantes comprennent la reconnaissance des partenaires pour leur participation et la formation des chercheurs en début de carrière à la recherche appliquée en partenariat. Enfin, ils ont établi une liste d’indicateurs spécifiques et mesurables pour évaluer la réussite, dont : la qualité et la quantité des résultats scientifiques, la relation avec le ou les partenaires, la pertinence et la connectivité de la recherche, l’accessibilité et la disponibilité des résultats pour les utilisateurs, la diffusion de résultats digestes et utilisables par différents publics, la formation et le renforcement des capacités, et les résultats finaux (y compris les résultats sociaux, environnementaux et économiques, ainsi que la satisfaction des partenaires). Les auteurs encouragent les personnes qui se lancent dans la recherche environnementale appliquée à envisager d’adopter ces stratégies, à réfléchir en permanence aux progrès réalisés vers des objectifs de recherche communs et à faire preuve de souplesse. Cela augmentera la probabilité de mener des recherches « fructueuses » et, ce faisant, contribuera à surmonter et à traiter les questions et les problèmes environnementaux.
The 4‐anilinoquinoline and 4‐anilinoquinazoline ring systems have been the focus of significant efforts in prior kinase drug discovery programs, which have led to approved medicines. Broad kinome ...profiles of these compounds have now been assessed with the advent of advanced screening technologies. These ring systems, while originally designed for specific targets including epidermal growth factor receptor (EGFR), but actually display a number of potent collateral kinase targets, some of which have been associated with negative clinical outcomes. We have designed and synthesized a series of 4‐anilinoquin(az)olines in order to better understand the structure‐activity relationships of three main collateral kinase targets of quin(az)oline‐based kinase inhibitors: cyclin G associated kinase (GAK), STE20‐like serine/threonine‐protein kinase (SLK) and serine/threonine‐protein kinase 10 (STK10). This was achieved through a series of quantitative structure‐activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites and extensive small‐molecule X‐ray structural analysis.
Avoiding collateral damage: The 4‐anilinoquinoline and 4‐anilinoquinazoline scaffolds have been the focus of significant efforts in prior kinase drug discovery programs, which have led to a number of approved medicines. We have now designed and synthesized a series of 4‐anilinoquin(az)olines to better understand the structure‐activity relationships of three main collateral kinase targets of quin(az)oline‐based kinase inhibitors: cyclin G associated kinase (GAK), STE20‐like serine/threonine‐protein kinase (SLK), and serine/threonine‐protein kinase 10 (STK10). This was achieved through a series of quantitative structure‐activity relationship analysis and water mapping of the kinase ATP binding sites.
Cerebral visual impairment (CVI) is a brain based visual disorder associated with the maldevelopment of central visual pathways. Individuals with CVI often report difficulties finding a target of ...interest in cluttered and crowded visual scenes. However, it remains unknown how manipulating task demands and other environmental factors influence visual search performance in this population.
We developed a novel and naturalistic virtual reality (VR) based static visual search task combined with eye tracking called the “virtual toy box” to objectively assess visual search performance in CVI.
A total of 38 individuals with CVI (mean age 13.18 years ± 3.58 SD) and 53 controls with neurotypical development (mean age 15.25 years ± 5.72 SD) participated in the study. In a first experiment, study subjects were instructed to search for a preselected toy presented among a varying number of surrounding distractor toys (set size ranging from 1 to 36 items). In a second experiment, we assessed the effects of manipulating item spacing and the size of the visual area explored (field of view; FOV).
Behavioral outcomes collected were success rate, reaction time, gaze error, visual search area, and off-screen percent (an index of task compliance). Compared to age-matched controls, participants with CVI showed an overall impairment with respect to all the visual search outcomes of interest. Specifically, individuals with CVI were less likely and took longer to find the target, and search patterns were less accurate and precise compared to controls. Visual search response profiles were also comparatively less efficient and were associated with a slower initial pre-search (visual orienting) response as indexed by higher slope and intercept values derived from the analysis of reaction time × set size functions. Search performance was also more negatively affected in CVI at the smallest as well as largest spacing conditions tested, while increasing FOV was associated with greater decreased gaze accuracy and precision
These results are consistent with a general profile of impaired visual search abilities in CVI as well as worsening performance with increased visual task demands and an overall sensitivity to visual clutter and crowding. The observed profile of impaired visual search performance may be associated with dysfunctions related to how visual selective attention is deployed in individuals with CVI.
•Higher order visual perceptual abilities are typically not assessed as part of a standard ophthalmological exam.•Visual search performance in CVI was characterized by using a novel virtual reality-based task combined with eye tracking.•Compared to age-matched controls, participants with CVI showed an overall impairment in performance on all visual search outcomes of interest.•The general profile observed in CVI was consistent with worsening performance with increased visual task demands and sensitivity to visual clutter and crowding.
•Low neuroticism and high openness were associated with high cognitive function.•Openness was associated with steeper cognitive decline after dementia diagnosis.•Models were coordinated and ...harmonized across 4 independent longitudinal studies.
There are individual differences in the rates of cognitive decline across later adulthood. Personality traits are among the factors that may account for these differences. The current project investigated whether personality traits were associated with trajectories of cognitive decline, and whether the associations were different before and after dementia diagnosis. The data was analyzed using linear mixed effects regression. Across study aims is a focus on replicability and generalizability. Each question was addressed in four independent longitudinal studies (EAS, MAP, ROS, SATSA), then meta-analyzed, providing estimates of replicability. Results indicated that low neuroticism and high openness were associated with total cognitive function. We detected evidence for cognitive decline in all four samples, and openness was associated with decline post dementia diagnosis.
We previously demonstrated that plasmid-deficient Chlamydia muridarum retains the ability to infect the murine genital tract but does not elicit oviduct pathology because it fails to activate ...Toll-like receptor 2 (TLR2). We derived a plasmid-cured derivative of the human genital isolate Chlamydia trachomatis D/UW-3/Cx, strain CTD153, which also fails to activate TLR2, indicating this virulence phenotype is associated with plasmid loss in both C. trachomatis and C. muridarum. As observed with plasmid-deficient C. muridarum, CTD153 displayed impaired accumulation of glycogen within inclusions. Transcriptional profiling of the plasmid-deficient strains by using custom microarrays identified a conserved group of chromosomal loci, the expression of which was similarly controlled in plasmid-deficient C. muridarum strains CM972 and CM3.1 and plasmid-deficient C. trachomatis CTD153. However, although expression of glycogen synthase, encoded by glgA, was greatly reduced in CTD153, it was unaltered in plasmid-deficient C. muridarum strains. Thus, additional plasmid-associated factors are required for glycogen accumulation by this chlamydial species. Furthermore, in C. trachomatis, glgA and other plasmid-responsive chromosomal loci (PRCLs) were transcriptionally responsive to glucose limitation, indicating that additional regulatory elements may be involved in the coordinated expression of these candidate virulence effectors. Glucose-limited C. trachomatis displayed reduced TLR2 stimulation in an in vitro assay. During human chlamydial infection, glucose limitation may decrease chlamydial virulence through its effects on plasmid-responsive chromosomal genes.
In acute myeloid leukemia (AML), recurrent DNA methyltransferase 3A (DNMT3A) mutations are associated with chemoresistance and poor prognosis, especially in advanced-age patients. Gene-expression ...studies in DNMT3A-mutated cells identified signatures implicated in deregulated DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here, we tested whether pharmacologically induced replication fork stalling, such as with cytarabine, creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations.
Leukemia cell lines, genetic mouse models, and isogenic cells with and without DNMT3A(mut) were used to evaluate sensitivity to nucleoside analogues such as cytarabine in vitro and in vivo, followed by analysis of DNA damage and signaling, replication restart, and cell-cycle progression on treatment and after drug removal. Transcriptome profiling identified pathways deregulated by DNMT3A(mut) expression.
We found increased sensitivity to pharmacologically induced replication stress in cells expressing DNMT3A(R882)-mutant, with persistent intra-S-phase checkpoint activation, impaired PARP1 recruitment, and elevated DNA damage, which was incompletely resolved after drug removal and carried through mitosis. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine washout demonstrated a higher rate of fork collapse in DNMT3A(mut)-expressing cells. RNA-seq studies supported deregulated cell-cycle progression and p53 activation, along with splicing, ribosome biogenesis, and metabolism.
Together, our studies show that DNMT3A mutations underlie a defect in recovery from replication fork arrest with subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during replication stress. See related commentary by Viny, p. 573.
Evidence suggests that Extracorporeal Cardiopulmonary Resuscitation (ECPR) can improve survival rates for nontraumatic out-of-hospital cardiac arrest (OHCA). However, when ECPR is indicated over 50% ...of potential candidates are unable to qualify in the current hospital-based system due to geographic limitations. This study employs a Geographic Information System (GIS) model to estimate the number of ECPR eligible patients within the United States in the current hospital-based system, a prehospital ECPR ground-based system, and a prehospital ECPR Helicopter Emergency Medical Services (HEMS)-based system.
We constructed a GIS model to estimate ground and helicopter transport times. Time-dependent rates of ECPR eligibility were derived from the Resuscitation Outcome Consortium (ROC) database, while the Cardiac Arrest Registry to Enhance Survival (CARES) registry determined the number of OHCA patients meeting ECPR criteria within designated transportation times. Emergency Medical Services (EMS) response time, ECPR candidacy determination time, and on-scene time were modeled based on data from the EROCA trial. The combined model was used to estimate the total ECPR eligibility in each system.
The CARES registry recorded 736,066 OHCA patients from 2013 to 2021. After applying clinical criteria, 24,661 (3.4%) ECPR-indicated OHCA were identified. When considering overall ECPR eligibility within 45 min from OHCA to initiation, only 11.76% of OHCA where ECPR was indicated were eligible in the current hospital-based system. The prehospital ECPR HEMS-based system exhibited a four-fold increase in ECPR eligibility (49.3%), while the prehospital ground-based system showed a more than two-fold increase (28.4%).
The study demonstrates a two-fold increase in ECPR eligibility for a prehospital ECPR ground-based system and a four-fold increase for a prehospital ECPR HEMS-based system compared to the current hospital-based ECPR system. This novel GIS model can inform future ECPR implementation strategies, optimizing systems of care.
Children with cerebrospinal fluid (CSF) pleocytosis are routinely admitted to the hospital and treated with parenteral antibiotics, although few have bacterial meningitis. We previously developed a ...clinical prediction rule, the Bacterial Meningitis Score, that classifies patients at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cells/microL, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10,000 cells/microL, and a history of seizure before or at the time of presentation.
To validate the Bacterial Meningitis Score in the era of widespread pneumococcal conjugate vaccination.
A multicenter, retrospective cohort study conducted in emergency departments of 20 US academic medical centers through the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. All children aged 29 days to 19 years who presented at participating emergency departments between January 1, 2001, and June 30, 2004, with CSF pleocytosis (CSF white blood cells > or =10 cells/microL) and who had not received antibiotic treatment before lumbar puncture.
The sensitivity and negative predictive value of the Bacterial Meningitis Score.
Among 3295 patients with CSF pleocytosis, 121 (3.7%; 95% confidence interval CI, 3.1%-4.4%) had bacterial meningitis and 3174 (96.3%; 95% CI, 95.5%-96.9%) had aseptic meningitis. Of the 1714 patients categorized as very low risk for bacterial meningitis by the Bacterial Meningitis Score, only 2 had bacterial meningitis (sensitivity, 98.3%; 95% CI, 94.2%-99.8%; negative predictive value, 99.9%; 95% CI, 99.6%-100%), and both were younger than 2 months old. A total of 2518 patients (80%) with aseptic meningitis were hospitalized.
This large multicenter study validates the Bacterial Meningitis Score prediction rule in the era of conjugate pneumococcal vaccine as an accurate decision support tool. The risk of bacterial meningitis is very low (0.1%) in patients with none of the criteria. The Bacterial Meningitis Score may be helpful to guide clinical decision making for the management of children presenting to emergency departments with CSF pleocytosis.
Atrial fibrillation is a very common arrhythmia whose prevalence is expected to increase significantly as the population ages. The associated stroke risk is a major cause of morbidity and mortality. ...Stroke prevention by anticoagulation carries its own risks, leading to the search for alternative strategies. Multiple techniques have been developed to exclude the left atrial appendage (the main source of thromboembolism in atrial fibrillation) from the circulation. Such techniques offer the hope of stroke prevention without the risks of anticoagulation. This article describes the percutaneous approaches being currently performed in the United States. Particular emphasis is placed on the use of transesophageal echocardiography to guide these procedures.
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