Collaboration and engagement with decision-makers are needed to reduce evidence complacency in wildlife management.

There exists an extensive, diverse, and robust evidence base to support complex decisions that address the planetary biodiversity crisis. However, it is generally not sought or used by environmental decision-makers, who instead draw on intuition, experience, or opinion to inform important decisions. Thus, there is a need to examine evidence exchange processes in wildlife management to understand the multiple inputs to decisions. Here, we adopt a novel approach, fuzzy cognitive mapping (FCM), to examine perceptions of individuals from Indigenous and Western governments on the reliability of evidence which may influence freshwater fisheries management decisions in British Columbia, Canada. We facilitated four FCM workshops participants representing Indigenous or Western regulatory/governance groups of fisheries managers. Our results show that flows of evidence to decision-makers occur within a relatively closed governance network, constrained to the few well-connected decision-making organizations (i.e., wildlife management agencies) and their close partners. This implies that increased collaboration (i.e., knowledge co-production) and engagement (i.e., knowledge brokerage) with wildlife managers and decision-makers are needed to produce actionable evidence and increase evidence exchange.

Dosage-dependent effects of FGFR2W290R mutation on craniofacial shape and cellular dynamics of the basicranial synchondroses.

Craniosynostosis is a common yet complex birth defect, characterized by premature fusion of the cranial sutures that can be syndromic or nonsyndromic. With over 180 syndromic associations, reaching genetic diagnoses and understanding variations in underlying cellular mechanisms remains a challenge. Variants of FGFR2 are highly associated with craniosynostosis and warrant further investigation. Using the missense mutation FGFR2W290R , an effective mouse model of Crouzon syndrome, craniofacial features were analyzed using geometric morphometrics across developmental time (E10.5-adulthood, n = 665 total). Given the interrelationship between the cranial vault and basicranium in craniosynostosis patients, the basicranium and synchondroses were analyzed in perinates. Embryonic time points showed minimal significant shape differences. However, hetero- and homozygous mutant perinates and adults showed significant differences in shape and size of the cranial vault, face, and basicranium, which were associated with cranial doming and shortening of the basicranium and skull. Although there were also significant shape and size differences associated with the basicranial bones and clear reductions in basicranial ossification in cleared whole-mount samples, there were no significant alterations in chondrocyte cell shape, size, or orientation along the spheno-occipital synchondrosis. Finally, shape differences in the cranial vault and basicranium were interrelated at perinatal stages. These results point toward the possibility that facial shape phenotypes in craniosynostosis may result in part from pleiotropic effects of the causative mutations rather than only from the secondary consequences of the sutural defects, indicating a novel direction of research that may shed light on the etiology of the broad changes in craniofacial morphology observed in craniosynostosis syndromes.

First clinical evaluation of the safety and efficacy of tarumase for the debridement of venous leg ulcers.

We report the first clinical evaluation of a new enzymatic wound debridement product containing tarumase in venous leg ulcer patients. As a first-in-human study, this was a prospective, open-label, multi-centre, dose escalation study across five dose cohorts and involving a total of 43 patients treated three times weekly for up to 4 weeks (12 applications). The primary and secondary endpoints of the study were to assess the systemic safety, local tolerability, and early proof of concept both for wound debridement and healing. Results indicated that the tarumase enzyme was well tolerated when applied topically to wounds, with no indications of systemic absorption, no evidence of antibody generation, and no systemic effects on coagulation pathways. Locally, there was no evidence of pain on application, no local itching, no increases in erythema, oedema, exudate or bleeding and only a few treatment emergent adverse events were reported. As the concentration of tarumase was escalated, trends towards faster and improved effectiveness of wound debridement were observed, especially in patients with significant slough at baseline. Trends towards faster rates of healing were also noted based on observations of increased granulation tissue, increased linear healing and reduction in surface area over the 4-week treatment period.

Electronic Consultations in a Community Neurology Practice: A Retrospective Study Informing Best Practice.

Objective: To describe our practice of electronic consultations (e-consults) and assess safety and risk factors for subsequent face-to-face consultations. Patients and Methods: A retrospective cohort study of all e-consults completed in a community neurology practice between May 5, 2018, and June 31, 2019, was completed. Clinical and demographic variables were compared between the successful and unsuccessful (defined by presence of subsequent face-to-face consultation) cohorts. Hazard ratios (HR) were calculated using Cox regression model. Kaplan-Meier probability analysis (with 95% CIs) of subsequent face-to-face consultation was performed. Case examples highlighting potential harm were summarized. Results: In total, 302 e-consults were reviewed. The most frequent referrals were for headache (n=125, 41.4%), dysesthesia (n=40, 13.2%), and abnormal imaging finding (n=27, 8.9%). The most common e-consult questions were for treatment (57.6%) and diagnostic evaluation (48.0%) recommendations. Moreover, 24.8% (n=75) of e-consults were followed by face-to-face consultations, with primary risk factors including female sex (HR, 1.9), referral for headache (HR, 1.7), and final diagnosis of migraine (HR, 2.0) or long-term migraine (HR, 5.0). Potential harm related to delayed diagnosis/treatment was identified in 6 (2.0%) patients with migraine and 4 (1.3%) without migraine presenting to emergency department. Conclusion: Utilization of e-consults may safely improve access to neurologic expertise and prevent the need for some visits, which may have required a face-to-face visit. In patients with chronic migraine, e-consults should be considered short-term and followed by face-to-face consultation as soon as access allows. Neurologists performing e-consults should be able to triage patients to face-to-face consultation, particularly when diagnosis is uncertain or the neurologic examination may help guide appropriate testing.

Feasibility and Usability of a Mobile App-Based Interactive Care Plan for Migraine in a Community Neurology Practice: Development and Pilot Implementation Study.

BACKGROUND: Migraine is a common and major cause of disability, poor quality of life, and high health care use. Access to evidence-based migraine care is limited and projected to worsen. Novel mobile health app-based tools may effectively deliver migraine patient education to support self-management, facilitate remote monitoring and treatment, and improve access to care. The risk that such an intervention may increase the care team workload is a potential implementation barrier. OBJECTIVE: This study aims to describe a novel electronic health record-integrated mobile app-based Migraine Interactive Care Plan (MICP) and evaluate its feasibility, usability, and impact on care teams in a community neurology practice. METHODS: Consecutive enrollees between September 1, 2020, and February 16, 2022, were assessed in a single-arm observational study of usability, defined by 74.3% (127/171) completing ≥1 assigned task. Task response rates, rate and type of care team escalations, and patient-reported outcomes were summarized. Patients were prospectively recruited and randomly assigned to routine care with or without the MICP from September 1, 2020, to September 1, 2021. Feasibility was defined by equal to or fewer downstream face-to-face visits, telephone contacts, and electronic messages in the MICP cohort. The Wilcoxon rank-sum test was used to compare continuous variables, and the chi-square test was used for categorical variables for those with at least 3 months of follow-up. RESULTS: A total of 171 patients were enrolled, and of these, 127 (74.3%) patients completed ≥1 MICP-assigned task. Mean escalations per patient per month was 0.9 (SD 0.37; range 0-1.7). Patient-confirmed understanding of the educational materials ranged from 26.6% (45/169) to 56.2% (95/169). Initial mean headache days per week was 4.54 (SD 2.06) days and declined to 2.86 (SD 1.87) days at week 26. The percentage of patients reporting favorable satisfaction increased from a baseline of 35% (20/57) to 83% (15/18; response rate of 42/136, 30.9% to 28/68, 41%) over the first 6 months. A total of 121 patients with MICP were compared with 62 patients in the control group. No differences were observed in the rate of telephone contacts or electronic messages. Fewer face-to-face visits were observed in the MICP cohort (13/121, 10.7%) compared with controls (26/62, 42%; P<.001). CONCLUSIONS: We describe the successful implementation of an electronic health record-integrated mobile app-based care plan for migraine in a community neurology practice. We observed fewer downstream face-to-face visits without increasing telephone calls, medication refills, or electronic messages. Our findings suggest that the MICP has the potential to improve patient access without increasing care team workload and the need for patient input from diverse populations to improve and sustain patient engagement. Additional studies are needed to assess its impact in primary care.

A comparative approach for characterizing the relationship among morphology, range-of-motion and locomotor behaviour in the primate shoulder.

Shoulder shape directly impacts forelimb function by contributing to glenohumeral (GH) range-of-motion (ROM). However, identifying traits that contribute most to ROM and visualizing how they do so remains challenging, ultimately limiting our ability to reconstruct function and behaviour in fossil species. To address these limitations, we developed an in silico proximity-driven model to simulate and visualize three-dimensional (3D) GH rotations in living primate species with diverse locomotor profiles, identify those shapes that are most predictive of ROM using geometric morphometrics, and apply subsequent insights to interpret function and behaviour in the fossil hominin Australopithecus sediba. We found that ROM metrics that incorporated 3D rotations best discriminated locomotor groups, and the magnitude of ROM (mobility) was decoupled from the anatomical location of ROM (e.g. high abduction versus low abduction). Morphological traits that enhanced mobility were decoupled from those that enabled overhead positions, and all non-human apes possessed the latter but not necessarily the former. Model simulation in A. sediba predicted high mobility and a ROM centred at lower abduction levels than in living apes but higher than in modern humans. Together these results identify novel form-to-function relationships in the shoulder and enhance visualization tools to reconstruct past function and behaviour.

Bioenergetic consequences of repeated catch-and-release fisheries interactions on adult steelhead across a range of ecologically relevant water temperatures.

The biological consequences of catch-and-release angling have been studied for decades, yet little is known about the compounding effects of repeated recreational fisheries recaptures on the physiology and behaviour of angled fish. Using heart rate biologgers and behavioural assays, this study investigated the physiological and behavioural consequences of multiple simulated angling events (i.e., repeated stressors) on female steelhead (Oncorhynchus mykiss), under current (6 °C) and future (11 °C) water temperature scenarios. While steelhead in the warmer water temperature scenario demonstrated alterations in cardiac function (e.g., increases in maximum heart rate and scope of heart rate) and evidence of behavioural impairments (e.g., decreases in chase activity and landing time) over the course of two simulated angling events, cold water treated fish had negligible change. Fish subjected to two simulated angling events under warm water temperature conditions tended to demonstrate an increase in recovery time and scope for heart rate, and a decrease in resting heart rate. A second experiment was conducted to test for sex-specific differences in the heart rate response of steelhead subjected to an increase in water temperature. Females demonstrated a higher scope for heart rate when compared to males during the event and during recovery. More work is needed to better understand the interaction between multiple angling events and recovery from these events at various water temperatures, and the biological basis for sex-specific differences in cardiac function and response to challenges. This study contributes to a growing body of evidence on the effects of repeated stressors on wild fish.

Environmental evidence in action: on the science and practice of evidence synthesis and evidence-based decision-making.

In civil society we expect that policy and management decisions will be made using the best available evidence. Yet, it is widely known that there are many barriers that limit the extent to which that occurs. One way to overcome these barriers is via robust, comprehensive, transparent and repeatable evidence syntheses (such as systematic reviews) that attempt to minimize various forms of bias to present a summary of existing knowledge for decision-making purposes. Relative to other disciplines (e.g., health care, education), such evidence-based decision-making remains relatively nascent for environment management despite major threats to humanity, such as the climate, pollution and biodiversity crises demonstrating that human well-being is inextricably linked to the biophysical environment. Fortunately, there are a growing number of environmental evidence syntheses being produced that can be used by decision makers. It is therefore an opportune time to reflect on the science and practice of evidence-based decision-making in environment management to understand the extent to which evidence syntheses are embraced and applied in practice. Here we outline a number of key questions related to the use of environmental evidence that need to be explored in an effort to enhance evidence-based decision-making. There is an urgent need for research involving methods from social science, behavioural sciences, and public policy to understand the basis for patterns and trends in environmental evidence use (or misuse or ignorance). There is also a need for those who commission and produce evidence syntheses, as well as the end users of these syntheses to reflect on their experiences and share them with the broader evidence-based practice community to identify needs and opportunities for advancing the entire process of evidence-based practice. It is our hope that the ideas shared here will serve as a roadmap for additional scholarship that will collectively enhance evidence-based decision-making and ultimately benefit the environment and humanity.

Migraine Patient Care Model Preferences in a Community Practice.

Background and Objectives: Developing high-value care models with limited resources for large populations of individuals with migraine requires advanced understanding of patient preferences for care delivery methods. In this study, we aimed to inform the development of migraine care models by assessing patient preferences for types of care delivery and determining differences based on migraine frequency and disability. Methods: We analyzed unpublished data from a cross-sectional survey of 516 randomly selected individuals with migraine within a community practice associated with Mayo Clinic, Rochester, MN. Results: Individuals with chronic migraine, compared with those with episodic migraine, were more likely to prefer a visit with a neurologist (p = 0.0005), synchronous telephone conference with primary care provider (PCP) and neurologist (p = 0.0102), and a written migraine action plan in the medical record (p = 0.0343). Compared with those with mild/no disability, individuals with moderate-to-severe disability were more likely to prefer a visit with a neurologist (p < 0.0001), synchronous video or telephone conference with PCP and neurologist (p < 0.0001), PCP communication with neurologist (p = 0.0099), electronic message to primary care team with access to neurologist (p = 0.0216), and written action plan in the medical record (p = 0.0011). Collectively, individuals most preferred telephone follow-up and least preferred communications with a nurse or pharmacist or generalized education (all p < 0.001). Discussion: We observed differences in migraine care delivery preferences between migraine frequency and level of migraine disability. Observations support development of care pathways that include a written migraine action plan, primary care-neurology collaboration including nontraditional interactions, and prioritization of traditional neurology consultation for the most disabled patients.

Posttraumatic Ruptured Axillary Mononeuropathy Without Shoulder Dislocation in an American Football Player: A Case Report and Review of the Literature.

ABSTRACT: A high school-aged right-handed adolescent boy presented with a 5-mo history of persistent proximal right arm weakness and numbness after an American football stinger injury without a documented history of a shoulder dislocation or humeral fracture. He developed diffuse deltoid muscle atrophy, persistent shoulder abduction weakness, and reduced pinprick sensation confined to the axillary distribution over 5 mos. Needle electromyography demonstrated dense fibrillation potentials and no voluntary activation in all three deltoid muscle heads, indicating a severe posttraumatic ruptured axillary mononeuropathy. The patient then underwent a complex three-cable sural nerve graft repair for attempted reinnervation of the axillary-innervated muscles. Isolated axillary nerve injuries are usually associated with anterior shoulder dislocations; however, a severe isolated persistent axillary mononeuropathy from a ruptured axillary nerve may occur in trauma patients without a clear history of shoulder dislocation. These patients may present with only mild persistent weakness of shoulder abduction. Electrodiagnostic testing to fully assess axillary nerve function should still be considered to identify patients with high-grade nerve injuries that may benefit from sural nerve grafting. The rapid recovery of our patient's initial symptoms with persistent severe axillary injury suggests a unique vulnerability of the nerve due to the neuroanatomy and possibly other factors.

The children's brain tumor network (CBTN) - Accelerating research in pediatric central nervous system tumors through collaboration and open science.

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

Human Induced Pluripotent Stem Cell Encapsulation Geometry Impacts Three-Dimensional Developing Human Engineered Cardiac Tissue Functionality.

Cardiac tissue engineering has been working to alleviate the immense burden of cardiovascular disease for several decades. To improve cardiac tissue homogeneity and cardiomyocyte (CM) maturation, in this study, we investigated altering initial encapsulation geometry in a three-dimensional (3D) direct cardiac differentiation platform. Traditional engineered cardiac tissue production utilizes predifferentiated CMs to produce 3D cardiac tissue and often involves various cell selection and exogenous stimulation methods to promote CM maturation. Starting tissue formation directly with human induced pluripotent stem cells (hiPSCs), rather than predifferentiated CMs, simplifies the engineered cardiac tissue formation process, making it more applicable for widespread implementation and scale-up. In this study, hiPSCs were encapsulated in poly (ethylene glycol)-fibrinogen in three tissue geometries (disc-shaped microislands, squares, and rectangles) and subjected to established cardiac differentiation protocols. Resulting 3D engineered cardiac tissues (3D-ECTs) from each geometry displayed similar CM populations (∼65%) and gene expression over time. Notably, rectangular tissues displayed less tissue heterogeneity and suggested more advanced features of maturing CMs, including myofibrillar alignment and Z-line formation. In addition, rectangular tissue showed significantly higher anisotropic contractile properties compared to square and microisland tissues (MI 0.28 ± 0.03, SQ 0.35 ± 0.05, RT 0.79 ± 0.04). This study demonstrates a straightforward method for simplifying and improving 3D-ECT production without the use of exogenous mechanical or electrical pacing and has the potential to be utilized in bioprinting and drug testing applications. Impact statement Current methods for improving cardiac maturation postdifferentiation remain tedious and complex. In this study, we examined the impact of initial encapsulation geometry on improvement of three-dimensional engineered cardiac tissue (3D-ECT) production and postdifferentiation maturation for three tissue geometries, including disc-shaped microislands, squares, and rectangles. Notably, rectangular 3D-ECTs displayed less tissue heterogeneity and more advanced features of maturing cardiomyocytes, including myofibrillar alignment, Z-line formation, and anisotropic contractile properties, compared to microisland and square tissues. This study demonstrates an initial human induced pluripotent stem cell-encapsulated rectangular tissue geometry can improve cardiac maturation, rather than implementing cell selection or tedious postdifferentiation manipulation, including exogenous mechanical and/or electrical pacing.

MusMorph, a database of standardized mouse morphology data for morphometric meta-analyses.

Complex morphological traits are the product of many genes with transient or lasting developmental effects that interact in anatomical context. Mouse models are a key resource for disentangling such effects, because they offer myriad tools for manipulating the genome in a controlled environment. Unfortunately, phenotypic data are often obtained using laboratory-specific protocols, resulting in self-contained datasets that are difficult to relate to one another for larger scale analyses. To enable meta-analyses of morphological variation, particularly in the craniofacial complex and brain, we created MusMorph, a database of standardized mouse morphology data spanning numerous genotypes and developmental stages, including E10.5, E11.5, E14.5, E15.5, E18.5, and adulthood. To standardize data collection, we implemented an atlas-based phenotyping pipeline that combines techniques from image registration, deep learning, and morphometrics. Alongside stage-specific atlases, we provide aligned micro-computed tomography images, dense anatomical landmarks, and segmentations (if available) for each specimen (N = 10,056). Our workflow is open-source to encourage transparency and reproducible data collection. The MusMorph data and scripts are available on FaceBase ( www.facebase.org , https://doi.org/10.25550/3-HXMC ) and GitHub ( https://github.com/jaydevine/MusMorph ).

The Sociolectal and Stylistic Variability of Rhythm in Stockholm.

The question of "staccato" rhythm in Stockholm's multiethnolect is investigated by comparing nPVIV measurements of the speech of 36 adult male speakers. The men, ages 24-43, come from a stratified sample of social classes and racial groups. Three contextual styles were recorded and analyzed: informal, formal, and very formal. The distribution of nPVIV values in informal speech across class and racial group indicates that speech rhythm splits three ways: low-alternation "staccato" rhythm among the racialized lower-class men, high-alternation rhythm among the white lower-class men, and an intermediate level of rhythm among higher-class men, regardless of racialized category. The "staccato" low-alternation feature is also less stylistically sensitive than the high-alternation feature, implying that the latter is a more established feature than the former. Further, the "staccato" feature is more stylistically sensitive among younger speakers than older speakers, implying an ongoing change from indicator to marker status. For all speakers, age has a stable main effect, which means that younger speakers, independent of racial group and class, have lower alternation than older speakers. Implied here is that low-alternation is a change from below that originates within the racialized working class. While it may be incrementally transmitting into the wider speech community, the white working class is the most resistant to its incursion.

Closing the knowledge-action gap in conservation with open science.

The knowledge-action gap in conservation science and practice occurs when research outputs do not result in actions to protect or restore biodiversity. Among the diverse and complex reasons for this gap, three barriers are fundamental: knowledge is often unavailable to practitioners and challenging to interpret or difficult to use or both. Problems of availability, interpretability, and useability are solvable with open science practices. We considered the benefits and challenges of three open science practices for use by conservation scientists and practitioners. First, open access publishing makes the scientific literature available to all. Second, open materials (detailed methods, data, code, and software) increase the transparency and use of research findings. Third, open education resources allow conservation scientists and practitioners to acquire the skills needed to use research outputs. The long-term adoption of open science practices would help researchers and practitioners achieve conservation goals more quickly and efficiently and reduce inequities in information sharing. However, short-term costs for individual researchers (insufficient institutional incentives to engage in open science and knowledge mobilization) remain a challenge. We caution against a passive approach to sharing that simply involves making information available. We advocate a proactive stance toward transparency, communication, collaboration, and capacity building that involves seeking out and engaging with potential users to maximize the environmental and societal impact of conservation science.

Cierre de la Brecha entre el Conocimiento y la Acción en la Conservación con Ciencia Abierta 21-311 Resumen La brecha entre el conocimiento y la acción en las ciencias de la conservación y en su práctica ocurre cuando los resultados de las investigaciones no derivan en acciones para proteger o restaurar la biodiversidad. Entre las razones complejas y diversas de esta brecha, existen tres barreras que son fundamentales: con frecuencia el conocimiento no está disponible para los practicantes, es difícil de interpretar o difícil de usar, o ambas. Los problemas con la disponibilidad, interpretabilidad y utilidad son solucionables mediante las prácticas de ciencia abierta. Consideramos los beneficios y los obstáculos de tres prácticas de ciencia abierta para su uso por parte de los científicos y practicantes de la conservación. Primero, las publicaciones de acceso abierto hacen que la literatura científica esté disponible para todos. Segundo, los materiales abiertos (métodos detallados, datos, códigos y software) incrementan la transparencia y el uso de los hallazgos de las investigaciones. Tercero, los recursos educativos abiertos permiten que los científicos y practicantes de la conservación adquieran las habilidades necesarias para utilizar los productos de las investigaciones. La adopción a largo plazo de las prácticas de ciencia abierta ayudaría a los investigadores y a los practicantes a lograr los objetivos de conservación mucho más rápido y de manera eficiente y a reducir las desigualdades que existen en la divulgación de información. Sin embargo, los costos a corto plazo para los investigadores individuales (incentivos institucionales insuficientes para participar en la ciencia abierta y en la movilización del conocimiento) todavía son un reto. Advertimos sobre las estrategias pasivas de divulgación que simplemente hacen que la información esté disponible. Abogamos por una postura proactiva hacia la transparencia, la comunicación, la colaboración y la construcción de las capacidades que incluyen la búsqueda de y la interacción con los usuarios potenciales para maximizar el impacto ambiental y social de las ciencias de la conservación.

Natural Resource Managers Use and Value Western-Based Science, but Barriers to Access Persist.

Natural resources management (NRM) is complex and relies on decisions supported by evidence, including Western-based science (WBS) and Indigenous and local knowledge. However, it has been shown that there is a disconnect between WBS and its application, whereby managers often draw on non-empirical sources of information (i.e., intuition or advice from colleagues). This article focuses on the role of WBS in decisions made in management of rainbow trout (Oncorhynchus mykiss) in the province of British Columbia, Canada. We conducted open-ended interviews with NRM branches of Indigenous and parliamentary governments, as well as with nongovernmental stakeholder groups, to examine (a) sources of WBS consulted in decision-making and (b) barriers to accessing WBS by managers. We found that respondents involved with NRM relied on a diverse set of sources for WBS, seldom relying exclusively on one source. However, respondents relied more on internal sources (government databases) compared to external ones (peer-reviewed journal articles). We also found that respondents described WBS as valuable and generally accessible, yet barriers were identified with respect to the interface and organization of government grey data and literature, paywalls associated with peer-reviewed journals and articles, and institutional capacity, time, and support. We recommend strategies and tools to facilitate accessibility of WBS in support of bridging the knowledge-action divide, including increased publishing of open access data/articles, systematic reviews, use of knowledge brokers, specialized WBS training, and knowledge co-production. It is our hope that identification of barriers and the implementation of improved access to WBS will result in more effective NRM by giving managers access to the tools and knowledge they need for evidence-based decision-making.

Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors.

Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5'-untranslated region (5'-UTR) of mRNA to facilitate ribosome scanning and translation initiation. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and specific polypurine sequence motifs and has been reported to inhibit translation of driver oncogenes in models of lymphoma. Here we report the identification of zotatifin binding motifs in the 5'-UTRs of HER2 and FGFR1/2 Receptor Tyrosine Kinases (RTKs). Dysregulation of HER2 or FGFR1/2 in human cancers leads to activation of the PI3K/AKT and RAS/ERK signaling pathways, thus enhancing eIF4A activity and promoting the translation of select oncogenes that are required for tumor cell growth and survival. In solid tumor models driven by alterations in HER2 or FGFR1/2, downregulation of oncoprotein expression by zotatifin induces sustained pathway-dependent anti-tumor activity resulting in potent inhibition of cell proliferation, induction of apoptosis, and significant in vivo tumor growth inhibition or regression. Sensitivity of RTK-driven tumor models to zotatifin correlated with high basal levels of mTOR activity and elevated translational capacity highlighting the unique circuitry generated by the RTK-driven signaling pathway. This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.