Objectives/Goals: Personalized cancer therapy based on genomic testing is advancing patient care. Genomic alterations in fibroblast growth factor receptor (FGFR) predict response to FGFR inhibitors; however, the role of RNA expression and protein activation is not known. We propose to examine the phospho-proteomic signature in FGFR-altered cancers to identify new candidates for FGFR-targeted therapies. Methods/Study Population: In our preliminary study, we have curated a cohort of FGFR2 mutants (13 FGFR2-fusions and 4 FGFR2 point mutations) with known clinical outcomes to FGFR inhibitors and 8 FGFR2 wild-type (WT) cholangiocarcinoma tumor samples to investigate the phospho-proteomic fingerprint using a clinical grade reverse phase protein array (RPPA). RPPAs are high throughput quantitative antibody-based proteomics assays that can quantify hundreds of proteins in thousands of patient tissues providing a high degree of sensitivity through laser tumor microdissection (LCM). We have selected proteins in the FGFR signaling pathway including FGFR2, AKT, ERK1.2, STAT1/3, FRS2, and PLCg to define the range of phospho-proteomic signal between FGFR2 WT and mutant cancers. All samples will undergo evaluation with RNASeq for gene expression. Results/Anticipated Results: Our initial analysis defined the range of RNA expression of FGFR2 and pFGFR2 protein signal (Y653/654 and Y769) between FGFR2 WT and FGFR2 mutant samples. On average, the FGFR2 mutant cohort displayed higher FGFR2 RNA expression compared to the FGFR2 WT cohort. There is no apparent correlation between RNA expression and clinical response to FGFR-targeted therapy. However, in this small cohort, there is no significant difference in FGFR2 phosphorylation between FGFR2 WT and mutant cancers. RPPA analysis of FGFR downstream signaling proteins reveals a wide range of phosphorylation, but no significant difference between FGFR2 WT and mutant cancers. Discussion/Significance of Impact: These findings illustrate the complexities of FGFR signaling between FGFR2 WT and mutant cancers. These data suggest that tumors with genomically WT FGFR may display increased pFGFR2 and downstream signaling phospho-proteins. We propose a larger study of cholangiocarcinoma to evaluate evidence of FGFR pathway activation in WT tumors.

An investigation into an outbreak of Salmonella Newport infections in Canada was initiated in July 2020. Cases were identified across several provinces through whole-genome sequencing (WGS). Exposure data were gathered through case interviews. Traceback investigations were conducted using receipts, invoices, import documentation, and menus. A total of 515 cases were identified in seven provinces, related by 0–6 whole-genome multi-locus sequence typing (wgMLST) allele differences. The median age of cases was 40 (range 1–100), 54% were female, 19% were hospitalized, and three deaths were reported. Forty-eight location-specific case sub-clusters were identified in restaurants, grocery stores, and congregate living facilities. Of the 414 cases with exposure information available, 71% (295) had reported eating onions the week prior to becoming ill, and 80% of those cases who reported eating onions, reported red onion specifically. The traceback investigation identified red onions from Grower A in California, USA, as the likely source of the outbreak, and the first of many food recall warnings was issued on 30 July 2020. Salmonella was not detected in any tested food or environmental samples. This paper summarizes the collaborative efforts undertaken to investigate and control the largest Salmonella outbreak in Canada in over 20 years.

We recently reported on the radio-frequency attenuation length of cold polar ice at Summit Station, Greenland, based on bi-static radar measurements of radio-frequency bedrock echo strengths taken during the summer of 2021. Those data also allow studies of (a) the relative contributions of coherent (such as discrete internal conducting layers with sub-centimeter transverse scale) vs incoherent (e.g. bulk volumetric) scattering, (b) the magnitude of internal layer reflection coefficients, (c) limits on signal propagation velocity asymmetries (‘birefringence’) and (d) limits on signal dispersion in-ice over a bandwidth of ~100 MHz. We find that (1) attenuation lengths approach 1 km in our band, (2) after averaging 10 000 echo triggers, reflected signals observable over the thermal floor (to depths of ~1500 m) are consistent with being entirely coherent, (3) internal layer reflectivities are ≈–60$\to$–70 dB, (4) birefringent effects for vertically propagating signals are smaller by an order of magnitude relative to South Pole and (5) within our experimental limits, glacial ice is non-dispersive over the frequency band relevant for neutrino detection experiments.

The 2022 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management, 7th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by an interdisciplinary team of healthcare providers and system planners caring for persons with an acute stroke or transient ischemic attack. These recommendations are a timely opportunity to reassess current processes to ensure efficient access to acute stroke diagnostics, treatments, and management strategies, proven to reduce mortality and morbidity. The topics covered include prehospital care, emergency department care, intravenous thrombolysis and endovascular thrombectomy (EVT), prevention and management of inhospital complications, vascular risk factor reduction, early rehabilitation, and end-of-life care. These recommendations pertain primarily to an acute ischemic vascular event. Notable changes in the 7th edition include recommendations pertaining the use of tenecteplase, thrombolysis as a bridging therapy prior to mechanical thrombectomy, dual antiplatelet therapy for stroke prevention,1 the management of symptomatic intracerebral hemorrhage following thrombolysis, acute stroke imaging, care of patients undergoing EVT, medical assistance in dying, and virtual stroke care. An explicit effort was made to address sex and gender differences wherever possible. The theme of the 7th edition of the CSBPR is building connections to optimize individual outcomes, recognizing that many people who present with acute stroke often also have multiple comorbid conditions, are medically more complex, and require a coordinated interdisciplinary approach for optimal recovery. Additional materials to support timely implementation and quality monitoring of these recommendations are available at www.strokebestpractices.ca.

ABSTRACT IMPACT: Urine tumor DNA non-invasively detects minimal residual disease and infers tumor mutational burden in locally advanced bladder cancer prior to radical cystectomy, which may potentially enable the selection of patients for bladder-sparing treatment or facilitate personalized adjuvant immunotherapy. OBJECTIVES/GOALS: Standard-of-care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. The inability to assess minimal residual disease (MRD) non-invasively limits our ability to offer bladder-sparing treatment. We sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS/STUDY POPULATION: We applied uCAPP-Seq, a targeted sequencing method for detecting utDNA, to urine cell-free DNA samples acquired on the day of radical cystectomy from 42 patients with bladder cancer. utDNA variant-calling was performed non-invasively without prior tumor mutational knowledge. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. Tumor mutational burden (TMB) was inferred from the number of non-silent mutations detected in urine cell-free DNA by applying a linear relationship derived from TCGA whole exome sequencing of 409 MIBC tumors. RESULTS/ANTICIPATED RESULTS: utDNA levels were significantly higher in patients with residual disease detected in their surgical pathology compared to those who achieved a pathologic complete response (P = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD significantly predicted the absence of pathologic complete response with a sensitivity of 81% and specificity of 81%. Positive utDNA MRD also portended significantly worse progression-free survival (HR = 7.4; P = 0.03) compared to negative utDNA MRD. Furthermore, we applied a linear relationship (Pearson r = 0.84; P < 0.0001) to identify patients with high inferred TMB who may have been candidates for early immune checkpoint blockade. DISCUSSION/SIGNIFICANCE OF FINDINGS: utDNA MRD analysis prior to surgery correlated significantly with pathologic response and progression-free survival, which may help select patients for bladder-sparing treatment. utDNA can also non-invasively infer TMB, which could facilitate personalized adjuvant therapy for patients in the future.

In recent years, a variety of efforts have been made in political science to enable, encourage, or require scholars to be more open and explicit about the bases of their empirical claims and, in turn, make those claims more readily evaluable by others. While qualitative scholars have long taken an interest in making their research open, reflexive, and systematic, the recent push for overarching transparency norms and requirements has provoked serious concern within qualitative research communities and raised fundamental questions about the meaning, value, costs, and intellectual relevance of transparency for qualitative inquiry. In this Perspectives Reflection, we crystallize the central findings of a three-year deliberative process—the Qualitative Transparency Deliberations (QTD)—involving hundreds of political scientists in a broad discussion of these issues. Following an overview of the process and the key insights that emerged, we present summaries of the QTD Working Groups’ final reports. Drawing on a series of public, online conversations that unfolded at www.qualtd.net, the reports unpack transparency’s promise, practicalities, risks, and limitations in relation to different qualitative methodologies, forms of evidence, and research contexts. Taken as a whole, these reports—the full versions of which can be found in the Supplementary Materials—offer practical guidance to scholars designing and implementing qualitative research, and to editors, reviewers, and funders seeking to develop criteria of evaluation that are appropriate—as understood by relevant research communities—to the forms of inquiry being assessed. We dedicate this Reflection to the memory of our coauthor and QTD working group leader Kendra Koivu.1

A medical information commons (MIC) is a networked data environment utilized for research and clinical applications. At three deliberations across the U.S., we engaged 75 adults in two-day facilitated discussions on the ethical and social issues inherent to sharing data with an MIC. Deliberants made recommendations regarding opt-in consent, transparent data policies, public representation on MIC governing boards, and strict data security and privacy protection. Community engagement is critical to earning the public's trust.

Studies examining associations between fetal serotonin reuptake inhibitor (SRI) exposure and child autism spectrum disorder (ASD) diagnoses or delayed language remain mixed and rarely prospectively follow children or employ gold-standard assessments. We prospectively followed a cohort of mother–child dyads from pregnancy through early elementary school (N = 178), and obtained maternal and alternate–caregiver ratings of behaviors related to ASD (N = 137), as well as direct, gold-standard assessments of child ASD symptoms and pragmatic language among dyads who experienced prenatal depression and either took SRIs or were medication free during pregnancy (N = 44). Prenatal SRI exposure was related to maternal ratings of ASD-related behaviors (β = 0.24 95% confidence interval; CI [0.07, 0.48]), and, among boys, alternative caregiver ratings (males-only β = 0.28 95% CI [0.02, 0.55], females-only β = −0.21 95% CI [–0.63, 0.08]). However, results of our direct assessments suggest an association between SRI exposure and reduced pragmatic language scores (β = –0.27, 95% CI [–0.53, –0.01], but not ASD (Autism Diagnostic Observation Schedule β = 0.14 95% CI [–0.15, 0.41]; Social Responsiveness Scale β = 0.08 95% CI [–0.25, 0.40]). These discrepancies point to issues regarding how ASD is assessed, and the possibility that SRIs may be more strongly associated with language or other broader behaviors that coincide with ASD. Larger prospective studies that incorporate thorough, gold-standard assessments of ASD, language, and other ASD-related behaviors are needed.

Genre looms large in contemporary Lukan scholarship. While many scholars are content to label Luke as biography and Acts as history, others argue that both volumes must belong to a single genre. This solution preserves the generic unity of Luke-Acts by shoehorning one or both volumes into ill-fitting categories; such a move only makes sense within an understanding of genre-as-classification. By exploring recent scholarship on genre and privileging ancient practice over ancient theory, we propose reading Luke-Acts as a unified narrative influenced by and modelled after a wide range of Greek prose narratives, rather than representing one genre in particular.

Selection by herbicides has resulted in widespread evolution of herbicide resistance in agricultural weeds. In California, resistance to glyphosate was first confirmed in rigid ryegrass in 1998. Objectives of this study were to determine the current distribution and level of glyphosate resistance in Italian ryegrass, and to assess whether resistance could be due to an altered target site. Seeds were sampled from 118 populations and seedlings were treated with glyphosate at 866 g ae ha−1. Percentage of survivors ranged from 5 to 95% in 54 populations. All plants from 64 populations died. One susceptible (S) population, four putatively resistant (R) populations, and one S accession from Oregon were used for pot dose–response experiments, shikimic acid analyses, and DNA sequencing. Seedlings were treated with glyphosate at eight rates, ranging from 108 to 13,856 g ae ha−1. Shoot biomass was evaluated 3 wk after treatment and fit to a log-logistic regression equation. On the basis of GR50 (herbicide rate required to reduce growth by 50%) values, seedlings from putatively R populations were roughly two to 15 times more resistant to glyphosate than S plants. Shikimic acid accumulation was similar in all plants before glyphosate treatment, but at 4 and 7 DAT, S plants from California and Oregon accumulated approximately two and three times more shikimic acid, respectively, than R plants. Sequencing of a cDNA fragment of the EPSPS coding region revealed two different codons, both of which encode proline at amino acid position 106 in S individuals. In contrast, all R plants sequenced exhibited missense mutations at site 106. Plants from one population revealed a mutation resulting in a proline to serine substitution. Plants from three R populations exhibited a mutation corresponding to replacement of proline with alanine. Our results indicate that glyphosate resistance is widespread in Italian ryegrass populations of California, and that resistance is likely due to an altered target enzyme.

In 2006, Tomas Koontz and Craig Thomas wrote, “If the 20th century was the year of the administration state then the 21st century may be the year of the collaborative state” (Koontz and Thomas, 2006). Koontz and Thomas were correct in one respect—collaborative management has come to be a part of environmental and natural resources decision making at almost every level of government and in almost every subset issue area. The question this essay addresses is: Is this necessarily a good thing? More specifically, are there situations in which collaborative management works well and others in which it should be avoided entirely?

Environmental Practice 17: 156–159 (2015)

There is increasing demand for the implementation of effects-based monitoring and surveillance (EBMS) approaches in the Great Lakes Basin to complement traditional chemical monitoring. Herein, we describe an ongoing multiagency effort to develop and implement EBMS tools, particularly with regard to monitoring potentially toxic chemicals and assessing Areas of Concern (AOCs), as envisioned by the Great Lakes Restoration Initiative (GLRI). Our strategy includes use of both targeted and open-ended/discovery techniques, as appropriate to the amount of information available, to guide a priori end point and/or assay selection. Specifically, a combination of in vivo and in vitro tools is employed by using both wild and caged fish (in vivo), and a variety of receptor- and cell-based assays (in vitro). We employ a work flow that progressively emphasizes in vitro tools for long-term or high-intensity monitoring because of their greater practicality (e.g., lower cost, labor) and relying on in vivo assays for initial surveillance and verification. Our strategy takes advantage of the strengths of a diversity of tools, balancing the depth, breadth, and specificity of information they provide against their costs, transferability, and practicality. Finally, a series of illustrative scenarios is examined that align EBMS options with management goals to illustrate the adaptability and scaling of EBMS approaches and how they can be used in management decisions.

Environmental Practice 15:409–426 (2013)

Sustainability has become a guiding principle, a goal, and, in many cases, a standard for businesses, governments, nongovernmental organizations (NGOs), institutions of higher education, and environmental practitioners alike. Over the last quarter century, a widespread flurry of action in the name of sustainability has been burgeoning in a variety of settings and nations. A simple Internet news search reveals literally thousands of examples of different actors and organizations taking action in the name of sustainability. From the development of new university curricula to corporate sustainability reports, sustainability is invoked as a driving force for an ever-increasing number of organizations. The concept has become a rallying cry for a new way of operating and functioning. Like the environmental movement of the 1970s, the sustainability movement is marked by mobilization and an increased awareness of the challenges facing our current generation, as well as those who will come after us. Yet, it is not clear that actions taken in the name of creating a sustainable future are all based upon a consistent understanding of the concept of sustainability. In other words, are we all speaking the same language when it comes to the concept of sustainability and, similarly, sustainable development?