A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets.

Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a versatile preclinical platform in which genetically defined cancers are produced using somatic tissue engineering in transgenic mice harboring a doxycycline-inducible short hairpin RNA against the target of interest. In this system, target inhibition is achieved by the addition of doxycycline, enabling simultaneous assessment of efficacy and toxicity in the same animal. As proof of concept, we focused on CDK9­a cancer target whose clinical development has been hampered by compounds with poorly understood target specificity and unacceptable toxicities. We systematically compared phenotypes produced by genetic Cdk9 inhibition to those achieved using a recently developed highly specific small molecule CDK9 inhibitor and found that both perturbations led to robust antitumor responses. Remarkably, nontoxic levels of CDK9 inhibition could achieve significant treatment efficacy, and dose-dependent toxicities produced by prolonged CDK9 suppression were largely reversible upon Cdk9 restoration or drug withdrawal. Overall, these results establish a versatile in vivo target validation platform that can be employed for rapid triaging of therapeutic targets and lend support to efforts aimed at advancing CDK9 inhibitors for cancer therapy.

Digital and informatics competencies: Requirements for nursing leaders in Canada.

The use of health information technologies continues to grow, especially with the increase in virtual care in response to COVID-19. As the largest health professional group in Canada, nurses are key stakeholders and their active engagement is essential for the meaningful adoption and use of digital health technologies to support patient care. Nurse leaders in particular are uniquely positioned to inform key technology decisions; therefore, enhancing their informatics capacity is paramount to the success of digital health initiatives and investments. The purpose of this commentary is to reflect on current projects relevant to the development of informatics competencies for nurse leaders in the Canadian context and offer our perspectives on ways to enhance current and future nurse leaders' readiness for participation in digital health initiatives. Addressing the digital health knowledge and abilities of nurse leaders will improve their capacity to champion and lead transformative health system changes through digital innovation.

Endovascular Thrombus Removal for Acute Iliofemoral Deep Vein Thrombosis.

BACKGROUND: The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) previously reported that pharmacomechanical catheter-directed thrombolysis (PCDT) did not prevent postthrombotic syndrome (PTS) in patients with acute proximal deep vein thrombosis. In the current analysis, we examine the effect of PCDT in ATTRACT patients with iliofemoral deep vein thrombosis. METHODS: Within a large multicenter randomized trial, 391 patients with acute deep vein thrombosis involving the iliac or common femoral veins were randomized to PCDT with anticoagulation versus anticoagulation alone (No-PCDT) and were followed for 24 months to compare short-term and long-term outcomes. RESULTS: Between 6 and 24 months, there was no difference in the occurrence of PTS (Villalta scale ≥5 or ulcer: 49% PCDT versus 51% No-PCDT; risk ratio, 0.95; 95% CI, 0.78-1.15; P=0.59). PCDT led to reduced PTS severity as shown by lower mean Villalta and Venous Clinical Severity Scores ( P<0.01 for comparisons at 6, 12, 18, and 24 months), and fewer patients with moderate-or-severe PTS (Villalta scale ≥10 or ulcer: 18% versus 28%; risk ratio, 0.65; 95% CI, 0.45-0.94; P=0.021) or severe PTS (Villalta scale ≥15 or ulcer: 8.7% versus 15%; risk ratio, 0.57; 95% CI, 0.32-1.01; P=0.048; and Venous Clinical Severity Score ≥8: 6.6% versus 14%; risk ratio, 0.46; 95% CI, 0.24-0.87; P=0.013). From baseline, PCDT led to greater reduction in leg pain and swelling ( P<0.01 for comparisons at 10 and 30 days) and greater improvement in venous disease-specific quality of life (Venous Insufficiency Epidemiological and Economic Study Quality of Life unit difference 5.6 through 24 months, P=0.029), but no difference in generic quality of life ( P>0.2 for comparisons of SF-36 mental and physical component summary scores through 24 months). In patients having PCDT versus No-PCDT, major bleeding within 10 days occurred in 1.5% versus 0.5% ( P=0.32), and recurrent venous thromboembolism over 24 months was observed in 13% versus 9.2% ( P=0.21). CONCLUSIONS: In patients with acute iliofemoral deep vein thrombosis, PCDT did not influence the occurrence of PTS or recurrent venous thromboembolism. However, PCDT significantly reduced early leg symptoms and, over 24 months, reduced PTS severity scores, reduced the proportion of patients who developed moderate-or-severe PTS, and resulted in greater improvement in venous disease-specific quality of life. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00790335.

Lobular intraepithelial neoplasia: Outcomes and optimal management.

INTRODUCTION: Lobular neoplasia is a term encompassing both atypical lobular hyperplasia and lobular carcinoma in situ. These pathological findings are of uncertain malignant potential and predispose to a higher lifetime risk of breast cancer. Debate surrounds the management of such lesions, with the rationale for diagnostic excision based on the possibility of upgrading to malignancy. In this study, we report the upgrade rate of these lesions and risk of subsequent development of breast cancer. METHODS: This is a retrospective review of a prospectively maintained data base of all biopsies of breast screening-detected abnormalities in a single Irish breast-screening unit. We included all patients with lobular neoplasia on core needle biopsy who underwent diagnostic excision from 2005 to 2012. We excluded those who had concurrent high-risk lesions on biopsy. End points included upgrade rate and subsequent diagnosis of malignancy on follow-up. RESULTS: During the study period, 66 patients met criteria for inclusion, with a mean age of 53.74 years. Upgrade rate following excision was 13.64% (n = 9/66). Of those not upgraded, 7.02% (n = 4/57) were subsequently diagnosed with malignancy. Median time to diagnosis was 59.61 months (range = 10.5-124.4). CONCLUSION: There is a significant rate of upgrade following diagnostic excision of lobular neoplasia, supporting the practice of diagnostic excision. There is an increased lifetime risk of breast cancer for women with a diagnosis of lobular neoplasia, with many of these cancers occurring outside the standard five-year monitoring period, suggesting a potential benefit in extending surveillance.

Instantiating informatics in nursing practice for integrated patient centred holistic models of care: a discussion paper.

AIM: A discussion on how informatics knowledge and competencies can enable nursing to instantiate transition to integrated models of care. BACKGROUND: Costs of traditional models of care are no longer sustainable consequent to the spiralling incidence and costs of chronic illness. The international community looks towards technology-enabled solutions to support a shift towards integrated patient-centred models of care. DESIGN: Discussion paper. DATA SOURCES: A search of the literature was performed dating from 2000-2015 and a purposeful data sample based on relevance to building the discussion was included. DISCUSSION: The holistic perspective of nursing knowledge can support and advance integrated healthcare models. Informatics skills are key for the profession to play a leadership role in design, implementation and operation of next generation health care. However, evidence suggests that nursing engagement with informatics strategic development for healthcare provision is currently variable. IMPLICATIONS FOR NURSING: A statistically significant need exists to progress health care towards integrated models of care. Strategic and tactical plans that are robustly pragmatic with nursing insights and expertise are an essential component to achieve effective healthcare provision. To avoid exclusion in the discourse dominated by management and technology experts, nursing leaders must develop and actively promote the advancement of nursing informatics skills. For knowledge in nursing practice to flourish in contemporary health care, nurse leaders will need to incorporate informatics for optimal translation and interpretation. CONCLUSION: Defined nursing leadership roles informed by informatics are essential to generate concrete solutions sustaining nursing practice in integrated care models.

Morbidly Adherent Placenta: Interprofessional Management Strategies for the Intrapartum Period.

"Morbidly adherent placenta" is a term that describes the continuum of placenta accreta, increta, and percreta. The incidence of this type of abnormal placentation has increased significantly over recent decades. The reason is probably multifactorial but, partly, because of factors such as the increasing number of cesarean births. Women at greatest risk are those who have myometrial damage caused by a previous cesarean birth, with either anterior or posterior placenta previa overlying the uterine scar. This condition poses significant risks of morbidity and/or mortality to the pregnant woman and her fetus. A multidisciplinary approach to care throughout pregnancy is essential. This article describes the classification of morbidly adherent placenta, risk factors, methods of diagnosis, potential maternal and fetal complications, and intrapartum clinical management strategies to optimize outcomes.

Complexities of a Provincial CIS Implementation: Thinking Beyond Scale.

CIS implementations are complex processes involving numerous teams, planning changes to both business and technical processes, and extensive change management. The complexity of implementation increases exponentially when dealing with implementation across an entire province rather than just a single site implementation. This paper addresses the One Person One Record Program in Nova Scotia, Canada where a single CIS will be implemented across the entire province involving 47 acute care facilities and 1400 individual ambulatory clinics. Developing and delivering localized role-specific training to end users is directly affected by the extensive arrange of unique user roles and is part of the complexity in this transformation program. Challenges arising from the additional complexity will be shared as well as lessons learned to support the implementations of future leaders with plans to lead such transformations in their own regions.

Development of a customizable mouse backbone spectral flow cytometry panel to delineate immune cell populations in normal and tumor tissues.

Introduction: In vivo studies of cancer biology and assessment of therapeutic efficacy are critical to advancing cancer research and ultimately improving patient outcomes. Murine cancer models have proven to be an invaluable tool in pre-clinical studies. In this context, multi-parameter flow cytometry is a powerful method for elucidating the profile of immune cells within the tumor microenvironment and/or play a role in hematological diseases. However, designing an appropriate multi-parameter panel to comprehensively profile the increasing diversity of immune cells across different murine tissues can be extremely challenging. Methods: To address this issue, we designed a panel with 13 fixed markers that define the major immune populations -referred to as the backbone panel- that can be profiled in different tissues but with the option to incorporate up to seven additional fluorochromes, including any marker specific to the study in question. Results: This backbone panel maintains its resolution across different spectral flow cytometers and organs, both hematopoietic and non-hematopoietic, as well as tumors with complex immune microenvironments. Discussion: Having a robust backbone that can be easily customized with pre-validated drop-in fluorochromes saves time and resources and brings consistency and standardization, making it a versatile solution for immuno-oncology researchers. In addition, the approach presented here can serve as a guide to develop similar types of customizable backbone panels for different research questions requiring high-parameter flow cytometry panels.

Mutant p53: it's not all one and the same.

Mutation of the TP53 tumor suppressor gene is the most common genetic alteration in cancer, and almost 1000 alleles have been identified in human tumors. While virtually all TP53 mutations are thought to compromise wild type p53 activity, the prevalence and recurrence of missense TP53 alleles has motivated countless research studies aimed at understanding the function of the resulting mutant p53 protein. The data from these studies support three distinct, but perhaps not necessarily mutually exclusive, mechanisms for how different p53 mutants impact cancer: first, they lose the ability to execute wild type p53 functions to varying degrees; second, they act as a dominant negative (DN) inhibitor of wild type p53 tumor-suppressive programs; and third, they may gain oncogenic functions that go beyond mere p53 inactivation. Of these possibilities, the gain of function (GOF) hypothesis is the most controversial, in part due to the dizzying array of biological functions that have been attributed to different mutant p53 proteins. Herein we discuss the current state of understanding of TP53 allele variation in cancer and recent reports that both support and challenge the p53 GOF model. In these studies and others, researchers are turning to more systematic approaches to profile TP53 mutations, which may ultimately determine once and for all how different TP53 mutations act as cancer drivers and whether tumors harboring distinct mutations are phenotypically unique. From a clinical perspective, such information could lead to new therapeutic approaches targeting the effects of different TP53 alleles and/or better sub-stratification of patients harboring TP53 mutant cancers.

Advancing faculty diversity in nursing education: Strategies for success.

Despite the established value of diversity, equity, and inclusion as critical components to achieving academic excellence, building diversity within nursing education remains a challenge. Institutional gatekeeping, overt racism, and implicit biases are barriers that perpetuate a low percentage of nursing faculty of color. From pre-search strategic prioritization to submission of the search committee report, a multi-prong, just, transparent, systematic, and strategic approach to hiring is needed to advance opportunities for hiring a diverse faculty. This article provides nursing administration leaders, search committee members, and faculty engaged in hiring practices with a stepwise review of specific strategies. Evidence and tools to mitigate bias, attract excellent and diverse applicant pools, conduct fair evaluations, and support ongoing reflection and improvement of hiring practices are described. An overview of types of implicit bias in hiring practices, descriptive evaluation rubrics, and self-reflection questions are included.

Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants.

Base editing can be applied to characterize single nucleotide variants of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular base-editing-activity 'sensors' that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor-sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated single nucleotide variants in multiple model systems. We demonstrate that sensor-validated tools streamline production of in vivo cancer models and that integrating sensor modules in pooled sgRNA libraries can aid interpretation of high-throughput base editing screens. Using this approach, we identify several previously uncharacterized mutant TP53 alleles as drivers of cancer cell proliferation and in vivo tumor development. We anticipate that the framework described here will facilitate the functional interrogation of cancer variants in cell and animal models.

Clinician investigator training in Canada: a review.

PURPOSE: The Royal College of Physicians and Surgeons of Canada undertook a review of its Clinician Investigator Program (CIP), 13 years after launching the program in response to shortages in clinical investigators. The primary study goals were to determine the outcomes, impact, strengths and weaknesses of CIP. METHODS: Focus groups and telephone interviews with current and past program directors (PD) and a detailed survey of current and former trainees were conducted. Thirteen PD and 45% of current and former trainees from 10 CIP participated. RESULTS: Since 1995, 12 CIP have been accredited and 553 residents have enrolled in CIP, with 194 completing CIP and residency training by 2008. PD recognized CIP as an excellent program that produces highly qualified clinical investigators; important for faculty renewal. Both trainees and PD identified the need to improve CIP funding. Most (84%) CIP trainees did not have prior graduate degrees. Most alumni had completed Masters (58%) or Doctoral (39%) programs during CIP and published on their CIP research (97%). Among alumni who completed CIP and residency, many obtained an academic appointment with protected time for research, with 39% receiving an external career award. Many (60%) alumni reported no drawbacks to CIP and recognized the added values included Royal College recognition, structured training, pursuit of graduate studies, integration of clinical/research training and enhanced mentorship. CONCLUSION: Since the progam's inception, the number of CIP in Canada has grown. CIP are recognized as important mechanisms for integrating clinical and research training during residency to produce highly qualified clinician investigators.

Educational Theory and Cognitive Science: Practical Principles to Improve Patient Education.

There can be multiple barriers to implementation of patient education, yet there are also multiple modalities and opportunities for engaging patients. Using frameworks and evidence from multiple disciplines can inform nursing design of patient education approaches. This article provides an introduction to educational theory and cognitive science principles such as constructivism, metacognition, deliberate practice, and cognitive load for consideration in improving the effectiveness and outcomes of patient education.

Goals for Collaborative Management of Obstetric Hemorrhage.

Hemorrhage remains a leading cause of preventable maternal morbidity and mortality worldwide and in the United States. Postpartum hemorrhage is the number one cause of severe morbidity during hospitalization for birth, despite hospital, state, and national initiatives. In addition, studies show that more than 90% of maternal deaths related to obstetric hemorrhage are preventable. This article reviews relevant physiologic changes of pregnancy that may have an impact on hemorrhage management and describes collaborative approaches for management of hemorrhage in this unique population.

Supporting the Development of Informatics Competencies Among Senior Nurse Leaders in Canada.

This poster will provide an overview of the various initiatives completed to support the development of informatics competencies among senior nurse leaders in Canada. These initiatives have included a literature review to uncover competencies of relevance to the Canadian context, and a Delphi study to achieve consensus on the competencies for Canada. Current and future plans will be discussed to translate these competencies into practice among senior nurse leaders.

Upgrade rates and outcomes of screen-detected atypical intraductal epithelial proliferation (AIDEP) diagnosed on core needle biopsy.

INTRODUCTION: Atypical intraductal epithelial proliferation (AIDEP) is a breast lesion categorised as "indeterminate" if identified on core needle biopsy (CNB). The rate at which these lesions are upgraded following diagnostic excision varies in the literature. Women diagnosed with AIDEP are thought to be at increased risk of breast cancer. Our aim was to identify the rate of upgrade to invasive or in situ carcinoma in a group of patients diagnosed with AIDEP on screening mammography and to quantify their risk of subsequent breast cancer. METHODS: We conducted a retrospective review of a prospectively maintained database containing all patients diagnosed with AIDEP on CNB between 2005 and 2012 in an Irish breast screening centre. Basic demographic data was collected along with details of the original CNB result, rate of upgrade to carcinoma and details of any subsequent cancer diagnoses. RESULTS: In total 113 patients were diagnosed with AIDEP on CNB during the study period. The upgrade rate on diagnostic excision was 28.3% (n = 32). 6.2% (n = 7) were upgraded to invasive cancer and 22.1% (n = 25) to DCIS. 81 patients were not upgraded on diagnostic excision and were offered 5 years of annual mammographic surveillance. 9.88% (8/81) of these patients went on to receive a subsequent diagnosis of malignancy. The mean time to diagnosis of these subsequent cancers was 65.41 months (range 20.18-145.21). CONCLUSION: Our data showing an upgrade rate of 28% to carcinoma reflects recently published data and we believe it supports the continued practice of excising AIDEP to exclude co-existing carcinoma.

Rab34 GTPase mediates ciliary membrane formation in the intracellular ciliogenesis pathway.

The primary cilium is an essential organizing center for signal transduction, and ciliary defects cause congenital disorders known collectively as ciliopathies.1-3 Primary cilia form by two pathways that are employed in a cell-type- and tissue-specific manner: an extracellular pathway in which the cilium grows out from the cell surface and an intracellular pathway in which the nascent cilium first forms inside the cell.4-8 After exposure to the external environment, cilia formed via the intracellular pathway may have distinct functional properties, as they often remain recessed within a ciliary pocket.9,10 However, the precise mechanism of intracellular ciliogenesis and its relatedness to extracellular ciliogenesis remain poorly understood. Here we show that Rab34, a poorly characterized GTPase recently linked to cilia,11-13 is a selective mediator of intracellular ciliogenesis. We find that Rab34 is required for formation of the ciliary vesicle at the mother centriole and that Rab34 marks the ciliary sheath, a unique sub-domain of assembling intracellular cilia. Rab34 activity is modulated by divergent residues within its GTPase domain, and ciliogenesis requires GTP binding and turnover by Rab34. Because Rab34 is found on assembly intermediates that are unique to intracellular ciliogenesis, we tested its role in the extracellular pathway used by polarized MDCK cells. Consistent with Rab34 acting specifically in the intracellular pathway, MDCK cells ciliate independently of Rab34 and its paralog Rab36. Together, these findings establish that different modes of ciliogenesis have distinct molecular requirements and reveal Rab34 as a new GTPase mediator of ciliary membrane biogenesis.

Alpha 2-macroglobulin binds CpG oligodeoxynucleotides and enhances their immunostimulatory properties by a receptor-dependent mechanism.

CpG oligodeoxynucleotides (ODN) stimulate the immune system and are under evaluation as treatments and vaccine adjuvants for infectious diseases, cancer, and immune system disorders. Although they have shown promising results in numerous clinical trials, the ultimate use of CpG ODN-based therapeutics may hinge on improved pharmacokinetics and reduced systemic side-effects. CpG ODN efficacy and potency might be enhanced greatly by packaging them into particles that protect them from degradation and specifically target them for uptake by immune-competent cells. The plasma proteinase inhibitor alpha 2-macroglobulin (alpha 2M) binds numerous biologically active macromolecules, including cytokines, chemokines, and growth factors, and can modulate their activity. Molecules bound to alpha 2M are protected from interactions with neighboring macromolecules and are targeted for receptor-mediated uptake by immune-competent cells. Here, we report that activated alpha 2M (alpha 2M*) binds CpG ODN and enhances their immunostimulatory properties significantly. Murine macrophages treated with alpha 2M*-ODN complexes respond more rapidly and produce a greater cytokine response than induced by free CpG ODN. Using human PBMC, alpha 2M*-ODN complexes exhibit fourfold enhanced potency and 15-fold greater efficacy for stimulating production of inflammatory cytokines. alpha 2M* targets delivery of CpG ODN specifically to immune-competent cells, which endocytose the complexes sixfold more rapidly than free CpG ODN. CpG ODN bound to alpha 2M* are also protected from degradation by nucleases. This novel targeting technology may improve CpG ODN-based therapeutics by increasing efficacy at reduced doses, thus reducing side-effects and cost.

Adapting and validating informatics competencies for senior nurse leaders in the Canadian context: Results of a Delphi study.

BACKGROUND: Nurse leaders in senior leadership positions in various parts of the world can play an important role in the acquisition, implementation and use of health information technologies. To date, international research related to nurse leader informatics competencies has been carried out in specific healthcare delivery contexts with very specific health information technology environments. In this body of literature, the definition of a 'nurse leader' has not been clearly defined. As a result, it is challenging for senior nurse leaders in leadership and management positions in other countries to apply this research to their unique contexts. PURPOSE: The objective of this study was to obtain consensus on the informatics competencies of priority to senior Canadian nurse leaders. The goal of completing this work was to adapt and validate a set of nurse leader informatics competencies to be endorsed and supported nationally. METHODS: This study used a modified Delphi technique with a panel of nurse leaders with significant informatics knowledge from across Canada. Three rounds of information gathering were completed electronically. In Round 1, participants were provided a series of 26 potential competency statements obtained from a review of the literature; they were asked to comment on the clarity and wording of each statement. Two statements were eliminated after Round 1 due to redundancy. In Rounds 2 and 3, participants rated the remaining competency statements on a 7-point Likert scale for relative priority to nurse leaders. RESULTS: A total of 25, 24 and 23 participants completed the survey in Rounds 1, 2 and 3 respectively. Consensus was achieved at the end of Round 3 with the inclusion of 24 competency statements. All of the statements had a mean of 5 or greater on a 7-point Likert scale (1=low priority and 7=high priority). CONCLUSIONS: The study participants agreed upon 24 informatics competency statements of priority to Canadian nurse leaders. These competencies will be presented to senior national nursing leaders and nursing informatics organizations for endorsement. Inspired by work completed in the United States, the authors plan to develop a self-assessment instrument for use by Canadian nurse leaders using the identified competency statements. Future anticipated work includes identifying and creating resources for nurse leaders to develop these important informatics competencies.

Alcohol consumption and lower extremity arterial disease among older adults: the cardiovascular health study.

Few studies of the relation of alcohol intake to lower-extremity arterial disease (LEAD) have included clinical events and objective measurements repeated longitudinally. As part of the Cardiovascular Health Study, a study of older adults from four US communities, 5,635 participants reported their use of beer, wine, and spirits yearly. Incident LEAD was identified by hospitalization surveillance. Technicians measured ankle-brachial index 6 years apart in 2,298 participants. A total of 172 cases of LEAD were documented during a mean of 7.5 years of follow-up between 1989 and 1999. Compared with abstention, the multivariable-adjusted hazard ratios were 1.10 (95% confidence interval (CI): 0.71, 1.71) for <1 alcoholic drink per week, 0.56 (95% CI: 0.33, 0.95) for 1-13 drinks per week, and 1.02 (95% CI: 0.53, 1.97) for > or =14 drinks per week (p for quadratic trend = 0.04). These relations were consistent within strata of sex, age, and apolipoprotein E genotype, and neither lipids nor inflammatory markers appeared to be important intermediates. Change in ankle-brachial index showed a similar relation (p for quadratic trend = 0.01). Alcohol consumption of 1-13 drinks per week in older adults may be associated with lower risk of LEAD, but heavier drinking is not associated with lower risk.