Evaluation of the effectiveness of a Strengths-Based Nursing and Healthcare Leadership program aimed at building leadership capacity: A concurrent mixed-methods study.

Background: Targeted interventions have been found effective for developing leadership practices in nurses. However, to date, no leadership training program based on the Strengths-Based Nursing and Healthcare Leadership approach exists. Objectives: Demonstrate the effectiveness of a Strengths-Based Nursing and Healthcare Leadership 6-month program designed for nurse and healthcare leaders on leadership capacity and psychological outcomes. Design: Concurrent mixed-methods with nurse and healthcare leaders from five healthcare organisations in Quebec and Ontario (Canada). Settings: Participants were recruited from five Canadian health care organizations: two in Toronto (Ontario) and three in Montreal (Quebec). Participants: A total of 50 nurse leaders and healthcare leaders were included in the quantitative component, and 22 (20 nurse leaders and two healthcare leaders) participated in the qualitative individual interviews. Methods: Quantitative and qualitative (interviews) methods were used. Quantitative data (pre-post surveys) were collected from the participants before their participation in the program (Time 0), as well as after the completion of the program (Time 1). Qualitative data (individual interviews) were collected from participants at the end of the program (Time 1). Analysis was conducted using descriptive statistics, paired-sample t-tests, and thematic analysis. Results: Quantitative results suggest a significant improvement in terms of leadership capabilities, work satisfaction, and reduction in perceived stress among participants. Three themes emerged from the qualitative data analysis: 1) focus on people's strengths, 2) structure and language based on Strengths-Based Nursing and Healthcare values, and 3) building support networks. Conclusions: The Strengths-Based Nursing and Healthcare Leadership program developed to build the leadership capabilities of nurse and healthcare leaders was found to be effective. The positive impact of the 6-month program was demonstrated. It was also shown that the leadership program can help improve the leadership competencies, well-being, and work satisfaction of participating nurses and healthcare leaders. Implication: This study reinforces the importance of working with educational, research, and healthcare organizations to establish leadership development programs and mentorship opportunities. Future leadership training should use a Strengths-Based Nursing and Healthcare Leadership lens when tackling leadership and stress in the workplace.

Nursing leaders' perceptions of the impact of the Strengths-Based Nursing and Healthcare Leadership program three months post training.

Background: Development of nursing leadership is necessary to ensure that nurse leaders of the future are well-equipped to tackle the challenges of a burdened healthcare system. In this context, the Strengths-Based Nursing and Healthcare Leadership program was delivered to 121 participants from 5 organizations in Canada in 2021 and 2022. To date, no study used a qualitative approach to explore nursing leaders' perceptions of a leadership Strengths-Based Nursing and Healthcare Leadership program three months post training. Objective: To describe nursing leaders' perceptions of the impact of the Strengths-Based Nursing and Healthcare Leadership program three months post training. Methods: Qualitative descriptive design was used with individual semi-structured interviews. A convenient sample of nurse leaders (n = 20) who had participated in the leadership program were recruited for an individual interview three months post training. The data generated by interviews were analyzed using a method of thematic content analysis. Results: Three themes emerged from the qualitative data analysis related to the leadership program that stayed with participants three months post training: 1) mentorship: a lasting relationship, 2) human connections through Story-sharing, and 3) focus on strengths. Two other themes emerged related to the changes that they have made since attending the program: 1) seeking out different perspectives to work better as a team and 2) create a positive work environment and to show appreciation for their staff. Conclusion: The present study offers evidence of the impact of the Strengths-Based Nursing and Healthcare Leadership program three months post training. Implication: This study reinforces the importance of training using a Strengths-Based Nursing and Healthcare Leadership lens when tackling leadership.

Creating Empowering Conditions for Nurses with Workplace Autonomy and Agency: How Healthcare Leaders Could Be Guided by Strengths-Based Nursing and Healthcare Leadership (SBNH-L).

The COVID-19 pandemic had the unintended consequence of placing nurses in the spotlight because their knowledge and skills were in desperate need. While it will be years until we fully understand the impact that this pandemic has exacted on the nursing workforce, early studies have found that nurses have been traumatized by this event and many intend to leave the profession This seismic event only further exacerbated an already vulnerable and strained nursing workforce that pre-existed worldwide prior to COVID-19. The pandemic also highlighted the many challenges facing nursing leadership, in particular, how to create conditions to maintain and sustain a healthy nursing workforce. Nurses' job satisfaction has emerged as an important predictor of whether nurses remain in an organization and stay in the profession. When examined more closely, job satisfaction has been related to nurses feeling empowered to exercise autonomy over their own practice and having agency. Autonomy and agency, in turn, are affected by their managers' leadership styles. Leaders are instrumental in setting the tone and creating the climate and culture that either values or devalues autonomy and agency. To help leaders create empowering conditions, we have developed a guide for leaders. This guide, based on the value-driven philosophy of leadership called Strengths-Based Nursing and Healthcare Leadership (SBNH-L), is founded on principles of person-centered, empowerment, relationship-focused, and innate capacities (ie, strengths) that are operationalized in eight core values. This guide can be used by leaders as their roadmap to create empowering workplace conditions that value and facilitate nurses' autonomy and agency.

Why Tumor Genetic Heterogeneity May Require Rethinking Cancer Genesis and Treatment.

Tumor genetic heterogeneity, in which individual tumors contain both multiple variant cancer-associated and normal genes, has been widely reported, although its significance has yet to be fully understood. We propose a genetic heterogeneity-based selection-centric hypothesis in which genetic heterogeneity, caused by the temporary reduction of DNA repair efficiency, occurs very early in human development, resulting in a small minority of cells in normal tissues acquiring cancer-associated genes that remain dormant. Cancer develops when precancer cells are selected for by altered tissue microenvironments; similar scenarios occur with development of metastases and therapeutic resistance in established cancer. This suggests that a normal cell selection treatment approach based on preferentially selecting normal cells within tumors may be effective in treating cancer.

Strengths-Based Nursing: A Process for Implementing a Philosophy Into Practice.

Strengths-Based Nursing (SBN) is both a philosophy and value-driven approach that can guide clinicians, educators, manager/leaders, and researchers. SBN is rooted in principles of person/family centered care, empowerment, relational care, and innate health and healing. SBN is family nursing yet not all family nursing models are strengths-based. The challenge is how to translate a philosophy to change practice. In this article, we describe a process of implementation that has organically evolved of a multi-layered and multi-pronged approach that involves patients and families, clinicians, educators, leaders, managers, and researchers as well as key stakeholders including union leaders, opinion leaders, and policy makers from both nursing and other disciplines. There are two phases to the implementation process, namely, Phase 1: pre-commitment/pre-adoption and Phase 2: adoption. Each phase consists of distinct steps with accompanying strategies. These phases occur both sequentially and concurrently. Facilitating factors that enable the implementation process include values which align, readiness to accept SBN, curiosity-courage-commitment on the part of early adopters, a critical mass of early adopters, and making SBN approach both relevant and context specific.

Characterization of the NPC1L1 gene and proteome from an exceptional responder to ezetimibe.

BACKGROUND: Strategies to reduce LDL-cholesterol involve reductions in cholesterol synthesis or absorption. We identified a familial hypercholesterolemia patient with an exceptional response to the cholesterol absorption inhibitor, ezetimibe. Niemann-Pick C 1-like 1 (NPC1L1) is the molecular target of ezetimibe. METHODS AND RESULTS: Sequencing identified nucleotide changes predicted to change amino acids 52 (L52P), 300 (I300T) and 489 (S489G) in exceptional NPC1L1. In silico analyses identified increased stability and cholesterol binding affinity in L52P-NPC1L1 versus WT-NPC1L1. HEK293 cells overexpressing WT-NPC1L1 or NPC1L1 harboring amino acid changes singly or in combination (Comb-NPC1L1) had reduced cholesterol uptake in Comb-NPC1L1 when ezetimibe was present. Cholesterol uptake was reduced by ezetimibe in L52P-NPC1L1, I300T-NPC1L1, but increased in S489G-NPC1L1 overexpressing cells. Immunolocalization studies found preferential plasma membrane localization of mutant NPC1L1 independent of ezetimibe. Flotillin 1 and 2 expression was reduced and binding to Comb-NPC1L1 was reduced independent of ezetimibe exposure. Proteomic analyses identified increased association with proteins that modulate intermediate filament proteins in Comb-NPC1L1 versus WT-NPC1L1 treated with ezetimibe. CONCLUSION: This is the first detailed analysis of the role of NPC1L1 mutations in an exceptional responder to ezetimibe. The results point to a complex set of events in which the combined mutations were shown to affect cholesterol uptake in the presence of ezetimibe. Proteomic analysis suggests that the exceptional response may also lie in the nature of interactions with cytosolic proteins.

Changing genetic paradigms: creating next-generation genetic databases as tools to understand the emerging complexities of genotype/phenotype relationships.

Understanding genotype/phenotype relationships has become more complicated as increasing amounts of inter- and intra-tissue genetic heterogeneity have been revealed through next-generation sequencing and evidence showing that factors such as epigenetic modifications, non-coding RNAs and RNA editing can play an important role in determining phenotype. Such findings have challenged a number of classic genetic assumptions including (i) analysis of genomic sequence obtained from blood is an accurate reflection of the genotype responsible for phenotype expression in an individual; (ii) that significant genetic alterations will be found only in diseased individuals, in germline tissues in inherited diseases, or in specific diseased tissues in somatic diseases such as cancer; and (iii) that mutation rates in putative disease-associated genes solely determine disease phenotypes. With the breakdown of our traditional understanding of genotype to phenotype relationships, it is becoming increasingly apparent that new analytical tools will be required to determine the relationship between genotype and phenotypic expression. To this end, we are proposing that next-generation genetic database (NGDB) platforms be created that include new bioinformatics tools based on algorithms that can evaluate genetic heterogeneity, as well as powerful systems biology analysis tools to actively process and evaluate the vast amounts of both genomic and genomic-modifying information required to reveal the true relationships between genotype and phenotype.

Making sense of intratumor genetic heterogeneity: altered frequency of androgen receptor CAG repeat length variants in breast cancer tissues.

To examine the significance of intratumor genetic heterogeneity (ITGH) of the androgen receptor (AR) gene in breast cancer, patient-matched samples of laser capture microdissected breast tumor cells, adjacent normal breast epithelia cells, and peripheral blood leukocytes were sequenced using a novel next generation sequencing protocol. This protocol measured the frequency of distribution of a variable AR CAG repeat length, a functional polymorphism associated with breast cancer risk. All samples exhibited some degree of ITGH with up to 30 CAG repeat length variants identified. Each type of tissue exhibited a different distribution profile of CAG repeat lengths with substantial differences in the frequencies of zero and 18-25 CAG AR variants. Tissue differences in the frequency of ARs with each of these CAG repeat lengths were significant as measured by paired, twin t-tests. These results suggest that preferential selection of 18-25 CAG repeat length variants in breast tumors may be associated with breast cancer, and support the observation that shorter CAG repeats may protect against breast cancer. They also suggest that merely identifying variant genes will be insufficient to determine the critical mutational events of oncogenesis, which will require measuring the frequency of distribution of mutations within cancerous and matching normal tissues.

Principles of strengths-based nursing leadership for strengths-based nursing care: a new paradigm for nursing and healthcare for the 21st century.

The current healthcare system is slowly evolving into a new system built on a vision of health promotion, primary care and community-based home care, with hospitals still being a core pillar of the healthcare system but not its primary service. This transformation requires a new approach to practice, namely, Strengths-Based Nursing Care (SBC). SBC is about mobilizing, capitalizing and developing a person's strengths to promote health and facilitate healing. For nurses to practise SBNC requires strong nursing leadership that creates conditions to enable them to do so. Strengths-Based Nursing Leadership complements and acts in synergy with, SBNC. This paper describes eight principles of Strengths-Based Nursing Leadership to support SBNC.

The androgen receptor gene mutations database: 2012 update.

The current version of the androgen receptor gene (AR) mutations database is described. A major change to the database is that the nomenclature and numbering scheme now conforms to all Human Genome Variation Society norms. The total number of reported mutations has risen from 605 to 1,029 since 2004. The database now contains a number of mutations that are associated with prostate cancer (CaP) treatment regimens, while the number of AR mutations found in CaP tissues has more than doubled from 76 to 159. In addition, in a number of androgen insensitivity syndrome (AIS) and CaP cases, multiple mutations have been found within the same tissue samples. For the first time, we report on a disconnect within the AIS phenotype-genotype relationship among our own patient database, in that over 40% of our patients with a classic complete AIS or partial AIS phenotypes did not appear to have a mutation in their AR gene. The implications of this phenomenon on future locus-specific mutation database (LSDB) development are discussed, together with the concept that mutations can be associated with both loss- and gain-of-function, and the effect of multiple AR mutations within individuals. The database is available on the internet (http://androgendb.mcgill.ca), and a web-based LSDB with the variants using the Leiden Open Variation Database platform is available at http://www.lovd.nl/AR.

Selection and mutation in the "new" genetics: an emerging hypothesis.

It has been anticipated that new, much more sensitive, next generation sequencing (NGS) techniques, using massively parallel sequencing, will likely provide radical insights into the genetics of multifactorial diseases. While NGS has been used initially to analyze individual human genomes, and has revealed considerable differences between healthy individuals, we have used NGS to examine genetic variation within individuals, by sequencing tissues "in depth", i.e., oversequencing many thousands of times. Initial studies have revealed intra-tissue genetic heterogeneity, in the form of multiple variants of a single gene that exist as distinct "majority and "minority" variants. This highly specialized form of somatic mosaicism has been found within both cancer and normal tissues. If such genetic variation within individual tissues is widespread, it will need to be considered as a significant factor in the ontogeny of many multifactorial diseases, including cancer. The discovery of majority and minority gene variants and the resulting somatic cell heterogeneity in both normal and diseased tissues suggests that selection, as opposed to mutation, might be the critical event in disease ontogeny. We, therefore, are proposing a hypothesis to explain multifactorial disease ontogeny in which pre-existing multiple somatic gene variants, which may arise at a very early stage of tissue development, are eventually selected due to changes in tissue microenvironments.

BAK1 gene variation and abdominal aortic aneurysms.

We sought to examine the role of genetics in the multifactorial disease, abdominal aortic aneurysm (AAA), by studying sequence variation in the BAK1 gene (BAK1) that codes for an apoptotic-promoting protein, as chronic apoptosis activation has been linked to AAA development and progression. BAK1 abdominal aorta cDNA from AAA patients and nondiseased individuals were compared with each other, as well as to the BAK1 genomic sequence obtained from matching blood samples. We found specific BAK1 single nucleotide polymorphism (SNP) containing alleles in both aneurysmic (31 cases) and healthy aortic tissue (5 cases) without seeing them in the matching blood samples. These same BAK1 SNPs have been reported, although rarely (average frequency <0.06%), in reference BAK1 DNA sequences. Based on this and other similar observations, we propose a novel hypothesis postulating that multiple variants of genes may preexist in "minority" forms within specific nondiseased tissues and be selected for, when intra- and/or extracellular conditions change. Therefore, the fact that different BAK1 variants can exist in both diseased and nondiseased AA tissues compared to matching blood samples, together with the rare occurrence of these same SNPs in reference sequences, suggests that selection may be a significant factor in AAA ontogeny.

Isolation of human proteasomes and putative proteasome-interacting proteins using a novel affinity chromatography method.

The proteasome is the primary subcellular organelle responsible for protein degradation. It is a dynamic assemblage of 34 core subunits and many differentially expressed, transiently interacting, modulatory proteins. This paper describes a novel affinity chromatography method for the purification of functional human holoproteasome complexes using mild conditions. Human proteasomes purified by this simple procedure maintained the ability to proteolytically process synthetic peptide substrates and degrade ubiquitinated parkin. Furthermore, the entire purification fraction was analyzed by mass spectrometry in order to identify proteasomal proteins and putative proteasome-interacting proteins. The mild purification conditions maintained transient physical interactions between holoproteasomes and a number of known modulatory proteins. In addition, several classes of putative interacting proteins co-purified with the proteasomes, including proteins with a role in the ubiquitin proteasome system for protein degradation or DNA repair. These results demonstrate the efficacy of using this affinity purification strategy for isolating functional human proteasomes and identifying proteins that may physically interact with human proteasomes.

An investigation into CAG repeat length variation and N/C terminal interactions in the T877A mutant androgen receptor found in prostate cancer.

Prostate cancer may progress by circumventing ablation therapy due to mutations in the androgen receptor (AR) gene. The most intensively studied is the T877A mutation in the ligand binding domain (LBD), which causes the AR to become promiscuous, i.e., respond to a number of different ligands. Our investigations have shown that the T877A mutation alters the inverse relationship between CAG repeat length and transactivation in a noticeable albeit minor manner, while increasing N/C terminal interactions. In the presence of beta-catenin, a coactivator over-expressed in prostate cancer, the inverse relationship between CAG repeat length and transactivation is reversed for the wild type (wt) AR as well. We have also used molecular modeling with the AR and FXXLF and LXXLL peptides to investigate N/C terminal and coactivator interactions. In T877A, this approach revealed an increase in the flexibility of amino acid residues in the activation function 2 (AF-2) domain in the LBD, and a larger solvent accessible surface in T877A compared to the wt AR AF-2 domain. Thus, the improved induced fit of the AR N-terminal domain FXXLF-containing peptide into the T877A LBD could be due to the increased flexibility and solvent accessibility of the AF-2 domain. These new observations suggest that the AR CAG effect can be overridden by prostate cancer mutations, and also further our understanding of hormone-refractory prostate cancer by helping to explain the promiscuity of the T877A mutation.

Human genome variation and pharmacogenetics.

A recent HGVS-sponsored symposium has examined, for the first time, the possible effects of the discovery of very large and widespread amounts of human genome variation on the emerging fields of pharmacogenetics and pharmacogenomics. This article discusses the effects of the resultant paradigm shifts and raises a number of important questions that need to be considered in order to truly advance the field in a meaningful and significant way.

Will knowledge of human genome variation result in changing cancer paradigms?

Our incomplete understanding of carcinogenesis may be a significant reason why some cancer mortality rates are still increasing. This lack of understanding is likely due to a research approach that relies heavily on genetic comparison between cancerous and non-cancerous tissues and cells, which has led to the identification of genes of cancer proliferation rather than differentiation. Recent observations showing that a tremendous degree of natural human genetic variation occurs are likely to lead to a shift in the basic paradigms of cancer genetics, in that there is a need to consider both the nature of the genes involved, and the idea that not every genetic variation identified in these genes may be associated with carcinogenesis. Based on studies using LCM and micro-genetic analyses, we propose that significant cancer initiating events may take place during the very early stages of development of cancer-susceptible tissues and that using such techniques might greatly help us in our understanding of carcinogenesis.

The Developmental/Health Framework within the McGill Model of Nursing: "laws of nature" guiding whole person care.

The Developmental/Health Framework (DHFW) within the McGill Model of Nursing (MMN) provides the foundational knowledge consistent with Nightingale's vision of working with the "laws of nature" to promote health and healing. The DHFW describes the processes, principles, and mechanisms rooted in the biological, developmental, and nursing sciences that are required to provide "whole person" care. The MMN provides a model of nursing based on a strengths-based approach within a collaborative partnership relationship. The DHFW has been used to modify the MMN to create a universal and comprehensive approach to nursing practice.

PhenCode: connecting ENCODE data with mutations and phenotype.

PhenCode (Phenotypes for ENCODE; http://www.bx.psu.edu/phencode) is a collaborative, exploratory project to help understand phenotypes of human mutations in the context of sequence and functional data from genome projects. Currently, it connects human phenotype and clinical data in various locus-specific databases (LSDBs) with data on genome sequences, evolutionary history, and function from the ENCODE project and other resources in the UCSC Genome Browser. Initially, we focused on a few selected LSDBs covering genes encoding alpha- and beta-globins (HBA, HBB), phenylalanine hydroxylase (PAH), blood group antigens (various genes), androgen receptor (AR), cystic fibrosis transmembrane conductance regulator (CFTR), and Bruton's tyrosine kinase (BTK), but we plan to include additional loci of clinical importance, ultimately genomewide. We have also imported variant data and associated OMIM links from Swiss-Prot. Users can find interesting mutations in the UCSC Genome Browser (in a new Locus Variants track) and follow links back to the LSDBs for more detailed information. Alternatively, they can start with queries on mutations or phenotypes at an LSDB and then display the results at the Genome Browser to view complementary information such as functional data (e.g., chromatin modifications and protein binding from the ENCODE consortium), evolutionary constraint, regulatory potential, and/or any other tracks they choose. We present several examples illustrating the power of these connections for exploring phenotypes associated with functional elements, and for identifying genomic data that could help to explain clinical phenotypes.

Somatic mosaicism and cancer: a micro-genetic examination into the role of the androgen receptor gene in prostate cancer.

Recent evidence has shown that the androgen receptor (AR) plays a major role in all prostate cancer stages, including both androgen-dependent and -independent tumors. A large number of studies have examined the possible effects of a functional polymorphism in the AR gene, a variable-length CAG repeat, on the development of prostate cancer, but the results to date have been inconclusive. We have considered the fact that the tissue heterogeneity present in almost all prostate cancer tumors has rarely been regarded as an indicator of AR genetic heterogeneity. To determine if genetic heterogeneity exists and is a significant event in prostate cancer development, we have examined prostate cancer tumors for somatic shortening of the AR gene CAG repeat. All 72 laser capture microdissected samples from archival prostate cancer tissues, as well as samples from freshly prepared prostate cancer tissues, showed some genetic heterogeneity (somatic mosaicism) for AR CAG repeat length. Cancerous tissues showed a much greater degree of genetic heterogeneity than adjacent benign tissues, as well as a very significant shortening of their CAG repeat lengths. However, CAG repeat length heterogeneity was not observed in normal prostate tissues. It is hypothesized that somatic mosaicism of the AR CAG repeat in prostate cancer tumors may be found to be an important genetic event in precancerous tissue, which may subsequently lead to the development of prostate cancer.