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Purpose To assess differences in Patient Aligned Care Team (PACT) performance between rural and urban primary care clinics within the Veterans Health Administration (VHA). Methods An Explanatory Sequential Mixed Methods design was conducted using VHA administrative data to assess performance of a national sample of 891 VHA primary care clinics. Generalized Estimating Equations with repeated measures were used to estimate associations between rurality and process-oriented endpoints including: chronic disease management through telehealth; use of telephone visits, group visits or secured messaging; same-day access; continuity with primary care provider; and postdischarge follow-up. Qualitative data collected during on-site visits with 5 clinics were used to provide insights into PACT processes from the perspectives of staff in rural and urban clinics. Findings After adjusting for patient- and practice-level characteristics, clinics located in large rural or small/isolated rural areas demonstrated difficulty enhancing access through use of telephone visits, group visits, or secured messaging and completing postdischarge follow-up calls, compared to urban clinics. Qualitative analysis indicated that staff from both rural and urban clinics reported similar barriers implementing these PACT processes. Both patient and staff behaviors and preferences impact implementation of these processes. Distance to care and access to high-speed Internet were also reported as barriers. Conclusions This study contributes to the understanding of PACT performance in rural settings by highlighting ways contextual and behavioral factors relate to performance. Increasing implementation of patient-centered medical home (PCMH) models, such as PACT, will require additional attention to the complex relationships between the practice and surrounding context.

Made available in DSpace on 2021-06-25T10:31:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-01 Krembil Foundation Canada Foundation for Innovation Natural Sciences and Engineering Research Council of Canada Canadian Institutes of Health Research MicroRNAs (miRNAs) play vital roles in the regulation of normal developmental pathways. However, cancer cells can co-opt these miRNAs, and the pathways that they regulate, to drive pro-tumourigenic phenotypes. Characterization of the miRNA transcriptomes of fetal organs is essential for identifying these oncofetal miRNAs, but it has been limited by fetal sample availability. As oncofetal miRNAs are absent from healthy adult lungs, they represent ideal targets for developing diagnostic and therapeutic strategies. We conducted small RNA sequencing of a rare collection of 25 human fetal lung (FL) samples and compared them to two independent cohorts (n = 140, n = 427), each comprised of adult non-neoplastic lung (ANL) and lung adenocarcinoma (LUAD) samples. We identified 13 oncofetal miRNAs that were expressed in FL and LUAD but not in ANL. These oncofetal miRNAs are potential biomarkers for LUAD detection (AUC = 0.963). Five of these miRNAs are derived from the imprinted C14MC miRNA cluster at the 14q32 locus, which has been associated with cancer development and abnormal fetal and placental development. Additionally, we observed the pulmonary expression of 44 previously unannotated miRNAs. The sequencing of these fetal lung samples also provides a baseline resource against which aberrant samples can be compared. British Columbia Cancer Research Centre International Research Center A.C. Camargo Cancer Center NYU Langone Medical Center British Columbia Children’s Hospital Research Institute Department of Medical Genetics University of British Columbia Division of Orthopedic Surgery Schroeder Arthritis Institute University Health Network Data Science Discovery Centre for Chronic Diseases Krembil Research Institute University Health Network Department of Medical Biophysics University of Toronto Department of Computer Science University of Toronto Faculty of Medicine São Paulo State University (UNESP) Faculty of Medicine São Paulo State University (UNESP) Canada Foundation for Innovation: 203373 Natural Sciences and Engineering Research Council of Canada: 203475 Canada Foundation for Innovation: 30865 Canadian Institutes of Health Research: FDN-143345

Background Learning healthcare systems have invested heavily in training primary care staff to provide care using patient-centered medical home models, but less is known about how to effectively lead such teams to deliver high quality care. Research is needed to better understand which healthcare leadership skills are most utilized or in need of development through additional training. Method Semi-structured telephone interviews with healthcare leaders familiar with Patient-Aligned Care Teams (PACT) implementation in the U.S. Department of Veterans Affairs (VA). We interviewed sixteen (N = 16) physician, nursing, and administrative leaders at VA facilities located in the upper Midwestern United States. Content analysis of interviews transcripts using template techniques. Results Participants described instrumental challenges that they perceived hindered leadership effectiveness, including the supervisory structure; pace of change; complexity of the clinical data infrastructure; an over-reliance on technology for communication; and gaps in available leadership training. Factors perceived as facilitating effective leadership included training in soft skills, face-to-face communication, and opportunities for formal training and mentorship. A cross-cutting theme was the importance of developing “soft skills” for effective PACT leadership. Conclusions Although formal leadership training and development were perceived as beneficial, healthcare leaders familiar with PACT implementation in the VA described a mismatch between the skills and knowledge PACT leaders need to succeed and the training available to them. Closing this gap could improve retention of skilled and knowledgeable healthcare leaders, thereby reducing the costs associated with training and leading to improvements in healthcare delivery.

BackgroundLong non-coding RNAs (lncRNAs) have long been implicated in cancer-associated phenotypes. Recently, a class of lncRNAs, known as cis-acting, have been shown to regulate the expression of neighboring protein-coding genes and may represent undiscovered therapeutic action points. The chromatin architecture modification gene HMGA1 has recently been described to be aberrantly expressed in lung adenocarcinoma (LUAD). However, the mechanisms mediating the expression of HMGA1 in LUAD remain unknown. Here we investigate the deregulation of a putative cis-acting lncRNA in LUAD, and its effect on the oncogene HMGA1.MethodsLncRNA expression was determined from RNA-sequencing data of tumor and matched non-malignant tissues from 36 LUAD patients. Transcripts with significantly deregulated expression were identified and validated in a secondary LUAD RNA-seq dataset (TCGA). SiRNA-mediated knockdown of a candidate cis-acting lncRNA was performed in BEAS-2B cells. Quantitative real-time PCR was used to observe the effects of lncRNA knockdown on the expression of HMGA1.ResultsWe identified the lncRNA RP11.513I15.6, which we refer to as HMGA1-lnc, neighboring HMGA1 to be significantly downregulated in both LUAD cohorts. Conversely, we found HMGA1 significantly overexpressed in LUAD and anticorrelated with HMGA1-lnc. In vitro experiments demonstrated siRNA-mediated inhibition of HMGA1-lnc in immortalized non-malignant lung epithelial cells resulted in a significant increase in HMGA1 gene expression.ConclusionOur results suggest that HMGA1-lnc is a novel cis-acting lncRNA that negatively regulates HMGA1 gene expression in lung cells. Further characterization of this regulatory mechanism may advance our understanding of the maintenance of lung cancer phenotypes and uncover a novel therapeutic intervention point for tumors driven by HMGA1.

Objective The aim of this study was to analyze perceptions and experiences of clinicians implementing the patient-centered medical home (PCMH). Background The PCMH model focuses on several important concepts, including team-based care management as well as care coordination and continuity among providers and across settings of care. Methods A qualitative analysis of data collected in 2016 from primary care personnel through a national survey was conducted. Results Four themes were found consistent with care management and care coordination: the importance of teamwork and optimized team member roles, need for adequate prioritization of care management and care coordination, need to refine tools and resources supporting care management and care coordination, and challenges with managing and coordinating care with and across complex systems. Conclusions Successful implementation requires adequate support for teamwork and ensuring team members can work according to their clinical competency. Nurses practicing in expanded roles need clear role guidelines and adequate time to function in these roles.

The tumour immune microenvironment is a crucial mediator of lung tumourigenesis, and characterizing the immune landscape of patient tumours may guide immunotherapy treatment regimens and uncover novel intervention points. We sought to identify the landscape of tumour-infiltrating immune cells in the context of long non-coding RNA (lncRNAs), known regulators of gene expression. We examined the lncRNA profiles of lung adenocarcinoma (LUAD) tumours by interrogating RNA sequencing data from microdissected and non-microdissected samples (BCCRC and TCGA). Subsequently, analysis of single-cell RNA sequencing data from lung tumours and flow-sorted healthy peripheral blood mononuclear cells identified lncRNAs in immune cells, highlighting their biological and prognostic relevance. We discovered lncRNA expression patterns indicative of regulatory relationships with immune-related protein-coding genes, including the relationship between AC008750.1 and NKG7 in NK cells. Activation of NK cells in vitro was sufficient to induce AC008750.1 expression. Finally, siRNA-mediated knockdown of AC008750.1 significantly impaired both the expression of NKG7 and the anti-tumour capacity of NK cells. We present an atlas of cancer-cell extrinsic immune cell-expressed lncRNAs, in vitro evidence for a functional role of lncRNAs in anti-tumour immune activity, which upon further exploration may reveal novel clinical utility as markers of immune infiltration.

Around the globe, epidemiologists, statisticians, biologists, and health officials are grappling with these questions. Though engineering perspectives are uncommon in epidemiological modeling, we believe that in this case public officials could greatly benefit from one. Of course, the COVID-19 pandemic isn't an obvious or typical engineering problem. But in its basic behavior it is an unstable, open-loop system. Left alone, it grows exponentially. However, there's good news, too: Like many such systems, it can be stabilized effectively and efficiently by applying the principles of control theory, most notably the use of feedback.

PURPOSE Appropriate delegation of clinical tasks from primary care providers (PCPs) to other team members may reduce employee burnout in primary care. However, (1) the extent to which delegation occurs within multidisciplinary teams, (2) factors associated with greater delegation, and (3) whether delegation is associated with burnout are all unknown. METHODS We performed a national cross-sectional survey of Veterans Affairs (VA) PCP-nurse dyads in Department of VA primary care clinics, 4 years into the VA's patient-centered medical home initiative. PCPs reported the extent to which they relied on other team members to complete 15 common primary care tasks; paired nurses reported how much they were relied on to complete the same tasks. A composite score of task delegation/reliance was developed by taking the average of the responses to the 15 questions. We performed multivariable regression to explore predictors of task delegation and burnout. RESULTS Among 777 PCP-nurse dyads, PCPs reported delegating tasks less than nurses reported being relied on (PCP mean ± standard deviation composite delegation score, 2.97± 0.64 [range, 1-4]; nurse composite reliance score, 3.26 ± 0.50 [range, 1-4]). Approximately 48% of PCPs and 35% of nurses reported burnout. PCPs who reported more task delegation reported less burnout (odds ratio [OR], 0.62 per unit of delegation; 95% confidence interval [CI], 0.49-0.78), whereas nurses who reported being relied on more reported more burnout (OR, 1.83 per unit of reliance; 95% CI, 1.33-2.5). CONCLUSIONS Task delegation was associated with less burnout for PCPs, whereas task reliance was associated with greater burnout for nurses. Strategies to improve work life in primary care by increasing PCP task delegation must consider the impact on nurses.

Introduction: The objectives of this study were to examine if self-reported access to primary care is associated with actual patient wait times and use of telephone visits, and to assess whether this relationship differs by rural residence. Methods: This study used 2016 administrative data from 994 primary care clinics within the Veterans Health Administration. Multiple-linear regression was used to examine relationships between patient perceptions of access and average actual patient wait time, use of telephone visits, and rural residence. Average panel size, clinic type, and panel severity were included as model covariates with cross-product terms for actual wait time, telephone use, and rurality to test for interactions. Results: This study found patient perceptions of access aggregated at the clinic level to be conditional on the relationship between use of telephone visits, actual patient wait times, and rural residence. As actual wait time for routine appointments increases, Veterans served by clinics with a higher percent of rural Veterans perceive telephone visits more positively. Discussion: These findings contribute to our understanding of factors associated with patient perceptions of access by highlighting complex interrelationships between strategies intended to improve access to care and how they can have differing impacts on perceptions among those living in rural or urban locations.

We use a convergent parallel mixed methods approach to explore barriers to the successful implementation of a team-based empowerment initiative within the Veterans Health Administration. Although p...

// Adam P. Sage 1,* , Brenda C. Minatel 1,* , Kevin W. Ng 1 , Greg L. Stewart 1 , Trevor J.B. Dummer 2 , Wan L. Lam 1 and Victor D. Martinez 1 1 Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada 2 Centre of Excellence in Cancer Prevention, School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada * These authors have contributed equally to this work Correspondence to: Victor D. Martinez, email: // Keywords : arsenic, cancer, genetics, epigenetics, non-coding RNA Received : November 30, 2016 Accepted : January 24, 2017 Published : February 05, 2017 Abstract Chronic exposure to arsenic affects more than 200 million people worldwide, and has been associated with many adverse health effects, including cancer in several organs. There is accumulating evidence that arsenic biotransformation, a step in the elimination of arsenic from the human body, can induce changes at a genetic and epigenetic level, leading to carcinogenesis. At the genetic level, arsenic interferes with key cellular processes such as DNA damage-repair and chromosomal structure, leading to genomic instability. At the epigenetic level, arsenic places a high demand on the cellular methyl pool, leading to global hypomethylation and hypermethylation of specific gene promoters. These arsenic-associated DNA alterations result in the deregulation of both oncogenic and tumour-suppressive genes. Furthermore, recent reports have implicated aberrant expression of non-coding RNAs and the consequential disruption of signaling pathways in the context of arsenic-induced carcinogenesis. This article provides an overview of the oncogenomic anomalies associated with arsenic exposure and conveys the importance of non-coding RNAs in the arsenic-induced carcinogenic process.

Background A particularly useful model for examining implementation of quality improvement interventions in health care settings is the PARIHS (Promoting Action on Research Implementation in Health Services) framework developed by Kitson and colleagues. The PARIHS framework proposes three elements (evidence, context, and facilitation) that are related to successful implementation. Purposes An evidence-based program focused on quality enhancement in health care, termed TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety), has been widely promoted by the Agency for Healthcare Research and Quality, but research is needed to better understand its implementation. We apply the PARIHS framework in studying TeamSTEPPS implementation to identify elements that are most closely related to successful implementation. Methodology/approach Quarterly interviews were conducted over a 9-month period in 13 small rural hospitals that implemented TeamSTEPPS. Interview quotes that were related to each of the PARIHS elements were identified using directed content analysis. Transcripts were also scored quantitatively, and bivariate regression analysis was employed to explore relationships between PARIHS elements and successful implementation related to planning activities. Findings The current findings provide support for the PARIHS framework and identified two of the three PARIHS elements (context and facilitation) as important contributors to successful implementation. Practice implications This study applies the PARIHS framework to TeamSTEPPS, a widely used quality initiative focused on improving health care quality and patient safety. By focusing on small rural hospitals that undertook this quality improvement activity of their own accord, our findings represent effectiveness research in an understudied segment of the health care delivery system. By identifying context and facilitation as the most important contributors to successful implementation, these analyses provide a focus for efficient and effective sustainment of TeamSTEPPS efforts.

Head and neck squamous cell carcinoma (HNSCC) has a poor survival rate mainly due to late stage diagnosis and recurrence. Despite genomic efforts to identify driver mutations and changes in protein-coding gene expression, developing effective diagnostic and prognostic biomarkers remains a priority to guide disease management and improve patient outcome. Recent reports of previously-unannotated microRNAs (miRNAs) from multiple somatic tissues have raised the possibility of HNSCC-specific miRNAs. In this study, we applied a customized in-silico analysis pipeline to identify novel miRNAs from raw small-RNA sequencing datasets from public repositories. We discovered 146 previously-unannotated sequences expressed in head and neck samples that share structural properties highly characteristic of miRNAs. The combined expression of the novel miRNAs revealed tissue and context-specific patterns. Furthermore, comparison of tumor with non-malignant tissue samples (n = 43 pairs) revealed 135 of these miRNAs as differentially expressed, most of which were overexpressed or exclusively found in tumor samples. Additionally, a subset of novel miRNAs was significantly associated with HPV infection status and patient outcome. A prognostic-model combining novel and known miRNA was developed (multivariate Cox regression analysis) leading to an improved death and relapse risk stratification (log rank p < 1e-7). The presence of these miRNAs was corroborated both in an independent dataset and by RT-qPCR analysis, supporting their potential involvement in HNSCC. In this study, we report the discovery of 146 novel miRNAs in head and neck tissues and demonstrate their potential biological significance and clinical relevance to head and neck cancer, providing a new resource for the study of HNSCC.

PURPOSE Patient engagement has been broadly defined as the process of actively involving and supporting patients in health care and treatment decision making. The aim of this study was to identify organizational factors that are associated with greater use of patient engagement care practices in Veterans Health Administration primary care clinics. METHODS We conducted a cross-sectional analysis of data from the 2016 Patient-Aligned Care Team (PACT) national survey of direct care clinicians (primary care clinicians, registered nurses, and clinical associates). Exploratory factor analysis was used to group conceptually related patient engagement survey items into 3 subscales: planning and goal setting; motivational interviewing; and organizational strategies to promote self-management. Our independent variables included literature-based factors reported to promote team-based care and interdisciplinary collaboration in primary care. We used generalized estimating equations with multivariate logistic regression analysis to identify independent correlates of high performance on each patient engagement domain (top 25th vs bottom 25th percentile). RESULTS A total of 2,478 direct care clinicians from 609 clinics completed all patient engagement items in the PACT survey. For all patient engagement sub-scales, respondents at high-performing clinics were more likely to report having regular team meetings to discuss performance improvement and having leadership responsible for implementing PACT. For 2 of 3 patient engagement subscales, high performance was also associated with having fully staffed PACT teams (≥3 team members per primary care clinician) and role clarity. CONCLUSIONS Several desirable organizational and contextual factors were associated with high performance of patient engagement care practices. Strategies to improve the organizational functioning of primary care teams may enhance patient engagement in care.

Recent studies have uncovered microRNAs (miRNAs) that have been overlooked in early genomic explorations, which show remarkable tissue- and context-specific expression. Here, we aim to identify and characterize previously unannotated miRNAs expressed in gastric adenocarcinoma (GA). Raw small RNA-sequencing data were analyzed using the miRMaster platform to predict and quantify previously unannotated miRNAs. A discovery cohort of 475 gastric samples (434 GA and 41 adjacent nonmalignant samples), collected by The Cancer Genome Atlas (TCGA), were evaluated. Candidate miRNAs were similarly assessed in an independent cohort of 25 gastric samples. We discovered 170 previously unannotated miRNA candidates expressed in gastric tissues. The expression of these novel miRNAs was highly specific to the gastric samples, 143 of which were significantly deregulated between tumor and nonmalignant contexts (p-adjusted < 0.05; fold change > 1.5). Multivariate survival analyses showed that the combined expression of one previously annotated miRNA and two novel miRNA candidates was significantly predictive of patient outcome. Further, the expression of these three miRNAs was able to stratify patients into three distinct prognostic groups (p = 0.00003). These novel miRNAs were also present in the independent cohort (43 sequences detected in both cohorts). Our findings uncover novel miRNA transcripts in gastric tissues that may have implications in the biology and management of gastric adenocarcinoma.

Background Though much is known about the benefits attributed to medical scribes documenting patient visits (e.g., reducing documentation time for the provider, increasing patient-care time, expanding the roles of licensed and non-licensed personnel), little attention has been paid to how care workers enact scribing as a part of their existing practice. The purpose of this study was to perform an ethnographic process evaluation of an innovative medical scribing practice with primary care teams in Veterans Health Administration (VHA) clinics across the United States. The aim of our study was to understand barriers and facilitators to implementing a scribing practice in primary care. Methods At three to six months after medical scribing was introduced, we used semi-structured interviews and direct observations during site visits to five sites to describe the intervention, understand if the intervention was implemented as planned, and to record the experience of the teams who implemented the intervention. This manuscript only reports on semi-structured interview data collected from providers and scribes. Initial matrix analysis based on categories outlined in the evaluation plan informed subsequent deductive coding using the social-shaping theory Normalization Process Theory. Results Through illustrating the slow accumulation of interactions and knowledge that fostered cautious momentum of teams working to normalize scribing practice in VHA primary care clinics, we show how the practice had 1) an organizing effect, as it centered a shared goal (the creation of the note) between the provider, scribe, and patient, and 2) a generative effect, as it facilitated care workers developing relationships that were both interpersonally and inter-professionally valuable. Based on our findings, we suggest that a scribing practice emphasizes the complementarity of existing professional roles, which thus leverage the interactional possibilities already present in the primary care team. Scribing, as a skill, forged moments of interprofessional fit. Scribing, in practice, created opportunities for interpersonal connection. Conclusions Our research suggests that individuals will notice different benefits to scribing based on their professional expectations and organizational roles related to documenting patient visits. Electronic supplementary material The online version of this article (10.1186/s12913-019-4355-z) contains supplementary material, which is available to authorized users.

Transcriptome sequencing has led to the widespread identification of long non-coding RNAs (lncRNAs). Subsequently, these genes have been shown to hold functional importance in human cellular biology, which can be exploited by tumors to drive the hallmarks of cancer. Due to the complex tertiary structure and unknown binding motifs of lncRNAs, there is a growing disparity between the number of lncRNAs identified and those that have been functionally characterized. As such, lncRNAs deregulated in cancer may represent critical components of cancer pathways that could serve as novel therapeutic intervention points. Pseudogenes are non-coding DNA sequences that are defunct relatives of their protein-coding parent genes but retain high sequence similarity. Interestingly, certain lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans particularly because of this sequence complementarity. We hypothesize that this phenomenon occurs more broadly than previously realized, and that aberrant expression of lncRNAs overlapping pseudogene loci provides an alternative mechanism of cancer gene deregulation. Using RNA-sequencing data from two cohorts of lung adenocarcinoma, each paired with patient-matched non-malignant lung samples, we discovered 104 deregulated pseudogene-derived lncRNAs. Remarkably, many of these deregulated lncRNAs (i) were expressed from the loci of pseudogenes related to known cancer genes, (ii) had expression that significantly correlated with protein-coding parent gene expression, and (iii) had lncRNA protein-coding parent gene expression that was significantly associated with survival. Here, we uncover evidence to suggest the lncRNA-pseudogene-protein-coding gene axis as a prominent mechanism of cancer gene regulation in lung adenocarcinoma, and highlights the clinical utility of exploring the non-coding regions of the cancer transcriptome.

Cancer care delivery is highly complex. Treatment involves coordination within oncology health-care teams and across other teams of referring primary and specialty providers (a team of teams). Each team interfaces with patients and caregivers to offer component parts of comprehensive care. Because patients frequently obtain specialty care from divergent health-care systems resulting in cross-system health-care use, oncology teams need mechanisms to coordinate and collaborate within and across health-care systems to optimize clinical outcomes for all cancer patients. Transactive memory is one potential strategy that can help improve comprehensive patient care delivery. Transactive memory is a process by which two or more team professionals develop a shared system for encoding, storing, and retrieving information. Each professional is responsible for retaining only part of the total information. Applying this concept to a team of teams results in system benefits wherein all teams share an understanding of specialized knowledge held by each component team. The patient’s role as the unifying member of the team of teams is central to successful treatment delivery. This clinical case presents a patient who is receiving oral treatment for advanced prostate cancer within two health systems. The case emphasizes the potential for error when multiple teams function without a point team (the team coordinating efforts of all other primary and specialty teams) and when the specialty knowledge of providers and patients is not well integrated into all phases of the care delivery process.

International implementation of the patient-centered medical home (PCMH) model for delivering primary care has dramatically increased in the last decade. A majority of research on PCMH's impact has emphasized the care provided by clinically trained staff. In this article, we report our ethnographic analysis of data collected from Department of Veterans Affairs staff implementing PACT, the VA version of PCMH. Teams were trained to use within-team delegation, largely accomplished through attention to clinical licensure, to differentiate staff in providing efficient, patient-centered care. In doing so, PACT may reinforce a clinically defined culture of care that countermands PCMH ideals. Such competing rubrics for care are brought into relief through a focus on the care work performed by clerks. Ethnographic analysis identifies clerks' care as a kind of emotional dirty work, signaling important areas for future anthropological study of the relationships among patient-centered care, stigma, and clinical authority.

Made available in DSpace on 2019-10-06T15:22:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-01-26 Canada Foundation for Innovation Canadian Institutes of Health Research University of British Columbia MicroRNAs (miRNAs) are crucial regulators of gene expression in normal development and cellular homeostasis. While miRNA repositories contain thousands of unique sequences, they primarily contain molecules that are conserved across several tissues, largely excluding lineage and tissue-specific miRNAs. By analyzing small non-coding RNA sequencing data for abundance and secondary RNA structure, we discovered 103 miRNA candidates previously undescribed in liver tissue. While expression of some of these unannotated sequences is restricted to non-malignant tissue, downregulation of most of the sequences was detected in liver tumors, indicating their importance in the maintenance of liver homeostasis. Furthermore, target prediction revealed the involvement of the unannotated miRNA candidates in fatty-acid metabolism and tissue regeneration, which are key pathways in liver biology. Here, we provide a comprehensive analysis of the undiscovered liver miRNA transcriptome, providing new resources for a deeper exploration of organ-specific biology and disease. Department of Integrative Oncology British Columbia Cancer Research Centre Krembil Research Institute University Health Network Faculty of Medicine São Paulo State University (UNESP) Faculty of Medicine São Paulo State University (UNESP) Canada Foundation for Innovation: 225404 Canada Foundation for Innovation: 30865

Research evaluating the effectiveness, function, and implementation of patient-centered medical homes (PCMHs) has found major socioprofessional transformations and contributions of primary care physicians and, to a lesser degree, nurses. Our longitudinal ethnographic research with teams implementing PCMH in Veterans Health Administration (VHA) primary care identifies the important but largely underutilized contributions of clerks to PCMH outcomes. Although the relationship of high-performing clerical staff to patient satisfaction is widely acknowledged, PCMH can be further enhanced by enabling clerks to use administrative tasks as conduits for investing in long-term personalized relationships with patients that foster trust in the PCMH and the broader health care organization. Such relationships are engendered through the care-coordination activities clerks perform, which may be bolstered by organizational investment in clerks as skilled health care team members.

IntroductionThe sponging of microRNAs by a long non-coding RNA (lncRNA) away from their coding gene targets is a conceptually-simple, yet biologically-complex method of lncRNA-mediated gene regulation. Currently, predictions of genes that participate in sponge-based regulation are largely based on sequence homology alone, which may not adequately reflect the cellular environment in which lncRNA:miRNA pairs interact. The vast number of potential interactions generated by these predictions impedes the identification of functional gene regulatory relationships, which necessitates an approach that considers biological context. XIST, the female-specific lncRNA canonically involved in silencing the X chromosome, has been suggested by many studies to act as a miRNA sponge. The sex-specificity of XIST provides the opportunity to study the biological feasibility of proposed XIST-miRNA interactions. Here we take a comprehensive approach by considering factors that affect possible regulation through XIST-miRNA sponging.ResultsTo identify the most feasible candidates in a particular tissue (lung adenocarcinomas), we considered protein-coding genes that (1) were positively correlated with XIST expression within sexes, (2) were targeted by miRNAs shared with XIST, and (3) expressed in lung adenocarcinoma. This revealed a robust set of 124 genes potentially positively regulated by XIST through the sequestration of 804 shared miRNAs. We then used the basic sex-specific nature of XIST to compare the changes in miRNA-target gene relationships in endogenously high-XIST and low-XIST systems to discover a high-confidence set of only 13 miRNA-gene pairs. As XIST is expressed exclusively in the nucleus, we validated the nuclear presence of several of these high-confidence miRNAs using RT-qPCR, confirming the co-localization required for XIST to interact with these species.ConclusionsWe use a biology-driven approach to identify genes defended from miRNA-based inhibition by the lncRNA XIST. Importantly, we identify that only a small subset of miRNAs predicted by sequence homology alone have the capacity to mediate the XIST-target gene axis, as they are enriched in the nucleus and able to co-localize with XIST for sponging. Our results reinforce the necessary consideration of biological features in future studies of lncRNA:miRNA interactions.

Deregulation of the imprinted DLK1-DIO3 locus at chromosome 14q32.1-14q32.31 has been associated with developmental and respiratory disorders, including cancer. In lung cancer, deregulation of imprinting at DLK1-DIO3 was recently described in smokers. Deregulated expression of a microRNA (miRNA) cluster mapping to this locus was also associated with patient outcome, suggesting the importance of this locus to lung cancer disease phenotypes. The DLK1-DIO3 locus is complex, and encodes several protein-coding genes, in addition to long and short non-coding RNAs. While the role of miRNAs is established, the biological importance of another relevant class of small RNAs, PIWI-interacting RNAs (piRNAs), has not been investigated. When somatically expressed, piRNAs regulate gene transcription through DNA methylation. Interestingly, their expression patterns have been observed to be altered in cancer and correlated with patient outcome. Here, we characterize the somatic expression of piRNAs encoded at DLK1-DIO3 in two independent cohorts of lung adenocarcinoma and lung squamous cell carcinoma and investigate their associations with patient outcome. We find that the expression of piRNAs encoded at DLK1-DIO3 enhances the prognostic potential of small non-coding RNAs specific to this locus in predicting patient outcome, further emphasizing the importance of regulation at this locus in lung cancer.

Chemotherapy resistance is a key contributor to the dismal prognoses for lung cancer patients. While the majority of studies have focused on sequence mutations and expression changes in protein-coding genes, recent reports have suggested that microRNA (miRNA) expression changes also play an influential role in chemotherapy response. However, the role of genetic alterations at miRNA loci in the context of chemotherapy response has yet to be investigated. In this study, we demonstrate the application of an integrative, multidimensional approach in order to identify miRNAs that are associated with chemotherapeutic resistance and sensitivity utilizing publicly available drug response, miRNA loci copy number, miRNA expression, and mRNA expression data from independent resources. By instigating a logical stepwise strategy, we have identified specific miRNAs that are associated with resistance to several chemotherapeutic agents and provide a proof of principle demonstration of how these various databases may be exploited to derive relevant pharmacogenomic results.

Small and rural hospitals face special challenges to implement and sustain organization-wide quality improvement (QI) initiatives due to limited resources and infrastructures. We studied the implementation of TeamSTEPPS, a national QI initiative, in 14 critical access hospitals. Drawing on QI and organization development theories, we propose five strategic preparation steps for TeamSTEPPS: assess needs, reflect on the context, set goals, develop a shared understanding, and select change agents. We explore how hospitals’ practices correspond to suggested best practices by analyzing qualitative data collected through quarterly interviews with key informants. We find that the level of deliberation was a key factor that differentiated hospitals’ practices. Hospitals that were more deliberate in preparing for the five strategic steps were more likely to experience engagement, perceive efficacy, foresee and manage barriers, and achieve progress during implementation. We discuss potential steps that hospitals may take to better prepare for TeamSTEPPS implementation.

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response.VHLinactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described VHLalone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation.

Identification of novel proteins that can potentially contribute to carcinogenesis is a requisite venture. Herein, we report the first biochemical characterization of the novel F-box and WD40 containing protein, FBXW4. We have identified interacting protein partners and demonstrated that FBXW4 is part of a ubiquitin ligase complex. Furthermore, the Fbxw4 locus is a common site of proviral insertion in a variety of retroviral insertional mutagenesis murine cancer models and Fbxw4 mRNA is highly expressed in the involuting murine mammary gland. To begin to characterize the biochemical function of Fbxw4, we used proteomic analysis to demonstrate that Fbxw4 interacts with Skp1 (SKP1), Cullin1 (CUL1), Ring-box1 (RBX1) and all components of the COP9 signalosome. All of these interactions are dependent on an intact F-box domain of Fbxw4. Furthermore, Fbxw4 is capable of interacting with ubiquitinated proteins within cells in an F-box dependent manner. Finally, we demonstrate that FBXW4 is mutated, lost and under-expressed in a variety of human cancer cell lines and clinical patient samples. Importantly, expression of FBXW4 correlates with survival of patients with non-small cell lung cancer. Taken together, we suggest that FBXW4 may be a novel tumor suppressor that regulates important cellular processes.

A seminal review by Ilgen, Barnes-Farrell, and McKellin (1993) of empirical performance appraisal research during the 1980s suggested that the research during this decade made a number of contributions to the performance appraisal field, but to a limited degree. This article attempts to overcome one of these limits in the 1980s appraisal research suggested by Ilgen et al.-that is, the investigation of the content of cognitive variables. Specifically, this examination is completed through the application of a cognitive process recently introduced in the management literature, thought self-leadership, to the performance appraisal process.

Once thought to be a part of the 'dark matter' of the genome, long non-coding RNAs (lncRNAs) are emerging as an integral functional component of the mammalian transcriptome. LncRNAs are a novel class of mRNA-like transcripts which, despite no known protein-coding potential, demonstrate a wide range of structural and functional roles in cellular biology. However, the magnitude of the contribution of lncRNA expression to normal human tissues and cancers has not been investigated in a comprehensive manner. In this study, we compiled 272 human serial analysis of gene expression (SAGE) libraries to delineate lncRNA transcription patterns across a broad spectrum of normal human tissues and cancers. Using a novel lncRNA discovery pipeline we parsed over 24 million SAGE tags and report lncRNA expression profiles across a panel of 26 different normal human tissues and 19 human cancers. Our findings show extensive, tissue-specific lncRNA expression in normal tissues and highly aberrant lncRNA expression in human cancers. Here, we present a first generation atlas for lncRNA profiling in cancer.