Fighting Fires and Battling the Clock: Advance Care Planning in Family Medicine Residency.

BACKGROUND AND OBJECTIVES: Few family physicians treating patients with life-limiting illness report regularly initiating advance care planning (ACP) conversations about illness understanding, values, or care preferences. To better understand how family medicine training contributes to this gap in clinical care, we asked how family medicine residents learn to engage in ACP in the workplace. METHODS: We coded semistructured interviews with family medicine residents (n=9), reflective memos (n=9), and autoethnographic field notes (n=37) using a constructivist-grounded theory approach. We next used the constant comparative method of grounded theory to develop two composite narratives describing participants' experiences that we then member-checked with participants. RESULTS: We identified six core categories of social process to describe how participants were taught to engage in advance care planning. These social processes included previously unidentified barriers to ACP that were specific to their role as learners. These barriers appeared to lead to cultural avoidance of prognosis, conflation of ACP and goals of care (GOC) conversations, and deferral of difficult conversations to nonprimary care settings. CONCLUSIONS: Family medicine educators should consider developing interventions such as flexible clinic schedules, dedicated ACP time, deliberate observed practice, and structured teaching to address potential barriers identified in this exploratory research. Family medicine leaders may wish to consider directly teaching residents and preceptors about crucial differences between ACP and GOC discussions. Shifting curricular focus toward eliciting values and illness understanding during ACP could help resolve a cultural avoidance of prognosis that limits family medicine residents' attempts to engage in ACP.

Normalization of organ-on-a-Chip samples for mass spectrometry based proteomics and metabolomics via Dansylation-based assay.

Mass spectrometry based 'omics pairs well with organ-on-a-chip-based investigations, which often have limited cellular material for sampling. However, a common issue with these chip-based platforms is well-to-well or chip-to-chip variability in the proteome and metabolome due to factors such as plate edge effects, cellular asynchronization, effluent flow, and limited cell count. This causes high variability in the quantitative multi-omics analysis of samples, potentially masking true biological changes within the system. Solutions to this have been approached via data processing tools and post-acquisition normalization strategies such as constant median, constant sum, and overall signal normalization. Unfortunately, these methods do not adequately correct for the large variations, resulting in a need for increased biological replicates. The methods in this work utilize a dansylation based assay with a subset of labeled metabolites that allow for pre-acquisition normalization to better correlate the biological perturbations that truly occur in chip-based platforms. BCA protein assays were performed in tandem with a proteomics pipeline to achieve pre-acquisition normalization. The CN Bio PhysioMimix was seeded with primary hepatocytes and challenged with VX after six days of culture, and the metabolome and proteome were analyzed using the described normalization methods. A decreased coefficient of variation percentage is achieved, significant changes are observed through the proteome and metabolome, and better classification of biological replicates acquired because of these strategies.

Anticancer Activity of ST101, A Novel Antagonist of CCAAT/Enhancer Binding Protein ß.

CCAAT/enhancer binding protein ß (C/EBPß) is a basic leucine zipper (bZIP) family transcription factor, which is upregulated or overactivated in many cancers, resulting in a gene expression profile that drives oncogenesis. C/EBPß dimerization regulates binding to DNA at the canonical TTGCGCAA motif and subsequent transcriptional activity, suggesting that disruption of dimerization represents a powerful approach to inhibit this previously "undruggable" oncogenic target. Here we describe the mechanism of action and antitumor activity of ST101, a novel and selective peptide antagonist of C/EBPß that is currently in clinical evaluation in patients with advanced solid tumors. ST101 binds the leucine zipper domain of C/EBPß, preventing its dimerization and enhancing ubiquitin-proteasome dependent C/EBPß degradation. ST101 exposure attenuates transcription of C/EBPß target genes, including a significant decrease in expression of survival, transcription factors, and cell-cycle-related proteins. The result of ST101 exposure is potent, tumor-specific in vitro cytotoxic activity in cancer cell lines including glioblastoma, breast, melanoma, prostate, and lung cancer, whereas normal human immune and epithelial cells are not impacted. Further, in mouse xenograft models ST101 exposure results in potent tumor growth inhibition or regression, both as a single agent and in combination studies. These data provide the First Disclosure of ST101, and support continued clinical development of ST101 as a novel strategy for targeting C/EBPß-dependent cancers.

Patient contracts for chronic medical conditions: Scoping review.

OBJECTIVE: To describe how and why patient contracts are used for the management of chronic medical conditions. DATA SOURCES: A scoping review was conducted in the following databases: MEDLINE, Embase, AMED, PsycInfo, Cochrane Library, CINAHL, and Nursing & Allied Health. Literature from 1997 to 2017 was included. STUDY SELECTION: Articles were included if they were written in English and described the implementation of a patient contract by a health care provider for the management of a chronic condition. Articles had to present an outcome as a result of using the contract or an intervention that included the contract. SYNTHESIS: Of the 7528 articles found in the original search, 76 met the inclusion criteria for the final review. Multiple study types were included. Extensive variety in contract elements, target populations, clinical settings, and cointerventions was found. Purposes for initiating contracts included behaviour change and skill development, including goal development and problem solving; altering beliefs and knowledge, including motivation and perceived self-efficacy; improving interpersonal relationships and role clarification; improving quality and process of chronic care; and altering objective and subjective health indices. How contracts were developed, implemented, and assessed was inconsistently described. CONCLUSION: More research is required to determine whether the use of contracts is accomplishing their intended purposes. Questions remain regarding their rationale, development, and implementation.

Working towards success in the Royal Australian and New Zealand College of Psychiatrists Modified Essay Question Exam.

OBJECTIVE: To describe an approach to support Royal Australian and New Zealand College of Psychiatrists (RANZCP) trainees achieve success in the Modified Essay Question (MEQ) examination. METHOD: Synthesis of the opinion of the authorship encompassing a range of relevant stakeholders, supported by a qualitative content analysis of published examination feedback from the RANZCP Committee for Examinations. RESULTS: In approaching the MEQs, candidates are encouraged to (1) read the scenario and questions carefully, (2) answer questions broadly and with justification, (3) manage time effectively, (4) undertake deliberate practice in preparation, and (5) 'check your own pulse' (i.e. limit the detrimental impact of anxiety on performance). CONCLUSION: Preparing for the MEQ examination through deliberate practice will help candidates become competent psychiatrists. The ability to critically think in clinical practice, a key focus of this assessment, is an essential skill all psychiatrists need to develop and maintain.

Advance care planning conversations in primary care: a quality improvement project using the Serious Illness Care Program.

BACKGROUND: Advance care planning (ACP) conversations are associated with improved end-of-life healthcare outcomes and patients want to engage in ACP with their healthcare providers. Despite this, ACP conversations rarely occur in primary care settings. The objective of this study was to implement ACP through adapted Serious Illness Care Program (SICP) training sessions, and to understand primary care provider (PCP) perceptions of implementing ACP into practice. METHODS: We conducted a quality improvement project guided by the Normalization Process Theory (NPT), in an interprofessional academic family medicine group in Hamilton, Ontario, Canada. NPT is an explanatory model that delineates the processes by which organizations implement and integrate new work. PCPs (physicians, family medicine residents, and allied health care providers), completed pre- and post-SICP self-assessments evaluating training effectiveness, a survey evaluating program implementability and sustainability, and semi-structured qualitative interviews to elaborate on barriers, facilitators, and suggestions for successful implementation. Descriptive statistics and pre-post differences (Wilcoxon Sign-Rank test) were used to analyze surveys and thematic analysis was used to analyze qualitative interviews. RESULTS: 30 PCPs participated in SICP training and completed self-assessments, 14 completed NoMAD surveys, and 7 were interviewed. There were reported improvements in ACP confidence and skills. NoMAD surveys reported mixed opinions towards ACP implementation, specifically concerning colleagues' abilities to conduct ACP and patients' abilities to participate in ACP. Physicians discussed busy clinical schedules, lack of patient preparedness, and continued discomfort or lack of confidence in having ACP conversations. Allied health professionals discussed difficulty sharing patient prognosis and identification of appropriate patients as barriers. CONCLUSIONS: Training in ACP conversations improved PCPs' individual perceived abilities, but discomfort and other barriers were identified. Future iterations will require a more systematic process to support the implementation of ACP into regular practice, in addition to addressing knowledge and skill gaps.

Discovery of Surfactins as Inhibitors of MicroRNA Processing Using Cat-ELCCA.

MicroRNAs (miRNAs) are a family of small noncoding RNAs that regulate gene expression. Due to their important activity in the fine-tuning of protein translation, abnormal expression of miRNAs has been linked to many human diseases, making the targeting of miRNAs attractive as a novel therapeutic strategy. Accordingly, researchers have been heavily engaged in the discovery of small molecule modulators of miRNAs. With an interest in the identification of new chemical space for targeting miRNAs, we developed a high-throughput screening (HTS) technology, catalytic enzyme-linked click chemistry assay (cat-ELCCA), aimed at the discovery of small molecule ligands for pre-miR-21, a miRNA that is frequently overexpressed in human cancers. From our HTS campaign, we found that natural products, a source of many impactful human medicines, may be a promising source of potential pre-miR-21-selective maturation inhibitors. Herein we describe our first efforts in natural product inhibitor discovery leading to the identification of a depsipeptide class of natural products as RNA-binding inhibitors of Dicer-mediated miRNA processing.

Neurobiological and Psychological Maintenance Mechanisms Associated with Anticipatory Reward in Bulimia Nervosa.

The purpose of this investigation is to identify the anticipatory reward mechanisms that maintain binge eating and purging in bulimia nervosa. Emerging data indicate the importance of reward and anticipatory processes as maintenance mechanisms of bulimia nervosa that can be targeted in treatment. The proposed research will identify neurobiological and psychological anticipatory mechanisms of binge eating and purging using functional magnetic resonance imaging (fMRI), and ecological momentary assessment (EMA) in the natural environment. In this investigation, 60 adults (30 with bulimia nervosa and 30 matched comparison participants) will undergo negative and positive mood inductions followed by an fMRI food selection task (and a comparison shopping task) to examine neurobiological and affective responses to food and non-food reward anticipation. Participants with bulimia nervosa will complete two weeks of EMA examining real-time affect changes in relation to the anticipation of binge eating and purging. These methods will facilitate rigorous assessment of the links between neurobiological (fMRI) and naturalistic (EMA) data in anticipatory reward processes. Findings from this investigation will inform the conceptualization and treatment of bulimia nervosa by identifying the role of reward anticipation in symptom maintenance, providing a crucial framework for targeting these anticipatory processes in existing and novel interventions.

Frequency of providing a palliative approach to care in family practice: a chart review and perceptions of healthcare practitioners in Canada.

BACKGROUND: Most patients nearing the end of life can benefit from a palliative approach in primary care. We currently do not know how to measure a palliative approach in family practice. The objective of this study was to describe the provision of a palliative approach and evaluate clinicians' perceptions of the results. METHODS: We conducted a descriptive study of deceased patients in an interprofessional team family practice. We integrated conceptual models of a palliative approach to create a chart review tool to capture a palliative approach in the last year of life and assessed a global rating of whether a palliative approach was provided. Clinicians completed a questionnaire before learning the results and after, on perceptions of how often they believed a palliative approach was provided by the team. RESULTS: Among 79 patients (mean age at death 73 years, 54% female) cancer and cardiac diseases were the top conditions responsible for death. One-quarter of patients were assessed as having received a palliative approach. 53% of decedents had a documented discussion about goals of care, 41% had nurse involvement, and 15.2% had a discussion about caregiver well-being. These indicators had the greatest discrimination between a palliative approach or not. Agreement that elements of a palliative approach were provided decreased significantly on the clinician questionnaire from before to after viewing the results. CONCLUSIONS: This study identified measurable indicators of a palliative approach in family practice, that can be used as the basis for quality improvement.

Does Switching Antipsychotics Ameliorate Weight Gain in Patients With Severe Mental Illness? A Systematic Review and Meta-analysis.

OBJECTIVE: Obesity and adverse metabolic outcomes in patients with severe mental illness are clinically significant but potentially preventable. Importantly, the evidence for switching to antipsychotics to reduce cardiometabolic burden is unclear. METHOD: PubMED, Embase, PsycINFO, and Cochrane were searched from inception to March 8, 2020. Articles reporting weight and metabolic changes after antipsychotic switching vs staying on the previous antipsychotic were meta-analyzed both across and within group. RESULTS: Of 61 identified studies, 59 were meta-analyzed (40% rated high quality). In the switch-vs-stay pairwise meta-analyses, only aripiprazole significantly reduced weight (-5.52 kg, 95% CI -10.63, -0.42, P = .03), while olanzapine significantly increased weight (2.46 kg, 95% CI 0.34, 4.57, P = .02). Switching to aripiprazole also significantly improved fasting glucose (-3.99 mg/dl, 95% CI -7.34, -0.64, P = .02) and triglycerides (-31.03 mg/dl, 95% CI -48.73, -13.34, P = .0001). Dropout and psychosis ratings did not differ between switch and stay groups for aripiprazole and olanzapine. In before-to-after switch meta-analyses, aripiprazole (-1.96 kg, 95% CI -3.07, -0.85, P < .001) and ziprasidone (-2.22 kg, 95% CI -3.84, -0.60, P = .007) were associated with weight loss, whereas olanzapine (2.71 kg, 95% CI 1.87, 3.55, P < .001), and clozapine (2.80 kg, 95% CI 0.26, 5.34, P = .03) were associated with weight gain. No significant weight or other cardiometabolic changes were observed when switching to amisulpride, paliperidone/risperidone, quetiapine, or lurasidone. CONCLUSIONS: Switching antipsychotics to agents with lower weight gain potential, notably to aripiprazole and ziprasidone, can improve weight profile and other cardiometabolic outcomes. When choosing switch agents, both the weight gain potential of the pre- and post-switch antipsychotic must be considered. Antipsychotic switching in psychiatrically stable patients must be weighed against the risk of psychiatric worsening.

Maternal prenatal depression, PTSD, and problematic parenting: the mediating role of maternal perceptions of infant emotion.

Background: Perinatal illness is alarmingly common and has negative effects on maternal and infant well-being. Depression and posttraumatic stress disorder (PTSD), specifically, are characterised by negative views of the self and others, which may impact a mother's perceptions of herself and her child. Objective: This study examined the relationship between depression and PTSD symptoms, maternal perceptions of infant emotions, and parenting behaviours. Methods: 120 pregnant, mostly low-income women and their infants (after birth) participated in a longitudinal study. Maternal depression and PTSD symptoms were assessed during pregnancy and 1 year postpartum; maternal perceptions of infant emotions and parenting quality were assessed at 1 year. Results: Correlation analyses revealed significant, negative associations between prenatal (but not postnatal) psychiatric symptoms and positive perceptions of infant emotions, as well as between positive perceptions of infant emotions and negative parenting. Results also revealed significant indirect effects of prenatal depressive and PTSD symptoms on negative parenting via perceptions of infant emotion (95% CIs:.0013 -.0200 and.0008 -.0083, respectively). Conclusion: Findings highlight that mothers should be routinely screened for psychiatric symptoms during the perinatal period, and perceptions of infant emotions may be an important target for parent-infant mental health interventions.

Long-Term Cryopreservation Preserves Blood-Brain Barrier Phenotype of iPSC-Derived Brain Microvascular Endothelial Cells and Three-Dimensional Microvessels.

Brain microvascular endothelial cells derived from induced pluripotent stem cells (dhBMECs) are a scalable and reproducible resource for studies of the human blood-brain barrier, including mechanisms and strategies for drug delivery. Confluent monolayers of dhBMECs recapitulate key in vivo functions including tight junctions to limit paracellular permeability and efflux and nutrient transport to regulate transcellular permeability. Techniques for cryopreservation of dhBMECs have been reported; however, functional validation studies after long-term cryopreservation have not been extensively performed. Here, we characterize dhBMECs after 1 year of cryopreservation using selective purification on extracellular matrix-treated surfaces and ROCK inhibition. One-year cryopreserved dhBMECs maintain functionality of tight junctions, efflux pumps, and nutrient transporters with stable protein localization and gene expression. Cryopreservation is associated with a decrease in the yield of adherent cells and unique responses to cell stress, resulting in altered paracellular permeability of Lucifer yellow. Additionally, cryopreserved dhBMECs reliably form functional three-dimensional microvessels independent of cryopreservation length, with permeabilities lower than non-cryopreserved two-dimensional models. Long-term cryopreservation of dhBMECs offers key advantages including increased scalability, reduced batch-to-batch effects, the ability to conduct well-controlled follow up studies, and support of multisite collaboration from the same cell stock, all while maintaining phenotype for screening pharmaceutical agents.

A cell-penetrant lactam-stapled peptide for targeting eIF4E protein-protein interactions.

Eukaryotic translation initiation factor 4E (eIF4E) has emerged as a promising cancer therapeutic target due to its role in the initiation of cap-dependent translation, a process that is accelerated during tumorigenesis. To regulate the initiation of cap-dependent translation, eIF4E participates in protein-protein interactions (PPI) with binding partners, 4E-BP1 and eIF4G, which act as an inhibitor and stimulator of translation, respectively. As both of these proteins interact with eIF4E by utilizing a short, α-helical stretch of amino acids, our laboratory has been working to develop helical mimetics of these proteins, in particular 4E-BP1, to inhibit eIF4E PPIs. Herein, we describe our continued efforts in this area and report the development and characterization of a cell-penetrant lactam stapled peptide for targeting cellular eIF4E.

Strategies to counter antipsychotic-associated weight gain in patients with schizophrenia.

Introduction: Patients living with schizophrenia have a marked risk of clinically significant weight gain and obesity compared to the general population. The risks have been highlighted following the introduction of second-generation antipsychotics. In turn, obesity is associated with a higher prevalence of cardiovascular disease, the most common cause of premature mortality in patients with schizophrenia.Areas covered: In this review, the authors outline possible mechanisms that induce obesity in patients with schizophrenia taking antipsychotics. The authors discuss the safety and effectiveness of three main approaches for attenuating antipsychotic-associated weight gain (AAWG), including lifestyle interventions, switching antipsychotics, and augmentation with other medications.Expert opinion: When selecting antipsychotics, effective treatment of psychotic symptoms should be highest priority but obesity and related metabolic comorbidities associated with antipsychotics should not be neglected. Further research into mechanisms of weight gain associated with antipsychotics will guide future treatments for AAWG and development of antipsychotics that produce minimal metabolic adverse effects. With current strategies only producing modest weight loss in already overweight and obese individuals, clinicians should transition to an approach where they aim to prevent weight gain when initiating antipsychotic treatment.

A click chemistry assay to identify natural product ligands for pre-microRNAs.

Despite the great diversity of structure and function and relevance to human health, RNA remains an underexploited area of drug discovery. A major bottleneck toward this goal has been the identification of probes and drug leads that are specific for select RNAs and methods that will facilitate such discovery efforts. Our laboratory has recently developed an innovative approach for assaying RNA-small molecule interactions, catalytic enzyme-linked click chemistry assay or cat-ELCCA, which is a functional assay that takes advantage of the power of catalytic signal amplification combined with the selectivity and bioorthogonality of click chemistry. Importantly, through application of this platform assay technology to the challenging problem of identifying selective inhibitors of pre-microRNA maturation, we identified natural products as a potential source of such compounds. Herein we describe this methodology in addition to the downstream pipeline toward the discovery of natural product ligands for pre-microRNAs. Through cat-ELCCA, our goal is to discover novel ligands to facilitate our investigation of RNA recognition by small molecules.