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Evaluating the Use of Long-Acting Injectables as a Method to Improve Treatment Adherence in Patients with Schizophrenia: A Scoping Review
Get PDFPurpose/Background Medication adherence is a major issue for patients suffering from schizophrenia and medication non-adherence can lead to psychiatric morbidity. Although long-acting injectable (LAI) antipsychotics have been shown to improve treatment adherence, most clinicians continue to rely on oral therapies to manage schizophrenia. This scoping review will assess evidence-based literature to determine the relationship between the use of LAIs and medication adherence in patients with schizophrenia.
Methods A literature review was conducted between August 2020 and January 2021 to find studies that have evaluated medication adherence with the use of long-acting injectables in patients with schizophrenia. Relevant literature initially selected was analyzed by a rapid critical appraisal (RCA). Ten articles ranging from the years 2005 to 2019 were selected to be in the scoping review. A synthesis and outcomes table was developed to examine the level of evidence for each article, assess the variables measured in each study, and track the outcome of each variable.
Results The data collection consisted of 10 articles with varying levels of evidence: a meta-analysis, randomized control trials, controlled trials without randomization, cohort studies, and a literature review. All articles addressed the effect of long-acting injectables on treatment adherence. The principal variable addressed was treatment adherence, but additional variables include reduced hospitalizations and reduced relapse rate. All studies in this scoping review confirm the advantages of long-acting injectables in quality patient outcomes.
Implications for Nursing Practice The studies examined support long-acting injectables to enhance treatment adherence, but there is not an abundance of evidence to suggest a practice or protocol change. More research is required in larger sample sizes and real-life settings to generalize to the general population
Predictors of Hyperkalemia and Outcomes of Dyskalemia in US Veterans with Advanced Chronic Kidney Disease Transitioning to Dialysis
Get PDFBackground: The kidneys play a crucial role in maintaining homeostasis of serum potassium levels (K+). Patients with advanced chronic kidney disease (CKD) are at a higher risk of experiencing dyskalemia events (i.e. hyper- and hypokalemia; especially the former) and thus future adverse outcomes. Currently, there is a dearth of literature on prediction models for hyperkalemia and the effects of dyskalemia on outcomes such as incidence of ischemic stroke and short-term hospital/emergency room (ER) utilization in an advanced CKD population transitioning to dialysis. Objectives: Using a nationally representative sample of US veterans with advanced CKD transitioning to dialysis, in the pre-dialysis period we studied the following aims: Aim 1) Develop and validate a prediction model for predicting hyperkalemia in individual patients; Aim 2) Examine the association of dyskalemias with time to first ischemic stroke; Aim 3) Examine the association of dyskalemias with time to short-term hospital/ER utilization. Methods: A retrospective cohort analysis of the Transition of Care in Chronic Kidney Disease cohort (n=102,477), a nationally representative sample of US veterans with advanced CKD transitioning to dialysis between October 1, 2007 through March 31, 2015 identified from the United States Renal Data System was conducted. Across the three study aims, we identified patients with an initial selection criterion (prior to dialysis initiation) of two estimated glomerular filtration rate (eGFR) of /min/1.73m2 90-365 days apart (second eGFR as index); at least one-year each of baseline period (prior to index) and follow-up period (following index but prior to dialysis initiation); and at least one K+ measurement each in the baseline and follow-up period. For each study aim, further inclusion criteria were used to yield a final sample size of 21,654, 21,357, and 21,366 for aim 1, aim 2, and aim 3, respectively. For Aim 1 (Chapter 2), we compared the performance (area under the receiver operating curve [AUROC]) of different machine learning methods including logistic regression (LR), random forest, extreme gradient boosting, and support vector machines using geographical splitting (for creating training and test set) with 10-fold cross validation to predict the outcome of hyperkalemia (K+ \u3e5.5 mEq/L). The method that yielded the best performance was used to build a reduced model with 10 predictors to develop a patient-level hyperkalemia risk score. For Aim 2 (Chapter 3), we assessed the association of baseline time-averaged K+ levels (distant exposure) and time-updated K+ levels (acute exposure) (both categorized as hypokalemia [K+ 5.5 mEq/L] and referent [3.5 mEq/L ≤ K+ ≤ 5.5 mEq/L]) with time to first ischemic stroke using Cox regression models. Finally, for Aim 3 (Chapter 4), we assessed the association of time-updated outpatient K+ levels (categorized as hypokalemia [K+ 5.5 mEq/L] and referent [3.5 mEq/L ≤ K+ ≤ 5.5 mEq/L]) with hospital/ER utilization (as separate events) using generalized estimating equations. Across all the three study aims (Aim 1, 2, and 3) several different sensitivity analyses were conducted to test the robustness of the results. Results: Across the analytic samples (Aim 1, 2, and 3), the mean age was 69 years, ~98% were males; ~28% were African Americans, ~69% had diabetes mellitus, and the one-year baseline averaged K+ was 4.5 mEq/L. In aim 1 (n=21,654), the LR model yielded the best performance with an average AUROC (95% confidence interval [CI]) of 0.765 (0.756-0.774) (training set) and 0.763 (0.753-0.771) (test set) using the geographical splitting with 10-fold cross validation. Using the LR method, the top 10 predictors identified were K+ value prior to index, age, having at least 1 K+ \u3e5.5 mEq/L in the baseline, index eGFR, baseline averaged SBP, baseline averaged HCO3-, number of K+ counts, thiazide use, number of outpatient visits, and NSAIDs use in baseline. The LR parameter estimates for the above listed predictors were used to develop a patient-level risk score for predicting hyperkalemia. In aim 2 (n=21,357), hypokalemia (distant exposure) was associated with higher risk of ischemic stroke (hazard ratio [HR]; 95 % CI: 1.35, 1.01-1.81). Conversely, hyperkalemia (acute exposure) was associated with a lower risk of ischemic stroke (HR; 95% CI: 0.82, 0.68-0.98). Finally, in aim 3 (n=21,366) using outpatient K+ levels, both hyperkalemia (odds ratio [OR]; 95% CI: 2.04; 1.88-2.21) and hypokalemia (OR; 95% CI: 1.66; 1.48-1.86) were associated with higher risk of hospital visit within 2 calendar days of outpatient K+ measurement. Similarly, both hyperkalemia (OR; 95% CI: 1.83; 1.65-2.03) and hypokalemia (OR; 95% CI: 1.24; 1.07-1.44) were associated with higher risk of ER visit within 2 calendar days of outpatient K+ measurement. Across all the three study aims, the results were robust to various sensitivity analysis. Conclusion: In an advanced CKD population transitioning to dialysis, in the pre-dialysis period, we developed an internally valid model for predicting hyperkalemia. We observed that hypokalemia as a chronic exposure is associated with higher risk of ischemic stroke and hyperkalemia as an acute exposure is associated with lower risk of ischemic stroke. Finally, both hyper- and hypokalemia are associated with higher risk of short-term hospital/ER visits. Further studies are needed to externally validate the hyperkalemia risk prediction model; understand the mechanisms underlying the association of dyskalemias with stroke; and expand on the association of dyskalemias with short-term hospital/ER visits by including cost as an outcome
The Effects of Air-Cell Based Cushions on Pressure Relief for Adults with Spinal Cord Injury: A Critically Appraised Topic
Get PDFMost acute care level patients with a SCI are dependent in performing pressure relief. Research was appraised and synthesized to answer the question: Are air-filled cushions effective for reducing pressure and development of pressure ulcers among adults with a spinal cord injury who are unable to independently perform pressure relief
Exploring Risk Factors of Alzheimer’s Disease Using Mouse Models
Get PDFMouse models of Alzheimer’s disease (AD) that accurately recapitulate pathology and molecular changes are crucial for understanding disease mechanisms and subsequent therapeutic development. We examined five commonly used mouse models of AD (5xFAD, J20, APPNL-F, APPNL-G-F, Tau P301S) and compared their whole- and phosphoproteomes with human AD (the integration of three published datasets) to study whether they can mimic protein/RNA expression discrepancies, molecular changes, and enriched pathways found in human AD cases. The mouse models especially 5xFAD and APPNL-G-F show proteomic signatures similar to human AD but lack human-specific AD progressions, such as dysregulation of synaptic pathways and networks. Integration of large-scale turnover profiling of over 10,000 proteins in 5xFAD and wild-type mice with multi-omic datasets demonstrated discordant mRNA/protein expression of amyloidome components, suggesting an interaction with β-amyloid (Aβ) may decrease protein degradation and trafficking
Methods Development in Inflammatory Bowel Disease
Get PDFInflammatory bowel disease (IBD) is a disease that is classified into two subtypes: ulcerative colitis (UC) and Crohn’s disease (CD). Symptoms can range from mild discomfort to requiring surgical intervention and affects approximately 1-in-200 adults in America alone, with global incidence rates increasing. While many treatments exist for IBD, perhaps the main reason for the lack of a cure is that there are many different pathogeneses that all lead to a very similar expression of symptoms. Over 240 IBD loci have been identified to date, yet the causative allele that drives the association has only been identified in ~60 of these 240. Even with the known IBD loci, it is estimated that the known heritability for CD and UC is minimal at 13% and 8%, respectively. Genetic risk research across many populations around the world show different rates, or even complete absence, of known risk loci identified is Caucasian populations. This wide irregularity in genetic risk across populations gives reason for additional genomic research both within and outside of previously focused populations. In this study, we approach two novel methods for the discovery of additional risk loci in IBD. One method utilized multi-omic data (e.g. whole exome sequencing, methylation, and RNA-seq) and machine learning approaches in a discordant/concordant sib-pair study. The machine learning methods used were iClusterPlus and MoCluster. The iClusterPlus analysis yielded four “top priority” genes with GBP2 as a novel discovery in IBD. MoCluster yielded 10 “top priority” genes with CSK as a novel discovery in IBD. Additionally, the MoCluster analysis identified five KEGG pathways as having strong relation with IBD: Platelet activation ; Viral protein interaction with cytokine and cytokine receptor ; NF-kappa B signaling pathway ; Ferroptosis ; and Epithelial cell signaling in Helicobacter pylori infection . A second method utilized the largest African American population of IBD patients to date in a dense endophenotype study. Using a stratified analysis to test for endophenotype-independent risk loci yielded five genes of interest. Three of the genes, TNFSF8, HLA-DQB1, and CHRNA4, were shown to increase risk of disease and two of the genes, ADCY7 and LSAMP, were found to be protective. In this study, I have identified novel genes and pathways for further IBD research. These methods have the potential to greatly increase the known genetic causes for IBD and other diseases by expanding the classifications of disease and utilizing these distinctions. An increased number of genetic loci with known, specific disease progressions will enable physicians with enhanced targeted screening capabilities, leading to an increase in quality of life for affected patients
Computer-Aided Drug Discovery for Helicobacter pylori
Get PDFHelicobacter pylori is a high-priority drug-resistant pathogen and is currently the only bacteria considered to be a class I carcinogen and there is a critical need to identify novel chemical matter to treat H. pylori infections. Hp is responsible for greater than 60% of gastric cancer related deaths and 89% of all gastric cancer morbidities. In a previous study, our lab identified novel Hp thienopyrmidine inhibitors that target respiratory complex I, an essential enzyme in respiration. Respiratory complex I is a large asymmetric multidomain and membrane bound enzyme and due to these innate features, it is not practical for biophysical or biochemical enzyme screening making it an ideal candidate for computer-aided drug discovery. To employ structure-based design we developed a homology model of the NuoD and NuoB subunits of respiratory complex I. The homology model was used to build a docking grid based on the sites of mutation from the generated resistant mutants, a previously found H. pylori complex I inhibitor, and known quinone binding. The docking grid was validated using a library of known actives and DUD-E generated decoys through enrichment. The validated model provided an AU-ROC of 0.92 and was used to determine a threshold for selecting molecules for biological evaluation. After previous success using our docking protocol, we screened the St. Jude Chemical Library comprising of approximately 600,000 compounds, which were then filtered for optimal drug-like properties, resulting in 74 Hp active compounds. With continued success of the virtual screening protocol, a set of 4.2 million compounds with molecular weight up to 400 g/mol and logP 4 from the ZINC20 in-stock screening library was docked. These hits will be used for continued development of our diverse chemical library and for hit-to-lead optimization to find novel and narrow-spectrum Hp inhibitors
The Role and Immunogenicity of CBFA2T3-GLIS2 in Pediatric Acute Megakaryoblastic Leukemia
Get PDFCBFA2T3-GLIS2 is the most prevalent fusion oncogene in pediatric acute megakaryoblastic leukemia in patients without Down syndrome (non-DS-AMKL) and is associated with an event free survival of only 8% even with high intensity chemotherapy and stem cell transplant in first remission. A cryptic inversion event on chromosome 16 joins the three nervy homology regions (NHR) of CBFA2T3 to the five zinc fingers of GLIS2. This configuration enables the encoded chimeric transcription factor to bind GLIS consensus sequences throughout the genome and recruit transcriptional activators and repressors to alter gene expression and enhance self-renewal capability. Few cooperating mutations have been identified in patients harboring this fusion which suggests it is the sole oncogenic driver. The molecular mechanism by which CBFA2T3-GLIS2 drives leukemogenesis is not well understood. Further, there are currently no studies exploring the immunogenicity of the fusion positive AMKL cells and immunotherapeutic approaches are lacking. To address these knowledge gaps, I developed two mouse models to study transcriptional regulation by the CBFA2T3-GLIS2 fusion oncogene and the ability of the immune system to recognize this malignancy with a goal of identifying therapeutic vulnerabilities for future translational studies. To understand transcriptional regulation by the fusion, I first turned to the literature. Studies on the wild type CBFA2T3 and GLIS2 proteins have demonstrated interactions with the transcriptional regulators ETO and CtBP1, respectively. Further, p300 has been shown to play a role in transcriptional regulation imparted by both transcription factors. I therefore hypothesized the fusion promotes transcriptional activation when the histone acetyltransferase p300 and the transcription factor ETO are recruited through NHR1 and NHR2, respectively. When the co-repressor CtBP1 is recruited through the PXDLS motif, located in the GLIS2 portion of the fusion, transcriptional repression predominates. Association of these co-factors with the fusion was confirmed through co-immunoprecipitations. Site-directed mutagenesis was then used to systematically delete NHR1 and NHR2 and mutate the PXDLS motif to evaluate the resultant effects on leukemogenesis imparted by the fusion. Murine models harboring the CBFA2T3-GLIS2 fusion without cooperating mutations have been unsuccessful and patient-derived xenograft (PDX) models are limited and difficult to manipulate. Therefore, I developed a novel humanized model of CBFA2T3-GLIS2 driven leukemia to understand the functional consequence of the mutant constructs. CD34+ stem cells were isolated from human cord blood and transduced with a lentivirus construct encoding the fusion and a GFP reporter. The cells were then differentiated to megakaryoblasts using human TPO and IL1β and sorted for purity prior to transplantation into immunodeficient NSG-SGM3 recipient mice. The fusion positive human primary megakaryoblasts induced a serially transplantable leukemia within 180 days that recapitulates CBFA2T3-GLIS2 positive patient samples on a transcriptional and translational level. Using the model, I found the fusion co-occupies sites throughout the genome with ETO and CtBP1 and induces upregulation of oncogenic signaling pathways including Hedgehog, JAK/STAT, Notch, and RUNX. Loss of NHR2 disrupted ETO association with the fusion, decreased fusion homodimerization, and abrogated leukemogenesis in vivo. I observed downregulation of JAK/STAT, Notch, and Hedgehog signaling pathways in cells with a fusion construct that lacks NHR2, suggesting these pathways may play a critical role in transformation. Future studies using CRISPR editing technology will be used to further elucidate the role of these pathways in AMKL transformation. An alternative to identifying proteins and biologic pathways necessary for transformation to target therapeutically is the use of immunotherapeutic approaches. In addition to a lack of knowledge about the CBFA2T3-GLIS2 transcriptional complex, there are currently no studies exploring the immunogenicity of the fusion positive AMKL cells. Since chemotherapy and stem cell transplantation fail to cure this disease, innovative treatment approaches are needed. While monoclonal antibody and chimeric antigen receptor T-cell (CAR-T) therapies have proven successful in acute lymphoblastic leukemia (ALL), similar successes haven’t been realized in acute myeloid leukemia (AML) due to the lack of targetable antigens that eradicate leukemia cells while minimizing off target toxicities such as depletion of normal myeloid cells which can lead to prolonged neutropenia. An alternative is T cell receptor engineered T cell (TCR-T) immunotherapy which uses heterodimers consisting of alpha and beta peptide chains to recognize polypeptide fragments presented by HLA molecules on the tumor cells. An advantage of this approach is the ability to recognize intracellular tumor specific and tumor associated antigen fragments in addition to extracellular proteins which results in a wider range of targets. To investigate the immunogenicity of CBFA2T3-GLIS2 positive AMKL cells, I first interrogated potential neoantigens spanning the fusion junction using the algorithm from NetMHCcons which identified two significant peptides. I then utilized immunopeptidomics to identify HLA class I presented peptides on the surface of AMKL PDX cells. One of the top hits was a peptide that corresponds to the 5’ untranslated region (UTR) of bone morphogenetic protein 2 (BMP2). Although its role in leukemia is not well described, BMP2 is aberrantly upregulated in CBFA2T3-GLIS2 positive AMKL and required for serial replating in colony forming unit assays; therefore, this peptide is of great interest as a candidate leukemia-associated antigen. To identify potential AMKL directed effector CD8+ T cells, I developed a novel HLA class I exact matched PBMC-humanized CBFA2T3-GLIS2 positive AMKL PDX murine model. I observed a variable response in leukemia burden reduction, with the greatest responses correlating with an increase in granzyme A production and a decrease in TCR diversity; consistent with a potential clonal expansion of leukemia-specific effector CD8+ T cells. Single TCR expressing stable cell lines will be generated for the top expanded clones and used to assess leukemia clearance in the model and to measure specificity and functionality for the putative candidate antigens through tetramer staining and peptide stimulation assays, respectively. These novel studies have shed light on the immunogenicity of CBFA2T3-GLIS2 mediated AMKL and have the potential to contribute to the development of a TCR-T immunotherapy in the setting of minimal residual disease to provide an alternative, effective treatment for this chemotherapy resistant malignancy
Intermediate Anticoagulation Dosing in COVID-19 ICU Patients: Evaluation Comparing Ventilated vs Non-Ventilated Populations
Get PDFSurges of COVID-19 have been seen to place large numbers of patients into the ICU. Establishing standards of care is critical not only for patient care, but to also implement a baseline of therapy to build upon with future research. COVID-19 produces a hypercoagulable state resulting in higher occurrences of clotting such as deep vein thrombosis (DVT), and pulmonary embolism (PE). Anticoagulation medications thin the blood to combat this aspect of the disease from occurring but does so at the risk of increasing bleeding potential. The purpose of this study is to evaluate the risk/benefit of anticoagulation usage between ventilated and non-ventilated COVID-19 ICU patients as both bleeding and clotting are linked to worsened outcomes. A retrospective analysis reviewed 103 COVID (+) intensive care unit (ICU) patients with approved standardized COVID anticoagulation from August 2020 through January 2021 at a small community hospital. Patient data was obtained by navigating through Citrix Visual Apps including Pharmacy, NextGen EHR, and Paragon Clinician Hub. Pros and cons observed in EHR navigation were reflected upon in Chapter 5. Primary goal is to compare the endpoint of thrombotic events along with secondary outcomes of bleeding and overall mortality between ventilated and non-ventilated patients. Chi-square tests and two-sided t-tests were utilized in obtaining significance. Significance was defined as p\u3c0.05 and confidence interval of 95%. This study found ventilated patients experienced significantly more clotting (30 vs 15, p = 0.0003) in addition to higher bleeding rates (14 vs 5; p = 0.0138) and worse mortality (24 vs 11; p = 0.0016). There were no significant differences with number of prophylactic or intermediate anticoagulants given between groups. Treatment heparin was used significantly more in the ventilated group, but this was due to the higher rates of thrombosis being treated. Apixaban treatment and enoxaparin intermediate dosing resulted in the highest prevalence of thrombotic events (30.3%, 29.41% prospectively) while heparin treatment accounted for the highest prevalence of bleeding events (17.39%). Overall, this study displays a potential need for higher anticoagulation in COVID-19 ICU ventilated patients at the risk of bleeding. Future studies required include regression analysis on treatment heparin PTT and enoxaparin Xa levels and associated thrombosis/bleeding events in ventilated patients
Boarding Barriers for Psychiatric Patients in Emergency Departments
Get PDFObjective To identify past or current literature about emergency department holds and psychiatric patients consisting of the evaluation of patient outcomes, satisfaction and equity of care. It is already known that shorter boarding times from the emergency department to a psychiatric unit have positive patient outcomes such as a decrease in readmissions, increase in patient satisfaction and efficiency in appropriate treatment.
Method A scoping review to analyze data by grouping articles into themes which included authors, date of publication, aims/purpose, methodology, sample, interventional details, and the key findings in each article. Excluded articles included those discussing COVID-19 and case management. The patient population that included those 18 to 40 years old, without medical comorbidities and all genders, race, and ethnic backgrounds. The specific aims were to identify the patient\u27s length of stay, experience and barriers to timely treatment or transfer to another facility. Insurance status and type of behavior or psychiatric diagnosis were further identified and results were delineated further.
Results Of the studies included (N=10), all pointed toward factors such as insurance type, psychiatric diagnosis, and the next step of treatment all affected length of stay. Patients who had any issues regarding these factors could have a length of stay (LOS) up to 17 days longer than others. Patients were found to be boarded for longer if they were self-paying or if they had government insurance. These delays were the result of the diminishing community resources in which patients can turn to during times of psychiatric need.
Implications for Nursing Practice The finding within the literature demonstrates how the stigma against psychiatric illness has led to the shortage of mental health professionals available as resources to those in crisis. Lack of community resources and education leads to a bigger strain on our healthcare system. By providing proper education to emergency room staff, hospital administrators have the ability to relieve the stress that has been created by boarding psychiatric patients
Evaluation of The Effectiveness of an On-site Referral System to Increase Mammography Screening Compliance: Scoping Review
Get PDFPurpose/Background Early detection of breast cancer through routine mammography screenings has increased the 5-year survival rate to 99% for women with cancer in the localized stage (American Cancer Society, 2021). However, this survival rate is lessened amongst women in the rural population (Leung et al., 2014). This scoping review investigates health disparities to identify interventions that improve mammography rates for women residing in rural areas.
Methods A scoping review was performed using an exclusive search for peer-reviewed mammography and rural health sources. Search phrases included were, (\u27Mammogram screening in rural areas\u27), (\u27Health care disparities in rural areas\u27), (\u27Secondary prevention in rural versus urban communities\u27), (\u27Healthcare in rural versus urban communities\u27), (Benefits of early detection of breast cancer\u27), (rural communities\u27 effect on breast cancer screening\u27), (\u27compliance to mammogram screening in rural areas\u27).
Results Results were synthesized using a Level of Evidence Synthesis Table and Outcomes Synthesis Table. The scoping review demonstrated improvement in mammogram rates in rural populations by implementing referral programs, EMR reminders for providers, and community outreach programs.
Implications for Nursing Practice This scoping review unveils rural health disparities and demonstrates effective interventions to improve mammogram participation amongst women in the rural population