Patient-Centered Outcomes After a Medication Adherence Intervention: a Pilot Study.

PRCIS: Self-determination theory (SDT) guided behavioral interventions are effective in improving several patient-centered metrics, including glaucoma-related distress. However, whether improvement in patient-centered metrics can drive an improvement in medication-taking behavior remains to be seen. OBJECTIVE: The 7-month Support, Educate, Empower (SEE) personalized glaucoma coaching program was previously shown to improve glaucoma medication adherence by 21 percent points. This study's goal was to assess the impact of the SEE program on self-determination theory (SDT) metrics and other patient-centered outcome measures. PARTICIPANTS AND METHODS: Glaucoma patients (≥40 y old, taking ≥1 medication) self-reporting poor medication adherence were recruited at the University of Michigan. Eight surveys (with 10 subscales) were completed before and after the 7-month SEE program. Three surveys assessed changes in SDT (Treatment Self-regulation Questionnaire, Healthcare-Climate Questionnaire, Perceived Competence) while the others assessed participants' Glaucoma Knowledge, Glaucoma Medication Self-efficacy, Glaucoma-related distress, Perceived benefits, confidence asking and getting questions answered. RESULTS: Thirty-nine participants completed the SEE program. Significant improvements were in 7 subscales, including all three SDT tenets of competence (mean change =0.9, SD =±1.2, adjusted P =0.0002), autonomy (0.5, ±0.9, 0.044), and relatedness ( P =0.002). Glaucoma-related distress (-2.0, ±3.2, 0.004), confidence in asking questions (1.1, ±2.0, 0.008), and confidence in getting questions answered (1.0, ±2.0, 0.009) also improved. Glaucoma-related distress was correlated with perceived competence ( r =-0.56, adjusted P =0.005), and an increase in perceived competence was associated with a decrease in glaucoma-related distress (ß=-0.43, 95% CI -0.67 - -0.20, adjusted P =0.007). CONCLUSIONS: The SEE program improved participants' autonomous motivation, perceived support, perceived competence, glaucoma-related distress, and competence. These results point to the promising potential of SDT-guided behavioral interventions in improving patient-centered metrics.

Effect of pulmonary embolism response team on advanced therapies administered: The University of Michigan experience.

BACKGROUND: Pulmonary Embolism Response Teams (PERT) were employed at multiple institutions to bridge the gap between varied treatment options for acute PE and unclear evidence for optimal management. There is limited data regarding the impact of PERT on the use of advanced therapies and clinical outcomes. METHODS: We performed a retrospective single-center cohort study comparing patients that presented to the ED with an acute PE before and after the creation of PERT in June 2017 at our institution. We assessed utilization of advanced therapies, LOS, and mortality. RESULTS: A total of 817 patients (168 pre-PERT, 649 post-PERT) were evaluated in the ED with an acute PE between October 2016 and December 2019. Both groups were similar in demographics, comorbidities, and PESI score. There was a decrease in advanced therapy use (16 % vs. 7.5 %, p = 0.006) after PERT creation. Most notable decreases were in catheter-based therapies (8.5 % vs. 2.2 %, p = 0.008) and IVC filter placement (5.3 % vs. 3.2 %, p < 0.001). Median ICU LOS (2.5 days vs. 2.3 days, p = 0.55) and hospital LOS (3.1 vs. 3.0, p = 0.92) did not vary pre-PERT vs. post-PERT. In-hospital mortality (8.5 % vs. 5.0 %, p = 0.29) and 30-day all-cause mortality (1.2 % vs. 0.5 %, p = 0.28) were not different between the two groups as well. CONCLUSION: At our institution, PERT was associated with a decrease in advanced therapies administered to acute PE patients without affecting mortality or LOS. Additional studies to assess impact of this multi-disciplinary care team model on interventional therapies and clinical outcomes for PE at a broader level are necessary.

Identification of functionally important miRNA targeted genes associated with child obesity trait in genome-wide association studies.

BACKGROUND: Genome-wide association studies (GWAS) have uncovered thousands of genetic variants that are associated with complex human traits and diseases. miRNAs are single-stranded non-coding RNAs. In particular, genetic variants located in the 3'UTR region of mRNAs may play an important role in gene regulation through their interaction with miRNAs. Existing studies have not been thoroughly conducted to elucidate 3'UTR variants discovered through GWAS. The goal of this study is to analyze patterns of GWAS functional variants located in 3'UTRs about their relevance in the network between hosting genes and targeting miRNAs, and elucidate the association between the genes harboring these variants and genetic traits. METHODS: We employed MIGWAS, ANNOVAR, MEME, and DAVID software packages to annotate the variants obtained from GWAS for 31 traits and elucidate the association between their harboring genes and their related traits. We identified variants that occurred in the motif regions that may be functionally important in affecting miRNA binding. We also conducted pathway analysis and functional annotation on miRNA targeted genes harboring 3'UTR variants for a trait with the highest percentage of 3'UTR variants occurring. RESULTS: The Child Obesity trait has the highest percentage of 3'UTR variants (75%). Of the 16 genes related to the Child Obesity trait, 5 genes (ETV7, GMEB1, NFIX, ZNF566, ZBTB40) had a significant association with the term DNA-Binding (p < 0.05). EQTL analysis revealed 2 relevant tissues and 10 targeted genes associated with the Child Obesity trait. In addition, Red Blood Cells (RBC), Hemoglobin (HB), and Package Cell Volume (PCV) have overlapping variants. In particular, the PIM1 variant occurred inside the HB Motif region 37,174,641-37,174,660, and LUC7L3 variant occurred inside RBC Motif region 50,753,918-50,753,937. CONCLUSION: Variants located in 3'UTR can alter the binding affinity of miRNA and impact gene regulation, thus warranting further annotation and analysis. We have developed a bioinformatics bash pipeline to automatically annotate variants, determine the number of variants in different categories for each given trait, and check common variants across different traits. This is a valuable tool to annotate a large number of GWAS result files.

MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors.

Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4. These compounds caused significant upregulation of the p53 pathway in MRT cells, and sensitivity was ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRTs, sensitized cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a 5-day idasanutlin pulse causing marked regression of all xenografts, including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene TP53 and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer. SIGNIFICANCE: This study identifies two targets, MDM2 and MDM4, as vulnerabilities in a deadly pediatric cancer and provides preclinical evidence that compounds inhibiting these proteins have therapeutic potential.

MiPanda: A Resource for Analyzing and Visualizing Next-Generation Sequencing Transcriptomics Data.

The Michigan Portal for the Analysis of NGS data portal (http://mipanda.org) is an open-access online resource that provides the scientific community with access to the results of a large-scale computational analysis of thousands of high-throughput RNA sequencing (RNA-seq) samples. The portal provides access to gene expression profiles, enabling users to interrogate expression of genes across myriad normal and cancer tissues and cell lines. From these data, tissue- and cancer-specific expression patterns can be identified. Gene-gene coexpression profiles can also be interrogated. The current portal contains data for over 20,000 RNA-seq samples and will be continually updated.