Re‐purposing anticoagulation clinics: expanding access to opioid agonist therapy in primary care settings

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136313/1/add13531.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136313/2/add13531_am.pd

An In Vitro analysis of the dimensional accuracy of dies obtained by using different impression trays

A study was been undertaken for determining the accuracy of dies made from different impression trays. In this study, four types of impression trays were used for making impression of prepared typhodont teeth attached to the articulator. The trays were complete-arch stock perforated metal and plastic trays, complete-arch custom tray and triple tray. Addition silicone impression material with different viscosities of putty, light-body and monophase were used according to the type of the tray used. Impressions were made by two-step putty wash impression technique in metal and plastic trays and one-step putty wash impression technique for triple tray. A single mix technique with monophase was followed for custom tray. A total of fourty impressions were made, in which ten impressions were made from each impression tray. Casts were poured with Type IV dental stone. The dimensions of the resultant dies were measured under travelling microscope. The dimensions of the dies obtained with custom tray were found to be closest to the dimensions of the prepared typhodont teeth, in comparision to the dies, obtained from other trays used in this study. The dimensional accuracy of the dies obtained from addition silicone impression material with stock metal and plastic trays and custom trays, was within acceptable limits, except those obtained with triple tray impressions

In vivo trafficking and immunostimulatory potential of an intranasally-administered primary dendritic cell-based vaccine

<p>Abstract</p> <p>Background</p> <p>Coccidioidomycosis or Valley fever is caused by a highly virulent fungal pathogen: <it>Coccidioides posadasii </it>or <it>immitis</it>. Vaccine development against <it>Coccidioides </it>is of contemporary interest because a large number of relapses and clinical failures are reported with antifungal agents. An efficient Th1 response engenders protection. Thus, we have focused on developing a dendritic cell (DC)-based vaccine for coccidioidomycosis. In this study, we investigated the immunostimulatory characteristics of an intranasal primary DC-vaccine in BALB/c mouse strain that is most susceptible to coccidioidomycosis. The DCs were transfected nonvirally with <it>Coccidioides-</it>Ag2/PRA-cDNA. Expression of DC-markers, Ag2/PRA and cytokines were studied by flow cytometry, dot-immunoblotting and cytometric bead array methods, respectively. The T cell activation was studied by assessing the upregulation of activation markers in a DC-T cell co-culture assay. For trafficking, the DCs were co-transfected with a plasmid DNA encoding HSV1 thymidine kinase (TK) and administered intranasally into syngeneic mice. The trafficking and homing of TK-expressing DCs were monitored with positron emission tomography (PET) using ¹⁸F-FIAU probe. Based on the PET-probe accumulation in vaccinated mice, selected tissues were studied for antigen-specific response and T cell phenotypes using ELISPOT and flow cytometry, respectively.</p> <p>Results</p> <p>We found that the primary DCs transfected with <it>Coccidioides</it>-Ag2/PRA-cDNA were of immature immunophenotype, expressed Ag2/PRA and activated naïve T cells. In PET images and subsequent biodistribution, intranasally-administered DCs were found to migrate in blood, lung and thymus; lymphocytes showed generation of T effector memory cell population (T_EM) and IFN-γ release.</p> <p>Conclusions</p> <p>In conclusion, our results demonstrate that the intranasally-administered primary DC vaccine is capable of inducing Ag2/PRA-specific T cell response. Unique approaches utilized in our study represent an attractive and novel means of producing and evaluating an autologous DC-based vaccine.</p

Characterizing isoform switching events in esophageal adenocarcinoma

Isoform switching events with predicted functional consequences are common in many cancers, but characterization of switching events in esophageal adenocarcinoma (EAC) is lacking. Next-generation sequencing was used to detect levels of RNA transcripts and identify specific isoforms in treatment- naïve esophageal tissues ranging from premalignant Barrett’s esophagus (BE), BE with low- or high-grade dysplasia (BE.LGD, BE.HGD), and EAC. Samples were stratified by histopathology and TP53 mutation status, identifying significant isoform switching events with predicted functional consequences. Comparing BE.LGD with BE.HGD, a histopathology linked to cancer progression, isoform switching events were identified in 75 genes including KRAS, RNF128, and WRAP53. Stratification based on TP53 status increased the number of significant isoform switches to 135, suggesting switching events affect cellular functions based on TP53 mutation and tissue histopathology. Analysis of isoforms agnostic, exclusive, and shared with mutant TP53 revealed unique signatures including demethylation, lipid and retinoic acid metabolism, and glucuronidation, respectively. Nearly half of isoform switching events were identified without significant gene-level expression changes. Importantly, two TP53-interacting isoforms, RNF128 and WRAP53, were significantly linked to patient survival. Thus, analysis of isoform switching events may provide new insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC

Characterizing isoform switching events in esophageal adenocarcinoma

Isoform switching events with predicted functional consequences are common in many cancers, but characterization of switching events in esophageal adenocarcinoma (EAC) is lacking. Next-generation sequencing was used to detect levels of RNA transcripts and identify specific isoforms in treatment- naïve esophageal tissues ranging from premalignant Barrett’s esophagus (BE), BE with low- or high-grade dysplasia (BE.LGD, BE.HGD), and EAC. Samples were stratified by histopathology and TP53 mutation status, identifying significant isoform switching events with predicted functional consequences. Comparing BE.LGD with BE.HGD, a histopathology linked to cancer progression, isoform switching events were identified in 75 genes including KRAS, RNF128, and WRAP53. Stratification based on TP53 status increased the number of significant isoform switches to 135, suggesting switching events affect cellular functions based on TP53 mutation and tissue histopathology. Analysis of isoforms agnostic, exclusive, and shared with mutant TP53 revealed unique signatures including demethylation, lipid and retinoic acid metabolism, and glucuronidation, respectively. Nearly half of isoform switching events were identified without significant gene-level expression changes. Importantly, two TP53-interacting isoforms, RNF128 and WRAP53, were significantly linked to patient survival. Thus, analysis of isoform switching events may provide new insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC

Improving Access to Primary and Pain Care for Patients Taking Opioids for Chronic Pain in Michigan: Recommendations from an Expert Panel

This multidisciplinary expert panel was convened to generate recommendations to address the limited access to care that patients experience when taking opioids for chronic pain. Recent policies and guidelines instituted to reduce inappropriate opioid prescribing have had unintended consequences for the 5-8 million patients taking long-term opioid therapy for chronic pain in the U.S. As providers discontinue prescribing and turn away patients dependent on opioids, this population faces limited access to both primary and pain-related care. The root causes of this access issue can be attributed to several overarching barriers, including new opioid-related policies, payment models, a lack of care coordination, stigma, and racial biases. Over multiple rounds of deliberation, the panel brainstormed possible solutions, considering feasibility, impact, and importance, and ultimately ranked their final recommendations in order of implementation priority. The final list included 11 recommendations, from which three overarching themes emerged: 1. Improving care models to better support patients with chronic pain Three recommendations involved improving care models, including the top two: increasing reimbursement for the time needed to treat complex chronic pain and establishing coordinated care models that bundle payments for multimodal pain treatment. 2. Enhancing provider education and training Four recommendations involving provider education efforts received slightly lower rankings and included training on biopsychosocial factors of pain care and clarifying the continuum between physical dependency and opioid use disorder. 3. Implementing practices to reduce racial biases and inequities The remaining four recommendations address racial biases and inequities, ranging from standardizing pain management protocols to reduce bias to increasing recruitment and retention of providers from underrepresented racial minorities. Throughout the process, panelists emphasized the interconnectedness of their proposed solutions, and indicated that multiple approaches are likely needed to meaningfully improve access to care for this patient population. Importantly, though this panel was convened in Michigan, and its expertise grounded in Michigan’s healthcare ecosystem, there are millions of patients taking opioids for chronic pain across the country, and reports of limited access to care are not unique to Michigan. Consequently, there may also be opportunity to apply these recommendations more broadly, in other states and at multiple levels of the United States healthcare system.This research was funded by the Michigan Health Endowment Fund (grant # R-1808-143371).http://deepblue.lib.umich.edu/bitstream/2027.42/168420/1/Lagisetty - Improving Access to Care for Patients Taking Opioids - 2021.pdfDescription of Lagisetty - Improving Access to Care for Patients Taking Opioids - 2021.pdf : White PaperSEL

Development of Graphical Models and Statistical Physics Motivated Approaches to Genomic Investigations

Identifying genes involved in disease pathology has been a goal of genomic research since the early days of the field. However, as technology improves and the body of research grows, we are faced with more questions than answers. Among these is the pressing matter of our incomplete understanding of the genetic underpinnings of complex diseases. Many hypotheses offer explanations as to why direct and independent analyses of variants, as done in genome-wide association studies (GWAS), may not fully elucidate disease genetics. These range from pointing out flaws in statistical testing to invoking the complex dynamics of epigenetic processes. In the studies outlined here, however, we focus on the hypothesis that interactions between genes may be a potential culprit. To probe this hypothesis, we begin by developing an algorithm, GeneEMBED, to model the total effect of protein coding variants in various genes across a molecular network of genetic interactions. Given a population of disease and healthy individuals, GeneEMBED systematically evaluates the relative contribution of a gene to disease. The associations are quantified by examining the patterns of differential perturbations in the gene\u27s interactions throughout a biological network. As a proof-of-concept, we applied GeneEMBED to two late-onset Alzheimer\u27s disease (AD) cohorts of 5,169 exomes and 969 genomes. We identified 143 candidate disease-associated genes across the two cohorts and three biological networks. These candidate genes were differentially expressed in both bulk and single-cell RNA expression data from post-mortem AD brains. Knockouts of these candidates in mice were known to lead to abnormal neurological phenotypes. Lastly, in vivo drosophila assays of candidates showed they modified neurodegenerative phenotypes. Next, we focus on the discrepancies between the functional impact of mutations across different genes. While tools to predict the degree of functional impact a given coding mutation will have on the encoded protein are widely successful, they often make predictions relative to the given gene. To this effect, we extend principles of statistical mechanics to biology to measure any given gene\u27s relative mutational intolerance. Importantly, these mutational intolerance scores can distinguish essential genes from non-essential genes in E.coli. In humans, they can segregate genes that cause autosomal dominant Mendelian diseases from non-disease genes. Similarly, highly mutationally intolerant genes were enriched in core and conserved biological processes across three different species. Conversely, mutationally tolerant genes were involved in adaptive processes, again across three different species. Most notably, we found that mutational intolerance scores highly correlated with experimentally measured fitness effects of gene knockdowns. Together, these efforts provide new tools with which to investigate disease-gene associations and provide insights into the biological dynamics of gene networks