Now showing items 41-60 of 5172

    • Changes in Antidementia Medications upon Admission to the Nursing Home: Who Decides and Why? Results From a National Survey of Nursing Home Administrators

      Lapane, Kate L; Ott, Brian R; Hargraves, J Lee; Cosenza, Carol; Liang, Shiwei; Alcusky, Matthew J (2023-10-28)
      Objective: Little is known about who is involved and what factors influence changes in antidementia medications for older adults living in nursing homes. The study sought to describe factors associated with initiation and discontinuation of antidementia medications in nursing home residents with dementia. Design: National survey of nursing homes with ≥30 beds; homes with dementia units were oversampled. Settings and participants: Nursing home administrators [eg, Directors of Nursing (DoNs)]. Methods: In 2022, 1293 homes were surveyed (response rate: 26.6%, n = 340). Weighted analyses provided nationally representative results corrected for nonresponse (n = 14,455). Results: DoNs reported that people always/almost always involved in antidementia medication decisions included nursing home prescriber (84.4%), nursing staff (33.2%), family (23.4%), resident (13.8%), community primary care provider (12.1%), and dementia specialist (5.8%). DoNs reported that antidementia medications were much more likely to be initiated if residents (55.8%) and family members (53.2%) wanted antidementia medications, a dementia specialist was involved (51.9%), resident had aggressive behaviors (44.8%), resisted care (31.6%), or had severe physical/cognitive impairment (22.3%). DoNs reported that antidementia medications were much more likely to be discontinued with dementia specialist involvement (46.5%), progression to severe impairment (39.2%), hospice involvement (31.5%), <6 months' prognosis (28.5%), emergence of aggressive behaviors (25.2%), or resisting care (19.0%) and much less likely to be discontinued if residents (30.2%) and family (27.3%) were reluctant to discontinue. One in 6 homes reported that residents had no immediate family/caregivers usually or almost always/always. Conclusions and implications: DoNs report that family/caregivers and dementia specialists have significant influence on antidementia medication decisions in nursing homes, but many residents lack their involvement. Real-world evidence on the risks and benefits of antidementia medications in nursing homes is needed to inform clinical guidance about appropriate use of antidementia medications in nursing homes.
    • Prevalence and predictors of shared decision-making in goals-of-care clinician-family meetings for critically ill neurologic patients: a multi-center mixed-methods study

      Fleming, Victoria; Prasad, Abhinav; Ge, Connie; Crawford, Sybil; Meraj, Shazeb; Hough, Catherine L; Lo, Bernard; Carson, Shannon S; Steingrub, Jay; White, Douglas B; et al. (2023-10-21)
      Background: Shared decision-making is a joint process where patients, or their surrogates, and clinicians make health choices based on evidence and preferences. We aimed to determine the extent and predictors of shared decision-making for goals-of-care discussions for critically ill neurological patients, which is crucial for patient-goal-concordant care but currently unknown. Methods: We analyzed 72 audio-recorded routine clinician-family meetings during which goals-of-care were discussed from seven US hospitals. These occurred for 67 patients with 72 surrogates and 29 clinicians; one hospital provided 49/72 (68%) of the recordings. Using a previously validated 10-element shared decision-making instrument, we quantified the extent of shared decision-making in each meeting. We measured clinicians' and surrogates' characteristics and prognostic estimates for the patient's hospital survival and 6-month independent function using post-meeting questionnaires. We calculated clinician-family prognostic discordance, defined as ≥ 20% absolute difference between the clinician's and surrogate's estimates. We applied mixed-effects regression to identify independent associations with greater shared decision-making. Results: The median shared decision-making score was 7 (IQR 5-8). Only 6% of meetings contained all 10 shared decision-making elements. The most common elements were "discussing uncertainty"(89%) and "assessing family understanding"(86%); least frequent elements were "assessing the need for input from others"(36%) and "eliciting the context of the decision"(33%). Clinician-family prognostic discordance was present in 60% for hospital survival and 45% for 6-month independent function. Univariate analyses indicated associations between greater shared decision-making and younger clinician age, fewer years in practice, specialty (medical-surgical critical care > internal medicine > neurocritical care > other > trauma surgery), and higher clinician-family prognostic discordance for hospital survival. After adjustment, only higher clinician-family prognostic discordance for hospital survival remained independently associated with greater shared decision-making (p = 0.029). Conclusion: Fewer than 1 in 10 goals-of-care clinician-family meetings for critically ill neurological patients contained all shared decision-making elements. Our findings highlight gaps in shared decision-making. Interventions promoting shared decision-making for high-stakes decisions in these patients may increase patient-value congruent care; future studies should also examine whether they will affect decision quality and surrogates' health outcomes.
    • Investigating effects of environmentally acquired epigenetic factors on the mammalian embryo transcriptome

      Krykbaeva, Marina (2023-10-20)
      The major aim of this work is to shed light on epigenetic effects on embryonic development. To this end, we implemented two experimental paradigms. First, we investigated the effect of maternal diet on the embryonic transcriptome. We used in vitro fertilization to isolate gamete-carried factors and single-embryo RNA-Seq to produce a high-resolution data set in 4-cell, morula, and blastocyst embryos, as well as oocytes. We found that although differential expression was observed in most stages of development, these changes were fairly small in size. Likewise, offspring created using an embryo transfer procedure did not exhibit phenotypic differences as a result of maternal diet. However, alterations in gene expression of mitochondrial respiration and lipid and cholesterol metabolism genes were detected in offspring tissue with a clear sex bias. Second, we compared transcriptomes of embryos produced using three methods of fertilization – natural mating (NM), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) as well as parthenogenesis. The largest differences were detected in IVF embryos, largely in the categories of translation and ribosome biogenesis. ICSI embryos exhibited a small deviation in differentiation-associated gene expression. Parthenogenesis, an embryo-like system with no paternal contributions, resulted in vast expression changes encompassing ~20% of expressed genes and was further used as a model system to confirm a role for sperm-carried RNAs in regulating embryo gene expression. Lastly, this single-embryo data set was used to characterize stochasticity in gene expression and confirm the presence of both “quiet” and “noisy” genes. Overall, we provide two large-scale data sets comprised of hundreds of embryos, which serves as a systematic approach to investigating the effect of epigenetic factors on the embryonic transcriptome.
    • Identifying vulnerabilities in sugar nucleotide metabolism of cancer cells

      Doshi, Mihir B (2023-10-20)
      Cancer cells exhibit elevated metabolic demands, imposing a need for metabolic reprogramming. The aim of the thesis is to identify a targetable metabolic vulnerability using an approach that leverages the altered pathways in cancer cells to induce the accumulation of inherently toxic metabolites to eliminate cancer cells selectively. Through a systematic analysis of transcriptomics and cancer dependency data, we identified UXS1, a Golgi enzyme responsible for converting UDP-glucuronic acid (UDPGA) to UDP-xylose that is conditionally essential in cells expressing high levels of its upstream enzyme UGDH. Here, we demonstrate that UGDH high cancer cells are dependent on UXS1 to prevent excess buildup of UDPGA, generated by UGDH. Excess UDPGA causes disruption of the structure and function of the Golgi, leading to aberrant protein glycosylation and improper protein trafficking of critical glycoproteins within cancer cells. We find that UGDH expression is elevated in various cancers, including lung adenocarcinoma and breast carcinoma. Furthermore, elevating UGDH expression is beneficial to cancer cells, because UDPGA functions as a substrate in the detoxification of chemotherapeutic agents. Therefore, chemo-resistant cells upregulate UGDH expression, enhancing their susceptibility to UXS1 ablation. Consequently, this study reveals the therapeutic potential of targeting UXS1 in cancer treatment, offering a novel approach to exploit the metabolism of sugar nucleotides in cancer cells.
    • mRNA Sequence Features Determine the Efficiency of Translation Termination and Association of the Nonsense-Mediated mRNA Decay Machinery with Elongating Ribosomes

      Mangkalaphiban, Kotchaphorn (2023-10-20)
      Translation of mRNA into protein is terminated when the ribosome encounters one of the three stop codons (UAA, UAG, and UGA) at the end of an open reading frame (ORF). Infrequently, stop codons are decoded by a near- cognate tRNA, allowing “readthrough” of the stop codon and synthesis of an extended polypeptide. When termination occurs prematurely, the mRNA is degraded by the nonsense-mediated mRNA decay (NMD) pathway. Premature and normal termination appear to differ in their efficiency, but the exact “rules” of how NMD distinguishes them mechanistically remain to be elucidated. Using ribosome profiling and bioinformatics analyses, this study aims to understand, at a transcriptome-wide level, the cis-acting elements that influence termination efficiency and how premature termination is recognized by Upf1, a key NMD factor. Analyses of yeast and human mRNA sequences in both normal and readthrough- inducing conditions revealed largely conserved roles of identities of the stop codon, the following nucleotide, P-site codon, and 3’-UTR length in readthrough efficiency regulation. The analyses of yeast mRNAs associated with Upf1-bound ribosomes demonstrated that Upf1 binds ribosomes in two distinct complexes across all mRNA ORFs, suggesting that Upf1 associates with the ribosome during translation elongation before premature termination takes place. Together, these results provide insights into the regulation of termination and the early steps of NMD at the transcriptome-wide level.
    • Eating Disorder Specialist Views on Gender Competency and Education for Treating Gender Minority Patients

      Ferrucci, Katarina A; Lapane, Kate L; Jesdale, Bill M; McPhillips, Emily; Dubé, Catherine E (2023-10-16)
      Studies exploring patient experience with eating disorder specialists have reported poor gender competency among clinicians, as revealed through patient-clinician interactions. Through interviews with eating disorder specialists, the authors sought to (1) clarify how and why current practice and clinical training may not meet the needs of transgender and gender-diverse patients, (2) assess where and how clinicians received education on gender identity, and (3) how changes can be made to meet educational and patient needs. Specialists were recruited, and semi-structured interviews were conducted. Narratives were coded by two independent coders, using thematic analysis. Four key themes emerged from 19 completed interviews: Training and education received, importance of receiving training or education, self-education, and improvements recommended by clinicians. Only ~ 16% (n = 3) of clinicians reported sufficient training both in graduate school and through their place of employment. Most with sufficient education received it at their clinic/practice. Despite lacking formal training, all clinicians engaged in some form of self-education on gender. These findings support the need for standardized and comprehensive graduate curricula, in-service training, and continuing education requirements. Advocacy is required to encourage accrediting organizations to mandate training on gender among mental health clinicians.
    • Non-canonical amino acid incorporation into AAV5 capsid enhances lung transduction in mice

      Chang, Hao; Du, Ailing; Jiang, Jun; Ren, Lingzhi; Liu, Nan; Zhou, Xuntao; Liang, Jialing; Gao, Guangping; Wang, Dan (2023-10-07)
      Gene therapy using recombinant adeno-associated virus (rAAV) relies on safe, efficient, and precise in vivo gene delivery that is largely dependent on the AAV capsid. The proteinaceous capsid is highly amenable to engineering using a variety of approaches, and most resulting capsids carry substitutions or insertions comprised of natural amino acids. Here, we incorporated a non-canonical amino acid (ncAA), Nε-2-azideoethyloxycarbonyl-L-lysine (also known as NAEK), into the AAV5 capsid using genetic code expansion, and serendipitously found that several NAEK-AAV5 vectors transduced various cell lines more efficiently than the parental rAAV5. Furthermore, one NAEK-AAV5 vector showed lung-specific transduction enhancement following systemic or intranasal delivery in mice. Structural modeling suggests that the long side chain of NAEK may impact on the 3-fold protrusion on the capsid surface that plays a key role in tropism, thereby modulating vector transduction. Recent advances in genetic code expansion have generated synthetic proteins carrying an increasing number of ncAAs that possess diverse biological properties. Our study suggests that ncAA incorporation into the AAV capsid may confer novel vector properties, opening a new and complementary avenue to gene therapy vector discovery.
    • Health effects of social connectedness in older adults living in congregate long-term care settings: A systematic review of quantitative and qualitative evidence

      Lim, Emily; Nielsen, Natalia; Lapane, Lucienne; Barooah, Adrita; Xu, Shu; Qu, Shan; McPhillips, Emily; Dubé, Catherine E; Lapane, Kate L (2023-10-07)
      Background: The overall impact of social connectedness on health outcomes in older adults living in nursing homes and assisted living settings is unknown. Given the unclear health impact of social connectedness for older adults in congregate long-term care settings worldwide, a comprehensive systematic review is required to evaluate the overall relationship between social connectedness and health outcomes for them. Objectives: The purpose of this article was to synthesize the literature regarding the health impact of social connectedness among older adults living in nursing homes or assisted living settings. Methods: Using PRISMA guidelines, we identified eligible studies from Scopus, MEDLINE, PsycINFO, CINAHL and Cochrane databases (1990-2021). Bias and quality reporting assessment was performed using standardized criteria for cohort, cross sectional and qualitative studies. At each stage, ≥ 2 researchers conducted independent evaluations. Results: Of the 7350 articles identified, 25 cohort (follow-up range: 1 month-11 years; with two also contributing to cross sectional), 86 cross sectional, eight qualitative and two mixed methods were eligible. Despite different instruments used, many residents living in nursing homes and assisted living settings had reduced social engagement. Quantitative evidence supports a link between higher social engagement and health outcomes most studied (e.g. depression, quality of life). Few studies evaluated important health outcomes (e.g. cognitive and functional decline). Most cohort studies showed that lack of social connectedness accelerated time to death. Conclusions: Social connectedness may be an important modifiable risk factor for adverse health outcomes for older adults living in nursing homes and assisted living facilities. Most studies were cross sectional and focused on quality of life and mental health outcomes. Longitudinal studies suggest that higher social engagement delays time to death. Evidence regarding other health outcomes important to older adults was scant and requires further longitudinal studies.
    • Integrating Equity Into Bicycle Infrastructure, Planning, and Programming: A Mixed Methods Exploration of Implementation Among Participants in the Bicycle Friendly Community Program

      Lemon, Stephenie C; Neptune, Amelia; Goulding, Melissa; Pendharkar, Jyothi Ananth; Dugger, Roddrick; Chriqui, Jamie F (2023-10-05)
      Introduction: Integrating equity considerations into bicycle infrastructure, planning, and programming is essential to increase bicycling and reduce physical inactivity-related health disparities. However, little is known about communities' experiences with activities that promote equity considerations in bicycle infrastructure, planning, and programming or about barriers and facilitators to such considerations. The objective of this project was to gain in-depth understanding of the experiences, barriers, and facilitators that communities encounter with integrating equity considerations into bicycle infrastructure, planning, and programming. Methods: We administered a web-based survey in 2022 to assess communities' experiences with 31 equity-focused activities in 3 areas: 1) community engagement, education, events, and programming (community engagement); 2) data collection, evaluation, and goal setting (data); and 3) infrastructure, facilities, and physical amenities (infrastructure). Respondents were people who represented communities in the US that participated in the League of American Bicyclists' Bicycle Friendly Community (BFC) Program. We then conducted 6 focus groups with a subset of survey respondents to explore barriers and facilitators to implementing equity-focused activities. Results: Survey respondents (N = 194) had experience with a mean (SD) of 5.9 (5.7) equity-focused activities. Focus group participants (N = 30) identified themes related to community engagement (outreach to and engagement of underrepresented communities, cultural perceptions of bicycling, and funding and support for community rides and programs); data (locally relevant data); and infrastructure (political will, community design, and infrastructure). They described barriers and facilitators for each. Conclusion: Communities are challenged with integrating equity into bicycle infrastructure, planning, and programming. Multicomponent strategies with support from entities such as the BFC program will be required to make progress.
    • PAM-flexible genome editing with an engineered chimeric Cas9

      Zhao, Lin; Koseki, Sabrina R T; Silverstein, Rachel A; Amrani, Nadia; Peng, Christina; Kramme, Christian; Savic, Natasha; Pacesa, Martin; Rodríguez, Tomás C; Stan, Teodora; et al. (2023-10-04)
      CRISPR enzymes require a defined protospacer adjacent motif (PAM) flanking a guide RNA-programmed target site, limiting their sequence accessibility for robust genome editing applications. In this study, we recombine the PAM-interacting domain of SpRY, a broad-targeting Cas9 possessing an NRN > NYN (R = A or G, Y = C or T) PAM preference, with the N-terminus of Sc + +, a Cas9 with simultaneously broad, efficient, and accurate NNG editing capabilities, to generate a chimeric enzyme with highly flexible PAM preference: SpRYc. We demonstrate that SpRYc leverages properties of both enzymes to specifically edit diverse PAMs and disease-related loci for potential therapeutic applications. In total, the approaches to generate SpRYc, coupled with its robust flexibility, highlight the power of integrative protein design for Cas9 engineering and motivate downstream editing applications that require precise genomic positioning.
    • Phosphaturic mesenchymal tumor: two cases highlighting differences in clinical and radiologic presentation

      Gu, Joey; Ge, Connie; Joshi, Ganesh; Most, Mathew; Tai, Ryan (2023-10-04)
      Phosphaturic mesenchymal tumors are rare, usually benign neoplasms that occur in the soft tissue or bone and are the cause of nearly all cases of tumor-induced osteomalacia. Tumor-induced osteomalacia due to phosphaturic mesenchymal tumor is a challenging diagnosis to make-patients present with variable clinical and radiologic findings and the culprit neoplasm is often small and can occur anywhere head to toe. We present two cases of phosphaturic mesenchymal tumor in the scapular body and plantar foot. In both cases, the patient endured years of debilitating symptoms before a tissue diagnosis was eventually reached. Descriptions of clinical presentation, laboratory workup, surgical resection, and imaging characteristics, with a focus on CT, MRI, and functional imaging, are provided to assist with the diagnosis and management of this rare entity. A brief review of current literature and discussion of the differential diagnoses of phosphaturic mesenchymal tumor is also provided.
    • Surface modification of neurovascular stents: from bench to patient

      Zoppo, Christopher T; Mocco, J; Manning, Nathan W; Bogdanov, Alexei A. Jr.; Gounis, Matthew J (2023-10-04)
      Flow-diverting stents (FDs) for the treatment of cerebrovascular aneurysms are revolutionary. However, these devices require systemic dual antiplatelet therapy (DAPT) to reduce thromboembolic complications. Given the risk of ischemic complications as well as morbidity and contraindications associated with DAPT, demonstrating safety and efficacy for FDs either without DAPT or reducing the duration of DAPT is a priority. The former may be achieved by surface modifications that decrease device thrombogenicity, and the latter by using coatings that expedite endothelial growth. Biomimetics, commonly achieved by grafting hydrophilic and non-interacting polymers to surfaces, can mask the device surface with nature-derived coatings from circulating factors that normally activate coagulation and inflammation. One strategy is to mimic the surfaces of innocuous circulatory system components. Phosphorylcholine and glycan coatings are naturally inspired and present on the surface of all eukaryotic cell membranes. Another strategy involves linking synthetic biocompatible polymer brushes to the surface of a device that disrupts normal interaction with circulating proteins and cells. Finally, drug immobilization can also impart antithrombotic effects that counteract normal foreign body reactions in the circulatory system without systemic effects. Heparin coatings have been explored since the 1960s and used on a variety of blood contacting surfaces. This concept is now being explored for neurovascular devices. Coatings that improve endothelialization are not as clinically mature as anti-thrombogenic coatings. Coronary stents have used an anti-CD34 antibody coating to capture circulating endothelial progenitor cells on the surface, potentially accelerating endothelial integration. Similarly, coatings with CD31 analogs are being explored for neurovascular implants.
    • Measuring The Enduring Imprint Of Structural Racism On American Neighborhoods

      Dyer, Zachary; Alcusky, Matthew J; Galea, Sandro; Ash, Arlene S. (2023-10-03)
      A long history of discriminatory policies in the United States has created disparities in neighborhood resources that shape ethnoracial health inequities today. To quantify these differences, we organized publicly available data on forty-two variables at the census tract level within nine domains affected by structural racism: built environment, criminal justice, education, employment, housing, income and poverty, social cohesion, transportation, and wealth. Using data from multiple sources at several levels of geography, we developed scores in each domain, as well as a summary score that we call the Structural Racism Effect Index. We examined correlations with life expectancy and other measures of health for this index and other commonly used area-based indices. The Structural Racism Effect Index was more strongly associated with each health outcome than were the other indices. Its domain and summary scores can be used to describe differences in social risk factors, and they provide powerful new tools to guide policies and investments to advance health equity.
    • Investigating the Role of Chronic Exercise and Autophagy in a Poly(GR) Mouse Model of Frontotemporal Dementia

      Learnard, Heather (2023-09-30)
      Understanding how exercise can attenuate social and cellular deficits seen in frontotemporal dementia (FTD) could provide a unique insight and potential for new therapeutic approaches to help patients suffering from FTD and other devastating FTD associated diseases such as Amyotrophic Lateral Sclerosis (ALS). This project helped study the effect of chronic exercise in a poly(GR)-specific mouse model of FTD, highlighting the specific response exercise has on autophagy and poly(GR) toxicity in this experimental system. The goal of this work was to identify the amount/type of exercise that would be most beneficial to reduce poly(GR) load or other neurotoxicity indicators; as well as, identifying the mechanism underlying autophagy disfunction with GR80 overexpression, and if exercise could also alleviate this disruption. Additionally, to compliment the cortical neuron FTD specific mouse model being used to investigate exercise, we also wanted to make a motor neuron mouse model to better understand poly(GR)’s contribution specifically to ALS. In doing this we used Homeobox Protein 9 (HB9) as a promoter due to its lack of expression in sensory and interneurons, in hopes to study motor neurons only. With a understanding of how poly(GR) impacts both FTD and ALS respectively we can better understand the disease pathology progression and hopefully uncover novel ways to intervene, treat, or prevent these disease more effectively.
    • Adolescent cancer prevention in rural, pediatric primary care settings in the United States: A scoping review

      Ryan, Grace W; Whitmire, Paula; Batten, Annabelle; Goulding, Melissa; Baltich Nelson, Becky; Lemon, Stephenie C; Pbert, Lori (2023-09-29)
      Adolescence is a critical period for establishing habits and engaging in health behaviors to prevent future cancers. Rural areas tend to have higher rates of cancer-related morbidity and mortality as well as higher rates of cancer-risk factors among adolescents. Rural primary care clinicians are well-positioned to address these risk factors. Our goal was to identify existing literature on adolescent cancer prevention in rural primary care and to classify key barriers and facilitators to implementing interventions in such settings. We searched the following databases: Ovid MEDLINE®; Ovid APA PsycInfo; Cochrane Library; CINAHL; and Scopus. Studies were included if they reported on provider and/or clinic-level interventions in rural primary care clinics addressing one of these four behaviors (obesity, tobacco, sun exposure, HPV vaccination) among adolescent populations. We identified 3,403 unique studies and 24 met inclusion criteria for this review. 16 addressed obesity, 6 addressed HPV vaccination, 1 addressed skin cancer, and 1 addressed multiple behaviors including obesity and tobacco use. 10 studies were either non-randomized experimental designs (n = 8) or randomized controlled trials (n = 2). The remaining were observational or descriptive research. We found a dearth of studies addressing implementation of adolescent cancer prevention interventions in rural primary care settings. Priorities to address this should include further research and increased funding to support EBI adaptation and implementation in rural clinics to reduce urban-rural cancer inequities.
    • Multicomponent Pharmacist Intervention Did Not Reduce Clinically Important Medication Errors for Ambulatory Patients Initiating Direct Oral Anticoagulants

      Kapoor, Alok; Patel, Parth; Mbusa, Daniel; Pham, Thu; Cicirale, Carrie; Tran, Wenisa; Beavers, Craig; Javed, Saud; Wagner, Joann; Swain, Dawn; et al. (2023-09-27)
      Background: Anticoagulants including direct oral anticoagulants (DOACs) are among the highest-risk medications in the United States. We postulated that routine consultation and follow-up from a clinical pharmacist would reduce clinically important medication errors (CIMEs) among patients beginning or resuming a DOAC in the ambulatory care setting. Objective: To evaluate the effectiveness of a multicomponent intervention for reducing CIMEs. Design: Randomized controlled trial. Participants: Ambulatory patients initiating a DOAC or resuming one after a complication. Intervention: Pharmacist evaluation and monitoring based on the implementation of a recently published checklist. Key elements included evaluation of the appropriateness of DOAC, need for DOAC affordability assistance, three pharmacist-initiated telephone consultations, access to a DOAC hotline, documented hand-off to the patient's continuity provider, and monitoring of follow-up laboratory tests. Control: Coupons and assistance to increase the affordability of DOACs. Main measure: Anticoagulant-related CIMEs (Anticoagulant-CIMEs) and non-anticoagulant-related CIMEs over 90 days from DOAC initiation; CIMEs identified through masked assessment process including two physician adjudication of events presented by a pharmacist distinct from intervention pharmacist who reviewed participant electronic medical records and interview data. Analysis: Incidence and incidence rate ratio (IRR) of CIMEs (intervention vs. control) using multivariable Poisson regression modeling. Key results: A total of 561 patients (281 intervention and 280 control patients) contributed 479 anticoagulant-CIMEs including 31 preventable and ameliorable ADEs and 448 significant anticoagulant medication errors without subsequent documented ADEs (0.95 per 100 person-days). Failure to perform required blood tests and concurrent, inappropriate usage of a DOAC with aspirin or NSAIDs were the most common anticoagulant-related CIMEs despite pharmacist documentation systematically identifying these issues when present. There was no reduction in anticoagulant-related CIMEs among intervention patients (IRR 1.17; 95% CI 0.98-1.42) or non-anticoagulant-related CIMEs (IRR 1.05; 95% CI 0.80-1.37). Conclusion: A multi-component intervention in which clinical pharmacists implemented an evidence-based DOAC Checklist did not reduce CIMEs. Nih trial number: NCT04068727.
    • Beyond genome-wide association studies: Investigating the role of noncoding regulatory elements in primary sclerosing cholangitis

      Pratt, Henry E; Wu, Tong; Elhajjajy, Shaimae I; Zhou, Jeffrey Y.; Fitzgerald, Kate; Fazzio, Tom; Weng, Zhiping; Pratt, Daniel S (2023-09-27)
      Background: Genome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC. Methods: Available epigenomic datasets were integrated to build a comprehensive atlas of cell type-specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4+ T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls. Results: Noncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls. Conclusions: Mechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.
    • Identifying new players in structural synaptic plasticity through dArc1 interrogation

      Xiao, Cong; M'Angale, P Githure; Wang, Shuhao; Lemieux, Adrienne; Thomson, Travis (2023-09-27)
      The formation, expansion, and pruning of synapses, known as structural synaptic plasticity, is needed for learning and memory, and perturbation of plasticity is associated with many neurological disorders and diseases. Previously, we observed that the Drosophila homolog of Activity-regulated cytoskeleton-associated protein (dArc1), forms a capsid-like structure, associates with its own mRNA, and is transported across synapses. We demonstrated that this transfer is needed for structural synaptic plasticity. To identify mRNAs that are modified by dArc1 in presynaptic neuron and postsynaptic muscle, we disrupted the expression of dArc1 and performed genomic analysis with deep sequencing. We found that dArc1 affects the expression of genes involved in metabolism, phagocytosis, and RNA-splicing. Through immunoprecipitation we also identified potential mRNA cargos of dArc1 capsids. This study suggests that dArc1 acts as a master regulator of plasticity by affecting several distinct and highly conserved cellular processes.
    • Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model

      Benatti, Hector Ribeiro; Prestigiacomo, Rachel D; Taghian, Toloo; Miller, Rachael; King, Robert; Gounis, Matthew J; Celik, Ugur; Bertrand, Stephanie; Tuominen, Susan; Bierfeldt, Lindsey; et al. (2023-09-26)
      Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repeated administration into the cerebrospinal fluid may be required for long-term therapeutic effect. Modifying oligonucleotide formulation has been postulated to prevent acute toxicity, but a sensitive and quantitative way to track seizure activity in pre-clinical studies is lacking. The use of intracerebroventricular (i.c.v.) catheters offers a solution for repeated dosing; however, fixation techniques in large animal models are not standardized and are not reliable. Here we describe a novel surgical technique in a sheep model for i.c.v. delivery of neurotherapeutics based on the fixation of the i.c.v. catheter with a 3D-printed anchorage system composed of plastic and ceramic parts, compatible with magnetic resonance imaging, computed tomography, and electroencephalography (EEG). Our technique allowed tracking electrical brain activity in awake animals via EEG and video recording during and for the 24-h period after administration of a novel oligonucleotide in sheep. Its anchoring efficiency was demonstrated for at least 2 months and will be tested for up to a year in ongoing studies.
    • High Throughput Tools for Tickborne Disease Surveillance and Investigation of Tick, Pathogen, and Commensal Microbiome Association at Single-Tick Resolution

      Chauhan, Gaurav (2023-09-25)
      The prevalence of tickborne diseases worldwide is increasing virtually unchecked due to lack of effective control strategies. The transmission dynamics of tickborne pathogens are influenced by the tick microbiome, tick co-infection with other pathogens. Understanding this complex system could lead to new strategies for pathogen control, but will require large-scale, high-resolution data. Here we present a strategy that combines citizen science with new molecular strategies to provide the single-tick resolution data urgently needed to inform management of tickborne pathogens. Our citizen science-based initiative, Project Acari, harnessed the power of volunteers across the US to collect more than 3,000 ticks. To assay collected ticks, we developed a high-throughput screening method using Molecular Inversion Probes (MIPs) that identify tick species, associated pathogens, and the species on which the tick most recently fed. Applying MIPs to 853 individual ticks successfully identified the species of 715 ticks, of which 85 were infected with pathogens of 12 different species. We also detected host DNA in 60 ticks. We also generated the first comprehensive data on both prokaryotic and eukaryotic microbiome of individual ticks using full-length 16S and 18S sequencing. Our findings corroborate reports of the influence of tick species, sex, and geography on the tick prokaryotic microbiome. We also identify novel associations between the carriage of B. burgdorferi and specific microbial taxa. Our work underscores the power of citizen science, paired with high-throughput processing, to elucidate the ecology of tickborne disease and to guide pathogen-control initiatives.