Now showing items 21-40 of 5088

    • A Bacterial Pathogen Induces Reversible Developmental Slowing by High Reactive Oxygen Species and Mitochondrial Damage in Caenorhabditis Elegans

      Mirza, Zeynep (2023-08-28)
      Host-pathogen interactions are complex by nature, and the host developmental stage increases this complexity. Development is an energetically demanding period when biomass production and cell differentiation events occur. We investigated how a developing organism copes with the additional energy-expensive burden of pathogen stress during this crucial period. We explored this question by utilizing Caenorhabditis elegans larvae as the host and the bacterium Pseudomonas aeruginosa as the pathogen. By screening 36 P. aeruginosa isolates, we found that the CF18 strain causes a severe but reversible developmental delay. CF18 slows larval development via induction of reactive oxygen species (ROS) and mitochondrial dysfunction. In response, the larvae upregulate mitophagy and antimicrobial and detoxification genes; however, mitochondrial unfolded protein response (UPRmt) is repressed. Consistent with these observations, antioxidant or iron supplementation or the removal of larvae from CF18 rescues developmental delay, mitochondrial damage, and high ROS. We examined the virulence factors of CF18 required for developmental delay via transposon mutagenesis, RNA-sequencing, and candidate gene deletion approaches. Our results showed that virulence factors regulated by quorum sensing and the GacA/S system were responsible for developmental slowing. We also demonstrated that well-studied mitochondrial toxins of P. aeruginosa, phenazines and hydrogen cyanide, are not required for CF18-induced developmental slowing. This study highlights the importance of ROS levels and mitochondrial health as determinants of developmental rate and how pathogens can attack these important features.
    • Anxiety and Depression Among US Nursing Home Residents with Chronic Obstructive Pulmonary Disease

      Osundolire, Seun; Goldberg, Robert J; Lapane, Kate L (2023-08-28)
      Background: Chronic obstructive pulmonary disease (COPD) is highly prevalent among nursing home residents; however, few studies have focused on the psychological impact of this clinically significant condition on nursing home residents. Objective: We examine the prevalence of, and factors associated with, anxiety and depression in nursing home residents with COPD. Methods: Using the US 2018 Minimum Dataset (MDS), we conducted a cross-sectional study among 239,615 residents aged ≥50 years old in US Medicare/Medicaid certified nursing homes with COPD. Anxiety and depression were diagnosed based on clinical diagnoses, physical examination findings, and treatment orders. Multivariable adjusted Poisson models with a generalized estimating equations approach account for the clustering among residents within nursing homes. Results: The average age of the study population was 79 years (SD: 10.6), 62.0% were women, and 43.7% had five or more comorbid conditions. In this population, 37.2% had anxiety, 57.6% had depression, and 27.5% had both mental health conditions. Women, current tobacco users, persons 50-64 years old, those who reported having moderate or severe pain, and nursing home residents with multimorbidity were more likely to have anxiety or depression than respective comparison groups. Conclusion: Anxiety and depression are common among US nursing home residents with COPD. Women, medically complex patients, and those who report having moderate-to-severe pain appear to be more likely to have anxiety and depression. Clinical teams should be aware of these findings when managing nursing home residents with COPD and use various nonpharmacological and medical interventions for the effective management of anxiety and depression. Longitudinal studies evaluating how anxiety and depression affect the management of COPD and related outcomes, and how best to improve the quality of life of nursing home residents with COPD, are warranted.
    • A comparative analysis of microglial inducible Cre lines

      Faust, Travis E; Feinberg, Philip A; O'Connor, Ciara; Kawaguchi, Riki; Chan, Andrew; Strasburger, Hayley; Frosch, Maximilian; Boyle, Margaret A; Masuda, Takahiro; Amann, Lukas; et al. (2023-08-26)
      Cre/loxP technology has revolutionized genetic studies and allowed for spatial and temporal control of gene expression in specific cell types. Microglial biology has particularly benefited because microglia historically have been difficult to transduce with virus or electroporation methods for gene delivery. Here, we investigate five of the most widely available microglial inducible Cre lines. We demonstrate varying degrees of recombination efficiency, cell-type specificity, and spontaneous recombination, depending on the Cre line and inter-loxP distance. We also establish best practice guidelines and protocols to measure recombination efficiency, particularly in microglia. There is increasing evidence that microglia are key regulators of neural circuits and major drivers of a broad range of neurological diseases. Reliable manipulation of their function in vivo is of utmost importance. Identifying caveats and benefits of all tools and implementing the most rigorous protocols are crucial to the growth of the field and the development of microglia-based therapeutics.
    • Improving diagnosis of non-malarial fevers in Senegal: Borrelia and the contribution of tick-borne bacteria [preprint]

      Levine, Zoë C; Sene, Aita; Mkandawire, Winnie; Deme, Awa B; Ndiaye, Tolla; Sy, Mouhamad; Gaye, Amy; Diedhiou, Younouss; Mbaye, Amadou M; Ndiaye, Ibrahima; et al. (2023-08-25)
      The worldwide decline in malaria incidence is revealing the extensive burden of non-malarial febrile illness (NMFI), which remains poorly understood and difficult to diagnose. To characterize NMFI in Senegal, we collected venous blood and clinical metadata from febrile patients and healthy controls in a low malaria burden area. Using 16S and unbiased sequencing, we detected viral, bacterial, or eukaryotic pathogens in 29% of NMFI cases. Bacteria were the most common, with relapsing fever Borrelia and spotted fever Rickettsia found in 15% and 3.7% of cases, respectively. Four viral pathogens were found in a total of 7 febrile cases (3.5%). Sequencing also detected undiagnosed Plasmodium, including one putative P. ovale infection. We developed a logistic regression model to distinguish Borrelia from NMFIs with similar presentation based on symptoms and vital signs. These results highlight the challenge and importance of improved diagnostics, especially for Borrelia, to support diagnosis and surveillance.
    • Heterozygous FOXJ1 Mutations Cause Incomplete Ependymal Cell Differentiation and Communicating Hydrocephalus

      Hou, Connie C; Li, Danielle; Berry, Bethany C; Zheng, Shaokuan; Carroll, Rona S; Johnson, Mark D; Yang, Hong Wei (2023-08-24)
      Heterozygous mutations affecting FOXJ1, a transcription factor governing multiciliated cell development, have been associated with obstructive hydrocephalus in humans. However, factors that disrupt multiciliated ependymal cell function often cause communicating hydrocephalus, raising questions about whether FOXJ1 mutations cause hydrocephalus primarily by blocking cerebrospinal fluid (CSF) flow or by different mechanisms. Here, we show that heterozygous FOXJ1 mutations are also associated with communicating hydrocephalus in humans and cause communicating hydrocephalus in mice. Disruption of one Foxj1 allele in mice leads to incomplete ependymal cell differentiation and communicating hydrocephalus. Mature ependymal cell number and motile cilia number are decreased, and 12% of motile cilia display abnormal axonemes. We observed decreased microtubule attachment to basal bodies, random localization and orientation of basal body patches, loss of planar cell polarity, and a disruption of unidirectional CSF flow. Thus, heterozygous FOXJ1 mutations impair ventricular multiciliated cell differentiation, thereby causing communicating hydrocephalus. CSF flow obstruction may develop secondarily in some patients harboring FOXJ1 mutations. Heterozygous FOXJ1 mutations impair motile cilia structure and basal body alignment, thereby disrupting CSF flow dynamics and causing communicating hydrocephalus.
    • TAL1 and LMO2 Promote Leukemia-Initiating Cell Quiescence and Chemotolerance in T-ALL

      O'Connor, Kevin W (2023-08-21)
      Relapse remains a major barrier to the successful treatment of children with T-cell acute lymphoblastic leukemia (T-ALL) and may represent a failure to eliminate leukemia-initiating cells (L-ICs) that possess distinguishing biological features from the bulk leukemic population. TAL1 and LMO2 are often coordinately misexpressed in T-ALL patients and their ectopic expression cooperates to transform thymic progenitors in mice. In this model, double negative-3 (DN3) stage thymic progenitors harbor L-ICs, yet only a subset of DN3 leukemic cells have L-IC activity. We interrogated L-IC heterogeneity in our Tal1/Lmo2 mouse T-ALL model using a combination of single cell RNA-sequencing (scRNA-seq) and H2B-GFP nucleosome labeling. We identified a cell cycle restricted DN3 subpopulation with high Notch1 activity and enrichment of Tal1/Lmo2 targets and T-cell quiescence genes. This dormant DN3 population significantly increased during leukemogenesis, exhibited chemotolerance and was enriched for genes associated with patient minimal residual disease (MRD). In vivo studies using the Tet-inducible H2B-GFP model revealed that Tal1 and Lmo2 cooperate to promote quiescence in DN3 cells. Examination of TAL1/LMO patient samples revealed that the L-IC enriched CD7+CD1a- thymic progenitors (hL-IC) were also chemotolerant and were also variably associated with quiescence. Collectively, our results document the emergence of dormant and chemotolerant L-ICs during Tal1/Lmo2-induced leukemogenesis in mice and relapsed T-ALL patients.
    • The Interactions Between Fluoropyrimidines and the Gut Microbiome that Lead to Drug Resistance in Bacteria and Can Alter the Drug Efficacy in the Host

      Rosener, Brittany (2023-08-21)
      Bacterial metabolism of host-targeting drugs can impact the success of host treatment. It has been found that host-targeting drugs may not only interact with the host cells but can inhibit growth of bacteria. With repeated exposure, this inadvertent impact on microbes can apply selective pressure leading to genetic adaptation of the host microbiome. This adaptation can, in turn, alter the bacterial metabolism of the drug and lead to a change in drug availability and toxicity in the host. One such set of drugs we explored are the fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluoro-3’-deoxyuridine (FUDR) used to treat tumors. Using E. coli loss-of-function screens, we identified 5-FU resistant strains that decreased drug toxicity on the C. elegans host. Furthermore, the mechanisms of resistance developed after repeated exposure to 5-FU and FUDR converged to a select set of resistance mechanisms involving the nucleotide synthesis and salvage pathway. We also found bacteria evolved in nutrient-poor media reduced the host drug toxicity whereas bacteria evolved in nutrient-rich media did not alter the drug toxicity on the host. Next, we identified similar mechanisms of resistance in Comamonas aquatica. 5-FU evolved C. aquatica but not FUDR evolved C. aquatica decreased drug toxicity in a C. elegans host. Lastly, we explored the selective pressure of 5-FU treatment on the gut microbiome Using a murine model and the E. coli knock-out library, we identified that selection by the gut environment matches previously studied mechanisms in which some E. coli strains preferentially colonize the gut. Then, we found 5-FU treatment enriches for mutants known to provide 5-FU resistance in vitro. Overall, we found that bacteria can become resistant to fluoropyrimidines leading to changes in drug efficacy for the host. Additionally, 5-FU treatment in mice can also select for genotypes in the gut that provide resistance to 5-FU exposure.
    • The Post-Transcriptional Regulation Mechanism and Functional Importance of a Key Maternal mRNA, GLP-1

      Coskun, Peren (2023-08-17)
      Translational control of maternal mRNAs is a major form of gene regulation during germline development and embryogenesis. C. elegans Notch homolog glp-1 maternal gene is necessary for germ cell proliferation, and embryonic fate determination. The RNA binding proteins POS-1 and GLD-1 directly regulate the translation of GLP-1 protein by binding to the specific elements within the glp-1 3’ UTR. When POS-1 or GLD-1 binding is disrupted by mutation of their respective elements, the expression pattern of a glp-1 3’ UTR reporter transgene changes in both the germline and in embryos. The mechanism by which POS-1 and GLD-1 mediate translation repression is not well understood. Previous work showed that loss of pos-1 increases the average polyA tail length of endogenous glp-1 transcripts in embryos. In this dissertation, we show that mutation of either the GLD-1 or POS-1 binding motifs in transgenic reporters does not change polyA site selection. This result rules out alternative polyA site selection as a mechanism of regulation. We also show that wild-type glp-1 transgenic reporter embryos have a shorter average polyA tail length compared to transgenic reporters with mutated GLD-1 or POS-1 binding motifs. We have studied the effect of cytoplasmic polymerases, deadenylases and translation initiation factors on our transgenic reporters. Our RNAi experiments show that two cytoplasmic polyA polymerases, GLD-2 and GLD-4, have strikingly different effects on the expression of reporter transgenes harboring GLD-1 or POS-1 binding motif mutations. By contrast, none of the deadenylases affect the transgenic reporter expression. We also observed strong derepression of all reporters upon reduction of the translation initiation factor ife-3. The results reveal that POS-1 and GLD-1 exert their repressive effects in different ways through cytoplasmic polyA polymerase activity, while IFE-3 mediated translation repression is independent of both POS-1 and GLD-1. Lastly, we have examined the biological significance of glp-1 3’UTR to the worm reproduction by using CRISPR/Cas9 mutagenesis to generate glp-1 3’UTR mutations in the endogenous locus. Characterization of a 71 base pair mutation that deletes the GLD-1 and POS-1 binding sites in the glp-1 3’UTR reveals a 2-fold reduction in the number of embryos produced and a 4-fold reduction in the hatch rate. Imaging results show that the mutant embryos appear to have patterning defects. Together, our results show that the glp-1 3’UTR contributes to reproductive health but is not essential to fertility.
    • Can psychological interventions prevent or reduce risk for perinatal anxiety disorders? A systematic review and meta-analysis

      Zimmermann, Martha; Julce, Clevanne; Sarkar, Pooja; McNicholas, Eileen; Xu, Lulu; Carr, Catherine W.; Boudreaux, Edwin D; Lemon, Stephenie C; Byatt, Nancy (2023-08-16)
      Objective: Little is known about the extent to which interventions can prevent perinatal anxiety disorders. We conducted a systematic review and meta-analysis to examine whether interventions can decrease the onset and symptoms of perinatal anxiety among individuals without an anxiety disorder diagnosis. Method: We conducted a comprehensive literature search across five databases related to key concepts: (1) anxiety disorders/anxiety symptom severity (2) perinatal (3) interventions (4) prevention. We included studies that examined a perinatal population without an anxiety disorder diagnosis, included a comparator group, and assessed perinatal anxiety. We included interventions focused on perinatal anxiety as well as interventions to prevent perinatal depression or influence related outcomes (e.g., physical activity). Results: Thirty-six studies were included. No study assessing the incidence of perinatal anxiety disorder (n = 4) found a significant effect of an intervention. Among studies assessing anxiety symptom severity and included in the quantitative analysis (n = 30), a meta-analysis suggested a small standardized mean difference of -0.31 (95% CI [-0.46, -0.16], p < .001) for anxiety at post intervention, favoring the intervention group. Both mindfulness (n = 6), and cognitive behavioral therapy approaches (n = 10) were effective. Conclusions: Interventions developed for perinatal anxiety were more effective than interventions to prevent perinatal depression. Psychological interventions show promise for reducing perinatal anxiety symptom severity, though interventions specifically targeting anxiety are needed.
    • Nurses with Physical Disabilities Experiences During Pre-licensure Education

      Mantlow, Kimberly D. (2023-08-15)
      PURPOSE: To describe the pre-licensure nursing educational experience of integration and inclusion among RNs with a physical disability during their education. SPECIFIC AIMS: 1) Describe the access RNs with a physical disability had to academic and social opportunities during their prelicensure education program that contributed to academic and social integration (inclusion). 2). Explore perceptions of RNs with a physical disability regarding inclusion and acceptance of their disability as a valued component of student diversity during their prelicensure education program. 3). Describe the contextual factors and key aspects of connection during the pre-licensure educational experiences of RNs who had a physical disability as positive (Disability-Diversity Connect) or negative and disintegrated (Disability-Diversity Disconnect). FRAMEWORK: This study was guided by The Disability-Diversity Disconnect (DDDM) by Aquino (2016). DESIGN: This study design used was qualitative description. It included semi-structured interviews using an interview guide based on the DDDM. RESULTS: 16 individuals with 14 different physical disabilities participated in this study. During data analysis four themes emerged: I Saved My Energy for Learning, Determination, Wanting to Find My People and Secrets, Living a Double Life which has a subtheme, Fear of Judgement. CONCLUSION: : Identification of factors related to inclusion within the academic environment provides insight for future work to examine the needs of prelicensure nursing students with physical disabilities and the potential to improve their future educational experiences.
    • Comparative neurogenetics of dog behavior complements efforts towards human neuropsychiatric genetics

      Morrill, Kathleen; Chen, Frances; Karlsson, Elinor K (2023-08-14)
      Domestic dogs display a wide array of heritable behaviors that have intermediate genetic complexity thanks to a long history of human-influenced selection. Comparative genetics in dogs could address the scarcity of non-human neurogenetic systems relevant to human neuropsychiatric disorders, which are characterized by mental, emotional, and behavioral symptoms and involve vastly complex genetic and non-genetic risk factors. Our review describes the diverse behavioral "phenome" of domestic dogs, past and ongoing sources of behavioral selection, and the state of canine behavioral genetics. We highlight two naturally disordered behavioral domains that illustrate how dogs may prove useful as a comparative, forward neurogenetic system: canine age-related cognitive dysfunction, which can be examined more rapidly given the attenuated lifespan of dogs, and compulsive disorders, which may have genetic roots in purpose-bred behaviors. Growing community science initiatives aimed at the companion dog population will be well suited to investigating such complex behavioral phenotypes and offer a comparative resource that parallels human genomic initiatives in scale and dimensionality.
    • A novel intrasaccular aneurysm device with high complete occlusion rate: initial results in a rabbit model

      Zoppo, Christopher T; Kolstad, Josephine W; King, Robert M; Wolfe, Thomas; Kraitem, Afif; Vardar, Zeynep; Badruddin, Aamir; Pereira, Edgard; Guerrero, Boris Pabón; Rosqueta, Arturo S; et al. (2023-08-01)
      Background: Intrasaccular flow-disrupting devices are a safe and effective treatment strategy for intracranial aneurysms. We utilized high-frequency optical coherence tomography (HF-OCT) and digital subtraction angiography (DSA) to evaluate SEAL Arc, a new intrasaccular device, and compare the findings with the well-established Woven EndoBridge (WEB) device in an animal model of saccular aneurysms. Methods: In a rabbit model, elastase-induced aneurysms were treated with SEAL Arc (n=11) devices. HF-OCT and DSA were performed after implant and repeated after 12 weeks. Device protrusion and malapposition were assessed at implant time and scored on a binary system. Aneurysm occlusion was assessed at 12 weeks with the WEB Occlusion Scale and dichotomized to complete (A and B) or incomplete (C and D) occlusion. The percentage of neointimal coverage after 12 weeks was quantified using HF-OCT. We compared these data to previously published historical controls treated with the gold-standard WEB device (n=24) in the same model. Results: Aneurysm size and device placement were not significantly different between the two groups. Complete occlusion was demonstrated in 80% of the SEAL Arc devices, which compared favorably to the 21% of the aneurysms treated with WEB devices (P=0.002). Neointimal coverage across SEAL Arc devices was 86±15% compared with 49±27% for WEB (P=0.001). Protruding devices had significantly less neointimal coverage (P<0.001) as did incompletely occluded aneurysms (P<0.001). Histologically, all aneurysms treated with SEAL Arc devices were completely healed. Conclusion: Complete early aneurysm occlusion was frequently observed in the SEAL Arc treated aneurysms, with significant neointimal coverage after 12 weeks.
    • Immunopeptidome profiling of human coronavirus OC43-infected cells identifies CD4 T-cell epitopes specific to seasonal coronaviruses or cross-reactive with SARS-CoV-2

      Becerra-Artiles, Aniuska; Nanaware, Padma P; Muneeruddin, Khaja; Weaver, Grant; Shaffer, Scott A; Calvo-Calle, J Mauricio; Stern, Lawrence J (2023-07-27)
      Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 has prompted increased attention to coronavirus biology and immunopathology, but the T-cell response to seasonal coronaviruses remains largely uncharacterized. Here we report the repertoire of viral peptides that are naturally processed and presented upon infection of a model cell line with seasonal coronavirus OC43. We identified MHC-bound peptides derived from each of the viral structural proteins (spike, nucleoprotein, hemagglutinin-esterase, membrane, and envelope) as well as non-structural proteins nsp3, nsp5, nsp6, and nsp12. Eighty MHC-II bound peptides corresponding to 14 distinct OC43-derived epitopes were identified, including many at very high abundance within the overall MHC-II peptidome. Fewer and less abundant MHC-I bound OC43-derived peptides were observed, possibly due to MHC-I downregulation induced by OC43 infection. The MHC-II peptides elicited low-abundance recall T-cell responses in most donors tested. In vitro assays confirmed that the peptides were recognized by CD4+ T cells and identified the presenting HLA alleles. T-cell responses cross-reactive between OC43, SARS-CoV-2, and the other seasonal coronaviruses were confirmed in samples of peripheral blood and peptide-expanded T-cell lines. Among the validated epitopes, spike protein S903-917 presented by DPA1*01:03/DPB1*04:01 and S1085-1099 presented by DRB1*15:01 shared substantial homology to other human coronaviruses, including SARS-CoV-2, and were targeted by cross-reactive CD4 T cells. Nucleoprotein N54-68 and hemagglutinin-esterase HE128-142 presented by DRB1*15:01 and HE259-273 presented by DPA1*01:03/DPB1*04:01 are immunodominant epitopes with low coronavirus homology that are not cross-reactive with SARS-CoV-2. Overall, the set of naturally processed and presented OC43 epitopes comprise both OC43-specific and human coronavirus cross-reactive epitopes, which can be used to follow CD4 T-cell cross-reactivity after infection or vaccination, and to guide selection of epitopes for inclusion in pan-coronavirus vaccines.
    • Challenges and solutions to superior chimeric antigen receptor-T design and deployment for B-cell lymphomas

      Gao, Jenny; Dahiya, Saurabh; Patel, Shyam A (2023-07-24)
      Chimeric antigen receptor-T (CAR-T) therapies represent a major breakthrough in cancer medicine, given the ex vivo-based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B-cell lymphomas. Although more than a decade has passed since the initial introduction of CAR-T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR-T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time-honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR-T products in early lines of therapy. Such barriers include antigen escape, "cold" tumour microenvironments, host inflammation and CAR-T cell exhaustion. We highlight solutions including point-of-care CAR-T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR-T deployment for B-cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first-in-class anti-CD3/CD20 bispecific antibodies-mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024.
    • Suppression of Sphingolipid Catabolism by a Nuclear Hormone Receptor Promotes Pathogen Resistance in C. elegans

      Nasrallah, Mohamad (2023-07-20)
      Sphingolipids are key structural components of cell membranes and function as signaling molecules that are required for diverse biological functions in all metazoan animals. Here we characterize a novel immunometabolic pathway that regulates sphingolipid catabolism to promote resistance to bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human HNF4. Tandem chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism and stress response genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. Genetic epistasis analysis revealed that nhr-66 functions with the PPARɑ homolog nhr-49 for host defense against P. aeruginosa and in the regulation of sphingolipid catabolism genes. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipid and ceramide levels, revealing an immunometabolic axis that is required for host survival during pathogen infection.
    • A mobile addiction service for community-based overdose prevention

      Pepin, Michael D; Joseph, Jillian K; Chapman, Brittany P; McAuliffe, Christina; O'Donnell, Logan K; Marano, Ryan L; Carreiro, Stephanie; Garcia, Erik J; Silk, Hugh; Babu, Kavita M (2023-07-19)
      Mainstays of opioid overdose prevention include medications for opioid use disorder (e.g., methadone or buprenorphine) and naloxone distribution. Inadequate access to buprenorphine limits its uptake, especially in communities of color, and people with opioid use disorders encounter multiple barriers to obtaining necessary medications including insurance, transportation, and consistent availability of telephones. UMass Memorial Medical Center and our community partners sought to alleviate these barriers to treatment through the deployment of a mobile addiction service, called the Road to Care. Using this approach, multidisciplinary and interprofessional providers deliver holistic addiction care by centering our patients' needs with respect to scheduling, location, and convenience. This program also extends access to buprenorphine and naloxone among people experiencing homelessness. Additional systemic and individualized barriers encountered are identified, as well as potential solutions for future mobile addiction service utilization. Over a two-year period, we have cared for 1,121 individuals who have accessed our mobile addiction service in over 4,567 encounters. We prescribed buprenorphine/naloxone (Suboxone®) to 330 individuals (29.4% of all patients). We have distributed nearly 250 naloxone kits directly on-site or and more than 300 kits via prescriptions to local pharmacies. To date, 74 naloxone rescue attempts have been reported back to us. We have demonstrated that a community-based mobile addiction service, anchored within a major medical center, can provide high-volume and high-quality overdose prevention services that facilitate engagement with additional treatment. Our experience is described as a case study below.
    • A Systems-Level Study of Transcriptional Regulation of C. elegans Metabolism

      Nanda, Shivani (2023-07-14)
      Metabolism is controlled to ensure organismal development and homeostasis. Several mechanisms regulate metabolism, including allosteric control and transcriptional regulation of metabolic enzymes and transporters. Until now, metabolism regulation has mostly been described for individual genes and pathways, and the extent of transcriptional regulation of the entire metabolic network largely remains largely unknown. In the first part of this thesis, I used variation in mRNA levels as a proxy for transcriptional regulation of metabolism and found that three-quarters of all metabolic genes are transcriptionally regulated in the nematode Caenorhabditis elegans. I also found that many annotated metabolic pathways are coexpressed. With the aid of gene expression data and the iCEL1314 metabolic network model, I defined coregulated sub-pathways in an unbiased manner. By utilizing a large gene expression compendium, I determined the conditions under which sub-pathways exhibit strong coexpression. Additionally, we developed 'WormClust', a web application that facilitates a gene-by-gene query of genes to view their association with metabolic (sub)- pathways. In the second part of this thesis, I addressed the "missing" annotations in C. elegans metabolism. Through the analysis of various datasets spanning space, time, and conditions, I associated orphan metabolic genes, transporters, transcription factors, and RNA-binding proteins with the existing metabolic network. Overall, this study illuminates the ubiquity of transcriptional regulation of metabolism and provides a blueprint for similar studies in other organisms, including humans.
    • Minimally Invasive Analysis of Allergic and Irritant Contact Dermatitis Identifies Distinguishing Biomarkers and Intercellular Signaling Pathways

      Frisoli, Michael L. (2023-07-07)
      Allergic contact dermatitis is one of the most common inflammatory skin diseases, yet identification of environmental triggers can be challenging, and treatment options are limited for patients with frequent exposures. The chemical patch test has been used for over a century to diagnose patient-specific allergen sensitivities; however, limited test sensitivity and subjective interpretability motivates the use of modern scientific tools to improve the patch test diagnostic process. Additionally complicating diagnosis, chemical patch application can cause skin inflammation through both allergic sensitivity as well as nonspecific irritation. To discover allergy-specific biomarkers, I induced both irritant and allergic contact dermatitis in human volunteers, sampled skin lesions by non-scarring methods, and quantified transcriptomic and proteomic changes. Using single cell RNA sequencing together with a newly adapted method for ligand-receptor cell signaling estimation, I identified allergy-specific, irritant-specific, and allergy/irritant-shared cell responses of estimated disease significance. Quantification of inflammatory proteins within skin interstitial fluid also identified several biomarkers that were capable of distinguishing allergic from irritant contact dermatitis with 100% specificity and over 80% sensitivity.
    • Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection : A Prospective Cohort Study

      Soni, Apurv; Herbert, Carly; Lin, Honghuang; Yan, Yi; Pretz, Caitlin; Stamegna, Pamela; Wang, Biqi; Orwig, Taylor; Wright, Colton; Tarrant, Seanan; et al. (2023-07-04)
      Background: The performance of rapid antigen tests (Ag-RDTs) for screening asymptomatic and symptomatic persons for SARS-CoV-2 is not well established. Objective: To evaluate the performance of Ag-RDTs for detection of SARS-CoV-2 among symptomatic and asymptomatic participants. Design: This prospective cohort study enrolled participants between October 2021 and January 2022. Participants completed Ag-RDTs and reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 every 48 hours for 15 days. Setting: Participants were enrolled digitally throughout the mainland United States. They self-collected anterior nasal swabs for Ag-RDTs and RT-PCR testing. Nasal swabs for RT-PCR were shipped to a central laboratory, whereas Ag-RDTs were done at home. Participants: Of 7361 participants in the study, 5353 who were asymptomatic and negative for SARS-CoV-2 on study day 1 were eligible. In total, 154 participants had at least 1 positive RT-PCR result. Measurements: The sensitivity of Ag-RDTs was measured on the basis of testing once (same-day), twice (after 48 hours), and thrice (after a total of 96 hours). The analysis was repeated for different days past index PCR positivity (DPIPPs) to approximate real-world scenarios where testing initiation may not always coincide with DPIPP 0. Results were stratified by symptom status. Results: Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDTs twice 48 hours apart resulted in an aggregated sensitivity of 93.4% (95% CI, 90.4% to 95.9%) among symptomatic participants on DPIPPs 0 to 6. When singleton positive results were excluded, the aggregated sensitivity on DPIPPs 0 to 6 for 2-time serial testing among asymptomatic participants was lower at 62.7% (CI, 57.0% to 70.5%), but it improved to 79.0% (CI, 70.1% to 87.4%) with testing 3 times at 48-hour intervals. Limitation: Participants tested every 48 hours; therefore, these data cannot support conclusions about serial testing intervals shorter than 48 hours. Conclusion: The performance of Ag-RDTs was optimized when asymptomatic participants tested 3 times at 48-hour intervals and when symptomatic participants tested 2 times separated by 48 hours. Primary funding source: National Institutes of Health RADx Tech program.
    • I saw Medusa's head sign and turned to stone

      Zoppo, Christopher T; Taros, Trenton; Singh, Jasmeet; Puri, Ajit; Kuhn, Anna Luisa (2023-07-04)
      Developmental venous anomalies (DVAs) are characterized by many radially oriented medullary veins surrounding a central draining vessel. When the imaging plane is perpendicular to the central vessel, these medullary veins resemble Medusa's head of snakes. Medusa's head sign, or caput medusae, can be appreciated on contrast enhanced CT scans and MRIs of the brain and is highly indicative of a DVA.