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CD4+ T Cell-Innate Immune Crosstalk is Critical during Staphylococcus aureus Craniotomy Infection
Get PDFAccess to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4+ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1-/- mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent that displayed Th1- and Th17-like characteristics, and adoptive transfer of either subset in Rag1-/- animals during early infection prevented S. aureus outgrowth. scRNA-Seq identified a robust IFN signature in several innate immune clusters, and examination of cell-to-cell interactions revealed extensive T cell crosstalk with monocytes/macrophages that was also observed in human craniotomy infection. A cooperative role for Th1 and Th17 responses was demonstrated by treatment of Ifng-/- mice with IL-17A neutralizing antibody that recapitulated phenotypes in Rag1-/- animals. Collectively, these findings implicate Th1- and Th17-mediated proinflammatory responses in shaping the innate immune landscape for S. aureus containment during craniotomy infection
The Peptidyl Arginine Deiminase Inhibitor BB-CLA Decreases the Inflammatory and Fibrotic Responses in Macrophages and Rheumatoid Arthritis Synovial Fibroblasts Exposed to Fibrinogen Modified with Malondialdehyde-Acetaldehyde Adduct and Citrulline
Get PDFBackground. Peptide citrullination and adduction with malondialdehyde-acetaldehyde adduct (MAA) are involved in the pathogenesis of rheumatoid arthritis (RA). Anti-cyclic citrullinated peptide antibodies are \u3e90% specific for the diagnosis of RA, and MAA co-localizes with citrullinated proteins in RA synovial fluid. In addition, macrophages demonstrate increased expression of peptidyl arginine deiminase-2 (PAD2), an isozyme of PAD, in response to these MAA-adducted proteins. PAD catalyzes protein citrullination and may mediate the immunogenic transformation of synovial proteins and subsequent auto-antibody formation in RA. Here, we determine whether inhibition of PAD effects inflammatory and fibrotic markers in macrophages and RA human fibroblast-like synoviocytes (HFLS-RA) in response to stimulation with MAA and citrulline (CIT)-modified fibrinogen (FIB).
Methods. U-937 cells were differentiated into activated macrophages and subsequently stimulated with unmodified FIB, FIB-MAA, FIB-CIT, or FIB-MAA-CIT in the presence (treatment group) and absence (control group) of BB-CLA for 48 hours. Supernatants collected from the media were assessed by ELISA for interleukin-1b (IL-1b), interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). HFLS from RA patients were stimulated with treatment and control supernatants from the macrophage cultures and assessed via immunofluorescent staining for the fibrotic markers vimentin and type II collagen.
Results. The effect of PAD inhibition on inflammatory cytokine levels (Figure 1) was pronounced with FIB-CIT and FIB-MAA-CIT stimulations and mild with FIB and FIB-MAA stimulations. If fold decrease could not be calculated due to cytokine levels reaching 0, it is denoted as *0. Macrophages stimulated with FIB, FIB-MAA, FIB-CIT, and FIB-MAA-CIT, respectively, showed decreases in IL-1b (*0, *0, 4-fold, 6-fold, respectively), IL-6 (*0, *0, *0, 3-fold), IL-8 (*0, 1.6-fold, 8-fold, 14-fold), and MCP-1 (1.3-fold, 2-fold, 15-fold, 17-fold). In the absence of PAD inhibition, control group cytokine levels generally followed the trend of FIB-MAA-CIT \u3e FIB-CIT \u3e FIB-MAA \u3e FIB. A similar pattern of cellular response was observed (Figure 2) in HFLS-RA cells stimulated with macrophage supernatants from the treatment group, where vimentin (1.3-fold for FIB, 2-fold for FIB-MAA, 2-fold for FIB-CIT, 4-fold for FIB-MAA-CIT) and type II collagen (9-fold, 11-fold, 18-fold, 21-fold) expression were diminished compared with the control group. In the absence of PAD inhibition, mean pixel density levels followed FIB-MAA-CIT \u3e FIB-CIT \u3e FIB-MAA \u3e FIB for both anti-vimentin and anti-type II collagen staining. Conclusions. This study provides insight into the degree to which inflammatory and fibrotic responses from macrophages and HFLS to MAA and CIT modified fibrinogen may be PAD-mediated. MAA and CIT modification of fibrinogen increased inflammatory cytokines from macrophages and fibrotic proteins from HFLS-RA. BB-CLA markedly diminishes these responses. These observations further the understanding of the roles of MAA and CIT modified antigen in the joint synovium of RA patients, and the therapeutic use of PAD inhibitors in RA treatment.https://digitalcommons.unmc.edu/emet_posters/1038/thumbnail.jp
Acceptability of Self-Swab HPV Cervical Cancer Screenings Among Arabic-Speaking Individuals
Get PDFhttps://digitalcommons.unmc.edu/com_fam_pres/1019/thumbnail.jp
Development and Evaluation of an Interdisciplinary Rotation for Anesthesia Residents in Laryngology
Get PDFThe medical fields of anesthesiology and otolaryngology (ENT – ears, nose, throat) are defined by overlapping clinical expertise as it relates to the management of airway issues. As a result of this shared clinical domain, interdisciplinary educational experiences provide an opportunity for collaboration and a broadened experience for resident physician learning. Our institution developed a two-week rotation in otolaryngology for first-year anesthesiology interns with the goal of utilizing interdisciplinary coaching to develop both technical and non-technical skills in airway management. The purpose of this project is to perform a formal evaluation of this rotation and share our training methods and processes.https://digitalcommons.unmc.edu/emet_posters/1042/thumbnail.jp
Value of Case Studies for Translating Evidence in Occupational Therapy: A New 3-Dimensional Model
Get PDFImportance: Occupational therapy (OT) practitioners often address complex occupational performance needs of diverse consumers. Professional reasoning, theory, and trial and error interventions can be demonstrated in case studies. Case studies are usually relegated to the lowest level in evidence hierarchies. Yet they have a long tradition in health care literature, and may particularly document the holism, inclusivity, uniqueness, and complexity of OT practice.
Objective: To determine how case studies make a distinct contribution to professional knowledge, using a new model for categorizing them.
Evidence Review: 103 case studies published in AJOT from 1990-2023 were rated by the authors “1” or “2” on features derived from 3 axes: (1) frequency such a case would be encountered in current professional practice (rare = 2), (2) complexity of the causes of the client’s occupational challenges (complex = 2), and (3) complexity of the OT intervention (multidimensional = 2).
Findings: 93.2% of case studies had some feature of novelty or complexity: 35.9% portrayed a rare/novel diagnosis, 63.1% displayed complex problem causes, and 83.5% involved multi-dimensional OT interventions. In 55.3% of the articles both the causes and the interventions were complex.
Conclusions and Relevance: The predominance of novelty/complexity among the articles supports the claim that case studies mostly describe professional decisions and outcomes in those therapy situations that are less amenable to group experimental studies (infrequent/novel, complex causes, complex interventions). The value of the 3-axis model of case studies was supported. Case studies are a distinct source of evidence supporting inclusive, client-centered practice
From Vector to Consequence: Integrating Vector Surveillance, Environmental Drivers, and Public Health Impact into Lyme Disease Risk Management
No full textLyme disease is the most common vector-borne disease in North America. This dissertation examines (1) how crowd-sourced compares to active vector surveillance and whether they are associated with Lyme disease, (2) how ecological factors relate to tick abundance and whether they can predict high disease years, and (3) estimated health and economic burden of Lyme disease and savings when interventions are applied. Tick abundance data from active and passive surveillance were compared and tested for association with Lyme disease in the first aim. We found differences in tick life-stage, species, and seasonality. Tick observations were positively correlated with Lyme disease. Observed differences in outputs suggest differences between tick populations and human encounters. These findings signal an opportunity for early identification of high disease years through integrated surveillance that informs the conduct of disease surveillance. In the second aim, we used logistic regression and gradient boosting machine learning to examine relationships between environment and tick abundance and high disease years. Several factors were found to predict tick abundance. Palmer Drought Severity Index, soil moisture, Snow Water Equivalent, days below 0°F, degree days, small mammal count and mouse ratio were all highly predictive of high Lyme disease burden. Environmental factors predict tick abundance best in the same and subsequent year, and high disease burden two years in advance. Monitoring environmental factors provides opportunities for public health intervention through prediction of tick abundance and higher Lyme disease incidence. In the third aim, Monte Carlo simulations were used to estimate the health and economic burden of Lyme disease and prevented burden when prevention interventions are implemented. We found on average 8,436 Lyme disease cases annually. High-incidence years saw \u3e3,700 more cases than low-incidence, with costs for patients and society exceeding 1.2 million in societal costs. Simulation modeling demonstrates Lyme disease\u27s significant impact on individuals and society. Annual forecasting-triggered public health intervention programs could reduce cost and burden
Facilitators of Routine Cervical Screening Receipt for Women With Intellectual and Developmental Disabilities in Nebraska
No full textWomen with intellectual and developmental disabilities (I/DD) experience disproportionately low rates of cervical screening relative to women without I/DD, despite its clear role in cancer prevention. This disparity is especially stark in Nebraska, where in 2023, only 56% of women with I/DD had cervical screen receipt, compared to 78.4% of their non-disabled peers.. Previous literature has explored barriers to cervical screening for women with I/DD using the socioecological model (SEM) as a framework. This dissertation used three methodologies: a case study, a scoping review, and survey research, to examine facilitators to cervical screening for women with I/DD using the SEM framework, with a specific emphasis on interventions.
First, a case report documents a Nebraska woman with I/DD and a history of trauma from her failed cervical screening attempt through a pelvic floor physical therapy plan of care to a successful cervical screen. The outcomes suggest that pelvic floor physical therapy may serve as a trauma-informed facilitator to prepare women with I/DD for successful cervical screening.
Next, a scoping review of the literature revealed that few interventions have been developed to improve cervical screening receipt rates for women with I/DD. The interventions that have been studied report modest success in increasing knowledge or receipt of cervical screening and focus primarily on the individual, interpersonal, and organizational levels of the SEM. No interventions target the SEM community or public policy levels, despite previously documented barriers and facilitators at those levels.
Finally, survey data identified facilitators of cervical screening for women with I/DD in Nebraska, including recent sexual activity, a knowledge of cervical screening, and help from a provider. However, court-appointed medical guardianship emerged as a significant barrier, raising concerns about autonomy in preventative care.
Together, these findings highlight the potential of interventions at multiple levels of the SEM to improve cervical screening receipt rates for women with I/DD. It moves the field beyond identifying barriers to applying and studying interventions that facilitate screening. This holistic view will assist in the design of interventions that increase autonomy and ensure equitable and accessible cervical screening for women with I/DD