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Search strategies for \u27The Role of Venous Sinus Stenting in Management of Spontaneous CSF Leaks: A Systematic Review and Meta-Analyses
Get PDFChemoreflex Sensitization Occurs in Both Male and Female Rats During Recovery from Acute Lung Injury
Get PDFIntroduction: Sex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI is not known. To bridge this gap, the current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery from ALI.
Methods: ALI was induced using a single intra-tracheal instillation of bleomycin (bleo, 2.5 mg/Kg) (day 1). Resting respiratory frequency (fR) was measured at 1-2 days pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo. The chemoreflex responses to hypoxia (10% O2, 0% CO2) and normoxic-hypercapnia (21% O2, 5% CO2) were measured before bleo administration (pre-bleo) and 1 mth post-bleo using whole-body plethysmography. The apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point.
Results: There were no significant differences in resting fR between male and female rats at the pre-bleo time point or in the increase in resting fR at D7 post-bleo. At 1 mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly lower in male rats. The AHI, post-sigh apneas, and sighs were not different between male and female rats pre-bleo and 1 mth post-bleo. However, at D7 post-bleo, the male rats exhibited a higher AHI than female rats. Both male and female rats exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia with no significant differences between sexes.
Conclusion: A sex difference in resting ventilatory parameters occurs post ALI with a prolonged increase in resting fR and larger AHI in male rats. On the other hand, we did not find any sex differences in the chemoreflex sensitization that occurs at 1 mth post-bleo. This work contributes to a better understanding of sex-based variations in lung disorders
Development, Validation, and Diagnostic Performance of a Novel Radiomic Model for Predicting Prostate Cancer Recurrence
Get PDFMulti-parametric magnetic resonance imaging (MP-MRI)-derived radiomics have been shown to capture sub-visual patterns for the quantitative characterization of prostate cancer (PC) phenotypes. The present dissertation seeks to develop, evaluate, and compare the performance of an MRI-derived radiomic model for the prediction of PC recurrence following definitive treatment with radical prostatectomy (RP).
MP-MRI was obtained from 339 patients who had a minimum of 2 years follow-up following RP at three institutions. The prostate was manually delineated as the region of interest and 924 radiomic features were extracted. All features were evaluated for stability via intraclass correlation coefficient (ICC) and image normalization was conducted via histogram matching.
Eighteen important and non-redundant features were found to be predictors of PC recurrence at a mean ± SD of 3.4±1.9 years and were aggregated into a radiomic model. Five-fold, ten-run cross-validation yielded a receiver-operator characteristic area under the curve (ROC-AUC) of 0.82±0.04 in the training set (n=290). In comparison, the University of California San Fransisco Cancer of the Prostate Risk Assessment score (UCSF-CAPRA) and Memorial Sloan Kettering Cancer Center (MSKCC) Pre-Radical Prostatectomy nomograms yielded AUC of 0.66±0.05 and 0.64±0.04, respectively (p\u3c0.01). Finally, when the radiomic model was applied to the test set (n=49), ROC-AUC was 0.72 and sensitivity, specificity, positive predictive value, and negative predictive value were 88%, 56%, 28% and 96%, respectively. Finally, correlational analysis revealed multiple significant correlations between radiomic and clinical features, but high potential of multicollinearity between variables must be considered before causal relationships could be established
Search strategies for Characterizing Metastatic Anogenital Squamous Cell Carcinoma in Immunosuppressed Patients: A Systematic Review
Get PDFAconitate Decarboxylase 1 Mediates the Acute Airway Inflammatory Response to Environmental Exposures
Get PDFBackground: Environmental lipopolysaccharide (LPS) and microbial component-enriched organic dusts cause significant lung disease. These environmental exposures induce the recruitment and activation of distinct lung monocyte/macrophage subpopulations involved in disease pathogenesis. Aconitate decarboxylase 1 (Acod1) was one of the most upregulated genes following LPS (vs. saline)exposure of murine whole lungs with transcriptomic profiling of sorted lung monocyte/macrophage subpopulations also highlighting its significance. Given monocyte/macrophage activation can be tightly linked to metabolism, the objective of these studies was to determine the role of the immunometabolic regulator ACOD1 inenvironmentalexposure-induced lung inflammation.
Methods: Wild-type (WT) mice were intratracheally (i.t.) instilled with 10 μg of LPS or saline. Whole lungs were profiled using bulk RNA sequencing or sorted to isolate monocyte/macrophage subpopulations. Sorted subpopulations were then characterized transcriptomically using a NanoString innate immunity multiplex array 48 h post-exposure. Next, WT and Acod1-/- mice were instilled with LPS, 25% organic dust extract (ODE), or saline, whereupon serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected. BALF metabolites of the tricarboxylic acid (TCA) cycle were quantified by mass spectrometry. Cytokines/chemokines and tissue remodeling mediators were quantitated by ELISA. Lung immune cells were characterized by flow cytometry. Invasive lung function testing was performed 3 h post-LPS with WT and Acod1-/- mice.
Results: Acod1-/- mice treated with LPS demonstrated decreased BALF levels of itaconate, TCA cycle reprogramming, decreased BALF neutrophils, increased lung CD4+ T cells, decreased BALF and lung levels of TNF-α, and decreased BALF CXCL1 compared to WT animals. In comparison, Acod1-/- mice treated with ODE demonstrated decreased serum pentraxin-2, BALF levels of itaconate, lung total cell, neutrophil, monocyte, and B-cell infiltrates with decreased BALF levels of TNF-α and IL-6 and decreased lung CXCL1 vs. WT animals. Mediators of tissue remodeling (TIMP1, MMP-8, MMP-9) were also decreased in the LPS-exposed Acod1-/- mice, with MMP-9 also reduced in ODE-exposed Acod1-/- mice. Lung function assessments demonstrated a blunted response to LPS-induced airway hyperresponsiveness in Acod1-/- animals.
Conclusion: Acod1 is robustly upregulated in the lungs following LPSexposure and encodes a key immunometabolic regulator. ACOD1mediates the proinflammatoryresponse toacute inhaledenvironmental LPS and organic dustexposure-induced lung inflammation
Health Vulnerability Mapping for Drought: A Case Study in a Predominantly Rural, Agricultural State
No full textInvestigation into Cardiac Myhc-α 334-352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity
Get PDFMyocarditis is one of the major causes of heart failure in children and young adults and can lead to dilated cardiomyopathy. Lymphocytic myocarditis could result from autoreactive CD4+ and CD8+ T cells, but defining antigen specificity in disease pathogenesis is challenging. To address this issue, we generated T cell receptor (TCR) transgenic (Tg) C57BL/6J mice specific to cardiac myosin heavy chain (Myhc)-α 334-352 and found that Myhc-α-specific TCRs were expressed in both CD4+ and CD8+ T cells. To investigate if the phenotype is more pronounced in a myocarditis-susceptible genetic background, we backcrossed with A/J mice. At the fourth generation of backcrossing, we observed that Tg T cells from naïve mice responded to Myhc-α 334-352, as evaluated by proliferation assay and carboxyfluorescein succinimidyl ester staining. The T cell responses included significant production of mainly pro-inflammatory cytokines, namely interferon (IFN)-γ, interleukin-17, and granulocyte macrophage-colony stimulating factor. While the naïve Tg mice had isolated myocardial lesions, immunization with Myhc-α 334-352 led to mild myocarditis, suggesting that further backcrossing to increase the percentage of A/J genome close to 99.99% might show a more severe disease phenotype. Further investigations led us to note that CD4+ T cells displayed the phenotype of cytotoxic T cells (CTLs) akin to those of conventional CD8+ CTLs, as determined by the expression of CD107a, IFN-γ, granzyme B natural killer cell receptor (NKG)2A, NKG2D, cytotoxic and regulatory T cell molecules, and eomesodermin. Taken together, the transgenic system described in this report may be a helpful tool to distinguish the roles of cytotoxic cardiac antigen-specific CD4+ T cells vs. those of CD8+ T cells in the pathogenesis of myocarditis
Reactive Aldehyde Species (RASP) Inhibitors Sequester MAA-Adducts and Reduce Pro-Inflammatory Cytokines
Get PDFBackground: Post-translational modifications of self-proteins have been implicated in the pathogenesis of Rheumatoid Arthritis (RA). One of these protein modifications termed malondialdehyde-acetaldehyde-adduct (MAA) has recently gained interest for its involvement in RA. This protein adduct contributes to inflammation by inducing immune cells to generate pro-inflammatory cytokines, T-cell specific responses, responses and circulating autoantibodies. Recently, novel reactive aldehyde species (RASP) inhibitors (ADX-629 and ADX-246) became available that have been shown to prevent the formation of MAA adducts by covalently binding and sequestering MDA and AA in a mouse model of alcoholic liver disease. These inhibitors prevented the release of key inflammatory cytokines and protected animals from progressive liver damage. While these experiments demonstrated the binding of RASP inhibitors to MDA and AA prior to MAA formation, they did not determine the capacity of these agents to scavenge pre-formed MAA protein adducts. Therefore, the purpose of this study was to determine if RASP inhibitors sequester MAA-adducts and block the subsequent cellular release of pro-inflammatory cytokines. Significance of the problem: MAA modified self-proteins may render harmful effects in patients with RA. Preventing inflammation and inflammation leading to fibrosis by inhibiting cellular binding of could represent significant advancement in the treatment of RA. Hypothesis: ADX-629 and -246 will prevent MAA protein adducts from binding to macrophage receptors and, as a result, prevent the release of pro-inflammatory cytokines. Experimental Design: Human monocytic cells (U-937 cell line) were activated to professional macrophages using phorbol 12-myristate 13-acetate (PMA) for 48 hours. Following pre-treatment with decreasing doses of ADX-629 or ADX-246 for 30 minutes, macrophages were incubated with 25µg/mL of fibrinogen (FIB) or MAA-modified fibrinogen (FIB-MAA) for 24 hours. Supernatants were collected for measurement of IL-6 and MCP-1 using commercially available kits. Cells were collected and tested for membrane integrity using a lactate dehydrogenase (LDH) assay. Results: In the absence of RASP inhibition, FIB-MAA stimulation of cells significantly increased the release IL-6 with mean concentration of approximately 30pg/mL compared to FIB alone 6-fold increase. (p\u3c0.0001). IL-6 release was significantly reduced with only 1 µM of ADX-629 and fell to native FIB levels with drug concentrations exceeding 10 µM (Figure 1A). ADX-246 demonstrated similar results (Figure 1B). Likewise, similar patterns were observed for the release of MCP-1 (data not shown). LDH assays showed no evidence of cellular toxicity regardless of ADX dose. Conclusions: In addition to confirming the capacity of RASP inhibitors to sequester MAA, results of this study demonstrate that both ADX-629 and ADX-246 attenuate or prevent MAA-modified proteins from initiating the macrophage-mediated release of pro-inflammatory cytokines implicated in RA pathogenesis. These findings support the need for additional in vivo investigations of these RASP inhibitors as novel therapies in in the management of RA and possibly in other conditions wherein MAA adducts mediate tissue damage.https://digitalcommons.unmc.edu/com_students_pres/1002/thumbnail.jp
Cross-Sectional Analysis of Primary Care Clinics\u27 Policies, Practices, and Availability of Patient Support Services During the COVID-19 Pandemic
Get PDFBACKGROUND: Healthcare accessibility and utilization are important social determinants of health. Lack of access to healthcare, including missed or no-show appointments, can have negative health effects and be costly to patients and providers. Various office-based approaches and community partnerships can address patient access barriers.
OBJECTIVES: (1) To understand provider perceptions of patient barriers; (2) to describe the policies and practices used to address late or missed appointments, and (3) to evaluate access to patient support services, both in-clinic and with community partners.
METHODS: Mailed cross-sectional survey with online response option, sent to all Nebraska primary care clinics (n = 577) conducted April 2020 and January through April 2021. Chi-square tests compared rural-urban differences; logistic regression of clinical factors associated with policies and support services computed odds ratios (OR) and 95% confidence intervals (CI).
RESULTS: Response rate was 20.3% (n = 117), with 49 returns in 2020. Perceived patient barriers included finances, higher among rural versus urban clinics (81.6% vs. 56.1%, p =.009), and time (overall 52.3%). Welcoming environment (95.5%), telephone appointment reminders (74.8%) and streamlined admissions (69.4%) were the top three clinic practices to reduce missed appointments. Telehealth was the most commonly available patient support service in rural (79.6%) and urban (81.8%, p =.90) clinics. Number of providers was positively associated with having a patient navigator/care coordinator (OR = 1.20, CI = 1.02-1.40). For each percent increase in the number of privately insured patients, the odds of providing legal aid decreased by 4% (OR = 0.96, CI = 0.92-1.00). Urban clinics were less likely than rural clinics to provide social work services (OR = 0.16, CI = 0.04-0.67) or assist with applications for government aid (OR = 0.22, CI = 0.06-0.90).
CONCLUSIONS: Practices to reduce missed appointments included a variety of reminders. Although finances and inability to take time off work were the most frequently reported perceived barriers for patients\u27 access to timely healthcare, most clinics did not directly address them. Rural clinics appeared to have more community partnerships to address underlying social determinants of health, such as transportation and assistance applying for government aid. Taking such a wholistic partnership approach is an area for future study to improve patient access
Disparities in Thyroid Cancer Diagnosis Based on Residence and Distance From Medical Facility
Get PDFCONTEXT: Rural-urban disparities have been reported in cancer care, but data are sparse on the effect of geography and location of residence on access to care in thyroid cancer.
OBJECTIVE: To identify impact of rural or urban residence and distance from treatment center on thyroid cancer stage at diagnosis.
METHODS: We evaluated 800 adults with differentiated thyroid cancer in the iCaRe2 bioinformatics/biospecimen registry at the Fred and Pamela Buffett Cancer Center. Participants were categorized into early and late stage using AJCC staging, and residence/distance from treating facility was categorized as short (≤ 12.5 miles), intermediate (\u3e 12.5 to \u3c 50 miles) or long (≥ 50 miles). Multivariable logistic regression was used to identify factors associated with late-stage diagnosis.
RESULTS: Overall, 71% lived in an urban area and 29% lived in a rural area. Distance from home to the treating facility was short for 224 (28%), intermediate for 231 (28.8%), and long for 345 (43.1%). All 224 (100%) short, 226 (97.8%) intermediate, and 120 (34.7%) long distances were for urban patients; in contrast, among rural patients, 5 (2.16%) lived intermediate and 225 (65.2%) lived long distances from treatment (
CONCLUSION: Older age at diagnosis, living in rural areas, and residing farther from the treatment center are all independently associated with late stage at diagnosis of thyroid cancer