Kaysie L. Banton

Background/Objectives: This study examined whether dexamethasone (Dex) and decanoic acid (DA) exert complementary effects on inflammatory signaling, catabolic gene expression, and peroxisome proliferator-activated receptor gamma (PPARγ) activation in human chondrocytes. Methods: Two donor-specific primary human chondrocyte models, each derived from a single knee donor, were used, in which cells were treated with Dex (≤0.1 µM), DA (≤500 µM), or combinations thereof. Acute Interleukin-1β(IL-1β)-induced PGE₂ release was evaluated in normal donor cells, whereas prolonged transcriptional responses and PPARγ DNA-binding activity were evaluated in OA donor cells. IL-1β-induced prostaglandin E₂ (PGE₂) release was measured by competitive ELISA after 24 h. Glyceraldehyde-3-phosphate dehydrogenase-normalized transcription of Collagen type II alpha 1, Collagen type I alpha 1, Aggrecan, SRY-Box Transcription Factor 9, Runt-Related Transcription Factor 2, and Matrix Metalloproteinase 13 (MMP13) was assessed by qRT-PCR at 7, 10–14, and 20–28 days. In addition, PPARγ DNA-binding activity was measured after 1 week. Interactions were evaluated by Loewe additivity and highest single agent (HSA) analyses. Results: Dex and DA each reduced PGE₂ release, whereas co-treatment increased potency and maximal inhibition, with a Loewe combination index of 0.4 at 1 nM Dex plus 19 µM DA. In the temporal analysis, Dex plus DA showed a positive MMP13 ΔCt difference versus Dex at 10–14 days (2.42 ± 2.14; p = 0.065) and a more consistent difference at 20–28 days (1.11 ± 0.25; p = 0.016). This agreed with fixed-dose HSA findings at 14 and 28 days (ΔHSA ≈ −75 for 0.1 µM Dex plus 100 µM DA versus Dex). Co-treatment was also associated with increased PPARγ activation beyond the HSA reference (ΔHSA ≈ 0.09 for 0.1 µM Dex plus 100–250 µM DA versus Dex). Conclusions: Dex plus DA co-treatment produced complementary effects on acute PGE₂ inhibition, as well as late-onset MMP13 suppression and PPARγ activity in the donor-specific chondrocyte models studied. These hypothesis-generating findings provide an in vitro rationale for future evaluation of this combination as a corticosteroid-sparing strategy.

Myoendothelial junctions (MEJs) are structures that allow chemical signals to be transmitted between endothelial cells (ECs) and vascular smooth muscle cells, which control vascular tone. MEJs contain hemoglobin alpha (Hbα) and endothelial nitric oxide synthase (eNOS) complexes that appear to control the production and scavenging of nitric oxide (NO) along with the activity of cytochrome b5 reductase 3 (CYB5R3). The aim of this study was to examine how hypoxia affected the regulation of proteins involved in the production of NO in brain ECs. In brief, human brain microvascular endothelial cells (HBMEC) were exposed to cobalt chloride (CoCl₂), a hypoxia mimetic, and a transcriptional analysis was performed using primers for eNOS, CYB5R3, and Hbα2 with ΔΔCt relative gene expression normalized to GAPDH. NO production was also measured after treatment using 4,5-diaminofluorescein diacetate (DAF-DA), a fluorescent NO indicator. When HBMEC were exposed to CoCl₂ for 48 h, eNOS and CYB5R3 messenger RNA significantly decreased (up to −17.8 ± 4.30-fold and −10.4 ± 2.8, respectively) while Hbα2 increased to detectable levels. Furthermore, CoCl₂ treatment caused a redistribution of peripheral membrane-generated NO production to a perinuclear region. To the best of our knowledge, this is the first time this axis has been studied in brain ECs and these findings imply that hypoxia may cause dysregulation of proteins that regulate NO production in brain MEJs.

Introduction: Dysphagia, a complication of traumatic brain injuries (TBIs), can lead to death. Cervical collar (c-collar) restriction may increase the risk for dysphagia. The objective was to determine how c-collars affect dysphagia rates. Methods: This retrospective cohort study included geriatric TBIs or cervical spine injuries (January 2016 to December 2018) at a Level 1 trauma center. Outcomes (dysphagia, aspiration, and respiratory failure) were compared by c-collar placement. Results: There were 684 patients: 21.5% had a c-collar and 78.5% did not. Demographics, injury severity score, and Glasgow Coma Scale were comparable. Dysphagia (53.7% vs. 39.3%, p = .002) and respiratory failure (17.0% vs. 6.9%, p = .0002) were more common among patients with c-collars. Aspiration rates (p = .11) were similar. After adjustment, patients with a c-collar had a significantly higher odds of dysphagia and respiratory failure. Among patients who did not receive swallow therapy, aspiration (p = .02) and respiratory failure (p < .0001) were more common for those with c-collars. Conclusions: C-collar placement increased the risk for dysphagia and respiratory failure. There was evidence that swallow therapy may modify the effect of c-collar placement. For patients who did not receive swallow therapy, aspiration was more common among those with a c-collar. Dysphagia screening among patients with a c-collar may improve patient quality.

Background: Since the national stay-at-home order for COVID-19 was implemented, clinicians and public health authorities worldwide have expressed growing concern about the potential repercussions of drug and alcohol use due to social restrictions. We explored the impact of the national stay-at-home orders on alcohol or drug use and screenings among trauma admissions. Methods: This was a retrospective cohort study at six Level I trauma centers across four states. Patients admitted during the period after the onset of the COVID-19 restrictions (defined as March 16, 2020-May 31, 2020) were compared with those admitted during the same time period in 2019. We compared 1) rate of urine drug screens and blood alcohol screens; 2) rate of positivity for drugs or alcohol (blood alcohol concentration ≥ 10 mg/dL); 3) characteristics of patients who were positive for drug or alcohol, by period using chi-squared tests or Fisher’s exact tests, as appropriate. Two-tailed tests with an alpha of p < 0.05 was used on all tests. Results: There were 4762 trauma admissions across the study period; 2602 (55%) in 2019 and 2160 (45%) in 2020. From 2019 to 2020, there were statistically significant increases in alcohol screens (34% vs. 37%, p = 0.03) and drug screens (21% vs. 26%, p < 0.001). Overall, the rate of alcohol positive patients significantly increased from 2019 to 2020 (32% vs. 39%, p = 0.007), while the rate of drug positive patients was unchanged (57% vs. 52%, p = 0.13). Of the 1025 (22%) patients who were positive for alcohol or drugs, there were significant increases in a history of alcoholism (41% vs. 26%, p < 0.001), and substance abuse (11% vs. 23%, p < 0.001) in the 2020 period. No other statistically significant differences were identified among alcohol or drug positive patients during COVID-19 compared to the same period in 2019. Conclusions: Our first wave of COVID-19 data suggests that trauma centers were admitting significantly more patients who were alcohol positive, as well those with substance use disorders, potentially due to the impact of social restrictions and guidelines. Further longitudinal research is warranted to assess the alcohol and drug positive rates of trauma patients over the COVID-19 pandemic.

Inflammatory responses to the novel coronavirus SARS-CoV-2, which causes COVID-19, range from asymptomatic to severe. Here we present a follow-up analysis of a longitudinal study characterizing COVID-19 immune responses from a father and son with distinctly different clinical courses. The father required a lengthy hospital stay for severe symptoms, whereas his son had mild symptoms and no fever yet tested positive for SARS-CoV-2 for 29 days. Father and son, as well as another unrelated COVID-19 patient, displayed a robust increase of SERPING1, the transcript encoding C1 esterase inhibitor (C1-INH). We further bolstered this finding by incorporating a serum proteomics dataset and found that serum C1-INH was consistently increased in COVID-19 patients. C1-INH is a central regulator of the contact and complement systems, potentially linking COVID-19 to complement hyperactivation, fibrin clot formation, and immune depression. Furthermore, despite distinct clinical cases, significant parallels were observed in transcripts involved interferon and B cell signaling. As symptoms were resolving, widespread decreases were seen in immune-related transcripts to levels below those of healthy controls. Our study provides insight into the immune responses of likely millions of people with extremely mild symptoms who may not be aware of their infection with SARS-CoV-2 and implies a potential for long-lasting consequences that could contribute to reinfection risk.

Background: Most guidelines recommend both pelvic packing (PP) and angioembolization for hemodynamically unstable pelvic fractures, however their sequence varies. Some argue to use PP first because orthopaedic surgeons are more available than interventional radiologists; however, there is no data confirming this. Methods: This cross-sectional survey of 158 trauma medical directors at US Level I trauma centers collected the availability of orthopaedic surgeons and interventional radiologists, the number of orthopaedic trauma surgeons trained to manage pelvic fractures, and priority treatment sequence for hemodynamically unstable pelvic fractures. The study objective was to compare the availability of orthopaedic surgeons to interventional radiologists and describe how the availability of orthopaedic surgeons and interventional radiologists affects the treatment sequence for hemodynamically unstable pelvic fractures. Fisher’s exact, chi-squared, and Kruskal-Wallis tests were used, alpha = 0.05. Results: The response rate was 25% (40/158). Orthopaedic surgeons (86%) were on-site more often than interventional radiologists (54%), p = 0.003. Orthopaedic surgeons were faster to arrive 39% of the time, and interventional radiologists were faster to arrive 6% of the time. There was a higher proportion of participants who prioritized PP before angioembolization at centers with above the average number (> 3) of orthopaedic trauma surgeons trained to manage pelvic fractures, as among centers with equal to or below average, p = 0.02. Arrival times for orthopaedic surgeons did not significantly predict prioritization of angioembolization or PP. Conclusions: Our results provide evidence that orthopaedic surgeons typically are more available than interventional radiologists but contrary to anecdotal evidence most participants used angioembolization first. Familiarity with the availability of orthopaedic surgeons and interventional radiologists may contribute to individual trauma center’s treatment sequence.

Background: Sepsis accounts for 10% of intensive care unit admissions and significant healthcare costs. Although the mortality rate from sepsis has been decreasing with better critical care, early identification of septic patients, and prompt interventions, the mortality rate remains 20%–30%. Method: Review of the English-language literature. Results: Norepinephrine is the first-line vasopressor in shock and is associated with a lower mortality rate as well as fewer adverse effects. Dopamine has similar actions but is associated with significantly more tachydysrhythmias and should be reserved for patients with bradycardia. Epinephrine and vasopressin are appropriate second-line vasopressors and may enable use of lower doses of norepinephrine while improving hemodynamics. Inotropes may be added in patients with cardiac dysfunction. Conclusion: Appropriate treatment of sepsis includes prompt identification, early antimicrobial drug therapy, appropriate fluid resuscitation, and initiation of vasopressors in the presence of continued septic shock. Further research needs to be done to better understand the ideal timing of the addition of a second agent and the optimal combinations of vasopressors for individual patients.