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1.
J Immunol ; 210(12): 1990-2000, 2023 06 15.
Article in English | MEDLINE | ID: mdl-37133342

ABSTRACT

Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma-bone fracture, muscle crush injury, and bowel ischemia-induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential expression of numerous miRNAs after severe trauma. Plasma exRNA isolated from trauma mice induced a dose-dependent cytokine production in macrophages, which was almost abolished in TLR7-deficient cells but unchanged in TLR3-deficient cells. Moreover, RNase or specific miRNA inhibitors against the selected proinflammatory miRNAs (i.e., miR-7a-5p, miR-142, let-7j, miR-802, and miR-146a-5p) abolished or attenuated trauma plasma exRNA-induced cytokine production, respectively. Bioinformatic analyses of a group of miRNAs based on cytokine readouts revealed that high uridine abundance (>40%) is a reliable predictor in miRNA mimic-induced cytokine and complement production. Finally, compared with the wild-type, TLR7-knockout mice had attenuated plasma cytokine storm and reduced lung and hepatic injury after polytrauma. These data suggest that endogenous plasma exRNA of severely injured mice and ex-miRNAs with high uridine abundance prove to be highly proinflammatory. TLR7 sensing of plasma exRNA and ex-miRNAs activates innate immune responses and plays a role in inflammation and organ injury after trauma.


Subject(s)
MicroRNAs , Multiple Trauma , Humans , Mice , Animals , Toll-Like Receptor 7/metabolism , Disease Models, Animal , MicroRNAs/genetics , Inflammation/genetics , Cytokines/metabolism
2.
J Burn Care Res ; 43(4): 792-801, 2022 07 01.
Article in English | MEDLINE | ID: mdl-34739051

ABSTRACT

The World Health Organization estimates ~180,000 deaths occur annually from burn-related injuries. Many victims who survive the initial burn trauma succumb to bacterial infections that lead to sepsis during treatment. Although advancements in burn care continue to improve in high-income countries due to their burn centers and advanced research, low and middle-income countries continue to see high frequencies of burn injuries and burn-related deaths due to secondary infections. Bacterial-derived sepsis is the most life-threatening danger for people that survive burn injuries. Here we provide evidence for the first time that a subeschar seroma forms postburn even in the absence of infection in mice. The seroma fills with a volume estimated at 500 µL of fluid, 25% of the blood supply, free of red blood cells. The seroma fluid supports robust Pseudomonas aeruginosa (PA) growth and contains inflammatory cytokines and chemokines, which recruit immature neutrophils and monocytes to the seroma in the absence of endothelial breakdown. These immune cells fail to contain PA expansion and dissemination. This recruitment of monocytes and immature neutrophils may result in sequestering these critical immune cells away from other tissues during a pivotal time during bacterial dissemination, promoting PA-mediated sepsis.


Subject(s)
Burns , Pseudomonas Infections , Sepsis , Soft Tissue Injuries , Animals , Disease Models, Animal , Humans , Mice , Pseudomonas aeruginosa , Sepsis/microbiology , Seroma
3.
Infect Immun ; 89(10): e0009121, 2021 09 16.
Article in English | MEDLINE | ID: mdl-34152806

ABSTRACT

Of the 486,000 burn injuries that required medical treatment in the United States in 2016, 40,000 people were hospitalized, with >3,000 fatalities. After burn injury, humans are at increased risk of sepsis and mortality from infections caused by Pseudomonas aeruginosa, an opportunistic pathogen. We hypothesize that systemic events were initiated from the burn that increased the host's susceptibility to P. aeruginosa. A nonlethal 10% total body surface area (TBSA), full-thickness flame burn was performed in CD-1 mice without and with subsequent P. aeruginosa (strain M2) infection. The 50% lethal dose for subcutaneous infection with P. aeruginosa M2 at the burn site immediately after the burn decreased by 6 log, with mortality occurring between 18 and 26 h, compared with P. aeruginosa-infected mice without burn injury. Bacteria in distal organs were detected by 18 h, concurrent with the onset of clinical symptoms. Serum proinflammatory cytokines (interleukin-6 [IL-6], IL-1ß, gamma interferon, and tumor necrosis factor alpha) and the anti-inflammatory cytokine IL-10 were first detected at 12 h postburn with infection and continued to increase until death. Directly after burn alone, serum levels of HMGB1, a danger-associated molecular pattern and TLR4 agonist, transiently increased to 50 ng/ml before returning to 20 ng/ml. Burn with P. aeruginosa infection increased serum HMGB1 concentrations >10-fold (250 ng/ml) at the time of death. This HMGB1-rich serum stimulated TLR4-mediated NF-κB activation in a TLR4 reporter cell line. Treatment of infected burned mice with P5779, a peptide inhibitor of HMGB1, increased the mean survival from 23 to 42 h (P < 0.0001). We conclude that the high level of serum HMGB1, which preceded the increase in proinflammatory cytokines, is associated with postburn mortality.


Subject(s)
Burns/immunology , Burns/microbiology , Pseudomonas Infections/immunology , Pseudomonas aeruginosa/immunology , Animals , Disease Models, Animal , Female , HMGB1 Protein/immunology , Inflammation/immunology , Inflammation/microbiology , Interferon-gamma/immunology , Interleukin-10/immunology , Interleukin-6/immunology , Mice , NF-kappa B/immunology , Sepsis/immunology , Sepsis/microbiology , Signal Transduction/immunology , Toll-Like Receptor 4/immunology , Tumor Necrosis Factor-alpha/immunology
4.
Shock ; 56(4): 601-610, 2021 10 01.
Article in English | MEDLINE | ID: mdl-33394971

ABSTRACT

BACKGROUND: Aeromedical evacuation can expose traumatically injured patients to low pressure (hypobaria) and hypoxia. Here, we sought to assess the impact of hypobaria on inflammation, organ injury, and mortality in a mouse model of polytrauma. METHODS: Eight to 12-week-old male C57BL/6J mice were subjected to sham or polytrauma consisting of bowel ischemia by superior mesenteric artery occlusion, hindlimb muscle crush, and tibia fracture. Two hours after injury, animals were randomized to undergo either 6 h of hypobaria or sea-level, room air conditions. At 8 or 24 h after injury, transthoracic echocardiography was performed. Acute kidney injury (AKI) biomarkers were measured by qRT-PCR. Plasma cytokine and endothelial injury markers were determined by enzyme-linked immunosorbent assay. RESULTS: Eight hours after traumatic injury, mice exhibited a marked increase in plasma IL-6 (57 pg/mL vs. 1,216 pg/mL), AKI with increased Ngal and Kim-1, and endothelial injury as evidenced by significantly increased plasma hyaluronic acid (96 ng/mL vs.199 ng/mL), thrombomodulin (23.2 ng/mL vs. 58.9 ng/mL), syndecan-1 (0.99 ng/mL vs. 4.34 ng/mL), and E-selectin (38.6 ng/mL vs. 62.7 ng/mL). The trauma mice also developed cardiac dysfunction with decreased cardiac output and stroke volume at 8 h postinjury. Hypobaric exposure after polytrauma led to decreased ejection fraction (81.0% vs. 74.2%, P < 0.01) and increased plasma hyaluronic acid (199 ng/mL vs. 260 ng/mL, P < 0.05), thrombomodulin (58.9 ng/mL vs. 75.4 ng/mL, P < 0.05), and syndecan-1 (4.34 ng/mL vs. 8.33 ng/mL, P < 0.001) at 8 h postinjury. CONCLUSIONS: Hypobaria exposure appeared to worsen cardiac dysfunction and endothelial injury following polytrauma and thus may represent a physiological "second hit" following traumatic injury.


Subject(s)
Acute Kidney Injury/etiology , Air Ambulances , Air Pressure , Endothelium, Vascular/injuries , Multiple Trauma/complications , Animals , Disease Models, Animal , Male , Mice , Mice, Inbred C57BL , Multiple Trauma/therapy
5.
Open Forum Infect Dis ; 6(11): ofz409, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31687419

ABSTRACT

OBJECTIVE: Clostridioides difficile infection (CDI) frequently causes colitis following antibiotic exposure and is a leading cause of gastrointestinal infectious mortality. Infection in the small bowel, C. difficile enteritis (CDE), was previously thought impossible, but case series have challenged this dogma. Clostridioides difficile enteritis prevalence, severity, and potential risk factors are unknown. METHODS: We retrospectively analyzed all total colectomy patients over a 20-year period at our institution. C. difficile enteritis was defined by clinical symptoms and positive C. difficile stool testing after colectomy. We compared CDE cases to controls using multivariable analysis to identify potential CDE risk factors. RESULTS: C. difficile enteritis occurred in 44 of 855 (5.1%) patients, a median of 130 days after colectomy. Compared to controls, CDE patients were similar in age, gender, and presence of immunosuppression. The majority (64%) had antibiotics <30 days prior to CDE. In multivariable analysis, CDE risk factors included perioperative acid suppression (hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.26-5.04; P = .009), colectomy for inflammatory bowel disease (HR, 2.95; CI, 1.29-6.72; P = .010), colectomy for CDI (HR, 9.95; CI, 2.70-36.63; P ≤ .001), and ß-lactam use in the setting of enteral feeds (HR, 17.83; CI, 2.75-115.68; P = .003). C. difficile enteritis presented with severe disease half of the time, with 81.8% requiring hospitalization. CONCLUSIONS: C. difficile enteritis is a rare clinical entity that should be considered in postcolectomy patients presenting with CDI symptoms, even years after surgery. Like traditional CDI, likely CDE risk factors include acid suppression and inflammatory bowel disease. Prior antibiotic use in the setting of enteral feeds may amplify CDE risk. C. difficile enteritis often presents as severe disease and frequently requires hospitalization.

6.
Cancer Causes Control ; 29(12): 1231-1237, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30515652

ABSTRACT

Achieving health equity requires addressing social determinants of health. Promoting health equity as it relates to cancer control is one of six priorities of the National Comprehensive Cancer Control Program (NCCCP). This article describes recent activities implemented by three NCCCP awardees (North-west Portland Area Indian Health Board, Kansas, Michigan) and the CDC-funded National Behavior Health Network (NBHN), whose aim is to reduce health disparities among those with mental health and/or substance disorders. North-west Portland administered tribal surveys to help better understand tribal cancer-related risk factors, health behaviors, provide baseline data to support their cancer plan, and obtain resources for targeted interventions. Kansas established a health equity workgroup with a vision of addressing health equity through implementation and uptake of activities among all Kansans. Michigan provided trainings in health equity and social justice and developed health equity learning labs. As a result of the successful implementation of the NBHN's Community of Practice, individuals currently living with mental illness and/or substance disorders have had increased access to tobacco cessation and other cancer support services. These efforts and key opportunities for public health practitioners and their partners to increase engagement in cancer health equity are summarized in this article.


Subject(s)
Health Equity , Neoplasms/prevention & control , Public Health , Delivery of Health Care , Humans , Kansas , Michigan
8.
South Med J ; 109(7): 395-400, 2016 07.
Article in English | MEDLINE | ID: mdl-27364020

ABSTRACT

OBJECTIVES: Patient safety event (PSE) reporting is a critical element for healthcare organizations that are striving for continuous quality improvement. Although resident physicians routinely provide the majority of direct patient care, the level of their participation in PSE reporting historically has been low. In addition, as part of the Accreditation Council for Graduate Medical Education's Next Accreditation System, the Clinical Learning Environment Review site visit assesses residents' engagement in PSE reporting at each accredited academic institution. The objective of this study was to understand the common barriers to PSE reporting and design an intervention to increase the number of PSE reports by resident physicians. METHODS: We surveyed 304 residents and fellows to assess attitudes toward the PSE reporting system and identify barriers to submitting online PSE reports. Based on this analysis of barriers, we piloted interventions with the internal medicine residency program and measured their effect on resident PSE reporting. RESULTS: Of the survey respondents, 58% had never submitted a PSE report. The most commonly identified barriers were too much time required to submit a report (38% of all respondents), lack of education on how or what to report (37%), lack of feedback or change after reporting (19%), and concern for repercussions or lack of anonymity (13%). Based on this analysis of barriers, we piloted interventions with the internal medicine residency program to educate residents about PSE reporting through a reminder message in their orientation e-mail, informational slides at the end of conferences that described what and how to report, a pocket card with reporting instructions, and leadership encouragement during walk rounds by chief medical residents and the program director. Compared with the 10 weeks before the start of the intervention, the number of PSE reports submitted by internal medicine residents more than doubled, from 16 to 37 reports (P < 0.01). This increase in resident PSE reporting was sustained for 20 weeks despite the interventions lasting only 8 weeks. CONCLUSIONS: A resident-driven intervention that fostered a culture of encouragement for PSE reporting through leadership support and targeted education increased the number of PSE reports submitted by internal medicine residents at our health system. Hospitals and health systems should seek to understand the common barriers to PSE reporting from this important group of direct patient care providers and administer structured educational programs to encourage their participation.


Subject(s)
Internal Medicine/education , Internship and Residency , Patient Safety/statistics & numerical data , Risk Management , Attitude of Health Personnel , Communication Barriers , Education/methods , Humans , Internship and Residency/methods , Internship and Residency/standards , Michigan , Program Evaluation , Quality Improvement , Risk Management/methods , Risk Management/standards , Surveys and Questionnaires
9.
Support Care Cancer ; 24(6): 2437-44, 2016 06.
Article in English | MEDLINE | ID: mdl-26638004

ABSTRACT

PURPOSE: To better understand satisfaction with care among American Indian and Alaska Native (AI/AN) persons with cancer, we explored dimensions of the provider relationship that contributed to satisfaction among caregivers and survivors who received cancer treatment in Oregon and Washington State. METHODS: Between November 2011 and April 2013, the project team interviewed 11 caregivers and 71 AI/AN cancer survivors residing in Oregon and Washington State. Interview questions aimed to elicit participant experiences with care providers and factors associated with cancer care satisfaction. Interviews were analyzed using an inductive content analysis approach in which concepts were identified and themes derived from interview data. RESULTS: Three overarching themes, each with two sub-themes, emerged from the data: (1) universal factors: bolstering understanding, involvement, and empathy in care; (2) minority-specific factors: incorporating culture and community into care; and (3) AI/AN-unique factors: interacting with Indian health clinics and Indian Health Service (IHS). CONCLUSIONS: The results of our study suggest that satisfaction with care among survivors and their caregivers must be examined within the context of culture and community, particularly among minority patients. Our study demonstrates providers' critical role in ensuring AI/AN patients emerge satisfied with cancer treatment by honoring their AI/AN-specific needs, such as respect for integration of traditional healing modalities and navigation of specialty care coordination.


Subject(s)
/psychology , Caregivers/standards , Indians, North American/psychology , Neoplasms/ethnology , Patient Satisfaction/ethnology , Alaska , Empathy , Female , Humans , Neoplasms/psychology , Neoplasms/therapy , Oregon , Qualitative Research , Survivors , United States , Washington
10.
J Cancer Educ ; 27(1 Suppl): S73-9, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22281722

ABSTRACT

In the Pacific Northwest, cancer is a leading cause of morbidity and mortality for American Indians and Alaska Natives (AI/AN). Misclassification of AI/AN race in state cancer registries causes cancer burden to be underestimated. Furthermore, local-level data are rarely available to individual tribes for use in health assessment and program planning. We corrected race coding in the cancer registries of Idaho, Oregon, and Washington using probabilistic record linkage to a file derived from patient registration records from Indian Health Service and a large urban clinic. We calculated cancer incidence and mortality measures by state, comparing AI/AN to non-Hispanic White (NHW) race. Record linkages identified a high prevalence of misclassified race. Differences in AI/AN cancer patterns were identified across the three state region. Compared to NHW, AI/AN experienced disproportionate late stage rates of some screen-detectable cancers. The correct classification of race is a crucial factor in cancer surveillance and can reveal regional differences even within a relatively small area. The availability of local-level cancer data can help inform tribes in appropriate intervention efforts.


Subject(s)
Data Collection , Indians, North American/statistics & numerical data , Inuit/statistics & numerical data , Minority Health/statistics & numerical data , Neoplasms/epidemiology , Registries/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Confidence Intervals , Early Detection of Cancer , Female , Geography , Humans , Idaho/epidemiology , Male , Middle Aged , Neoplasms/ethnology , Northwestern United States/epidemiology , Oregon/epidemiology , Risk , United States/epidemiology , United States Indian Health Service , Washington/epidemiology , Young Adult
11.
J Cancer Educ ; 25(3): 329-36, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20146041

ABSTRACT

This community-based intervention study examines the impact of Cancer 101, a cancer education resource developed in collaboration with American Indians/Alaska Natives to improve cancer knowledge, action regarding cancer control in tribal settings, and survival rates for members of their communities. Pre/post-surveys used to assess knowledge, attitudes, perceived benefits and future activities at baseline, immediately post-training, and at 4-6 months. Participants demonstrated significant change in knowledge, attitude, and cancer control activities. Cancer 101 provides a critical pathway to increase knowledge and promote action to reduce the burden and improve survival of cancer within tribal communities.


Subject(s)
Community Health Services , Health Education , Health Knowledge, Attitudes, Practice , Indians, North American/education , Inuit/education , Neoplasms/prevention & control , Adolescent , Adult , Female , Health Surveys , Humans , Indians, North American/statistics & numerical data , Inuit/statistics & numerical data , Longitudinal Studies , Male , Middle Aged , Neoplasms/mortality , Survival Rate , Young Adult
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