Trauma is the leading cause of death and disability in patients aged 1-46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive ...transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood.
We developed a murine model of trauma hemorrhage (TH) followed by resuscitation with plasma and leukoreduced RBCs (in a 1:1 ratio) that were banked for 0 (fresh) or 14 (stored) days. Two days later, lungs were infected with Pseudomonas aeruginosa K-strain (PAK). Resuscitation with stored RBCs significantly increased the severity of lung injury caused by P. aeruginosa, as demonstrated by higher mortality (median survival 35 h for fresh RBC group and 8 h for stored RBC group; p < 0.001), increased pulmonary edema (mean 95% CI 106.4 μl 88.5-124.3 for fresh RBCs and 192.5 μl 140.9-244.0 for stored RBCs; p = 0.003), and higher bacterial numbers in the lung (mean 95% CI 1.2 × 10(7) -1.0 × 10(7) to 2.5 × 10(7) for fresh RBCs and 3.6 × 10(7) 2.5 × 10(7) to 4.7 × 10(7) for stored RBCs; p = 0.014). The mechanism underlying this increased infection susceptibility and severity was free-heme-dependent, as recombinant hemopexin or pharmacological inhibition or genetic deletion of toll-like receptor 4 (TLR4) during TH and resuscitation completely prevented P. aeruginosa-induced mortality after stored RBC transfusion (p < 0.001 for all groups relative to stored RBC group). Evidence from studies transfusing fresh and stored RBCs mixed with stored and fresh RBC supernatants, respectively, indicated that heme arising both during storage and from RBC hemolysis post-resuscitation plays a role in increased mortality after PAK (p < 0.001). Heme also increased endothelial permeability and inhibited macrophage-dependent phagocytosis in cultured cells. Stored RBCs also increased circulating high mobility group box 1 (HMGB1; mean 95% CI 15.4 ng/ml 6.7-24.0 for fresh RBCs and 50.3 ng/ml 12.3-88.2 for stored RBCs), and anti-HMGB1 blocking antibody protected against PAK-induced mortality in vivo (p = 0.001) and restored macrophage-dependent phagocytosis of P. aeruginosa in vitro. Finally, we showed that TH patients, admitted to the University of Alabama at Birmingham ER between 1 January 2015 and 30 April 2016 (n = 50), received high micromolar-millimolar levels of heme proportional to the number of units transfused, sufficient to overwhelm endogenous hemopexin levels early after TH and resuscitation. Limitations of the study include lack of assessment of temporal changes in different products of hemolysis after resuscitation and the small sample size precluding testing of associations between heme levels and adverse outcomes in resuscitated TH patients.
We provide evidence that large volume resuscitation with stored blood, compared to fresh blood, in mice increases mortality from subsequent pneumonia, which occurs via mechanisms sensitive to hemopexin and TLR4 and HMGB1 inhibition.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Multisystem inflammatory syndrome in adults (MIS-A) was reported in association with the coronavirus disease 2019 (COVID-19) pandemic. MIS-A was included in the list of adverse ...events to be monitored as part of the emergency use authorizations issued for COVID-19 vaccines.
Methods
Reports of MIS-A patients received by the Centers for Disease Control and Prevention (CDC) after COVID-19 vaccines became available were assessed. Data collected on the patients included clinical and demographic characteristics and their vaccine status. The Vaccine Adverse Events Reporting System (VAERS) was also reviewed for possible cases of MIS-A.
Results
From 14 December 2020 to 30 April 2021, 20 patients who met the case definition for MIS-A were reported to CDC. Their median age was 35 years (range, 21–66 years), and 13 (65%) were male. Overall, 16 (80%) patients had a preceding COVID-19-like illness a median of 26 days (range 11–78 days) before MIS-A onset. All 20 patients had laboratory evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Seven MIS-A patients (35%) received COVID-19 vaccine a median of 10 days (range, 6–45 days) before MIS-A onset; 3 patients received a second dose of COVID-19 vaccine 4, 17, and 22 days before MIS-A onset. Patients with MIS-A predominantly had gastrointestinal and cardiac manifestations and hypotension or shock.
Conclusions
Although 7 patients were reported to have received COVID-19 vaccine, all had evidence of prior SARS-CoV-2 infection. Given the widespread use of COVID-19 vaccines, the lack of reporting of MIS-A associated with vaccination alone, without evidence of underlying SARS-CoV-2 infection, is reassuring.
Seven of 20 MIS-A patients received COVID-19 vaccination before illness onset. All patients had evidence of prior SARS-CoV-2 infection. Given widespread COVID-19 vaccinations in the United States, the lack of reporting of MIS-A associated with vaccination alone is reassuring.
Bacterial pneumonia and sepsis are both common causes of end-organ dysfunction, especially in immunocompromised and critically ill patients. Pre-clinical data demonstrate that bacterial pneumonia and ...sepsis elicit the production of cytotoxic tau and amyloids from pulmonary endothelial cells, which cause lung and brain injury in naïve animal subjects, independent of the primary infection. The contribution of infection-elicited cytotoxic tau and amyloids to end-organ dysfunction has not been examined in the clinical setting. We hypothesized that cytotoxic tau and amyloids are present in the bronchoalveolar lavage fluid of critically ill patients with bacterial pneumonia and that these tau/amyloids are associated with end-organ dysfunction.
Bacterial culture-positive and culture-negative mechanically ventilated patients were recruited into a prospective, exploratory observational study. Levels of tau and Aβ42 in, and cytotoxicity of, the bronchoalveolar lavage fluid were measured. Cytotoxic tau and amyloid concentrations were examined in comparison with patient clinical characteristics, including measures of end-organ dysfunction.
Tau and Aβ42 were increased in culture-positive patients (n = 49) compared to culture-negative patients (n = 50), independent of the causative bacterial organism. The mean age of patients was 52.1 ± 16.72 years old in the culture-positive group and 52.78 ± 18.18 years old in the culture-negative group. Males comprised 65.3% of the culture-positive group and 56% of the culture-negative group. Caucasian culture-positive patients had increased tau, boiled tau, and Aβ42 compared to both Caucasian and minority culture-negative patients. The increase in cytotoxins was most evident in males of all ages, and their presence was associated with end-organ dysfunction.
Bacterial infection promotes the generation of cytotoxic tau and Aβ42 within the lung, and these cytotoxins contribute to end-organ dysfunction among critically ill patients. This work illuminates an unappreciated mechanism of injury in critical illness.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Traumatic brain injury (TBI) is the leading cause of injury-related death and disability in patients under the age of 46 years. Survivors of the initial injury often endure systemic complications ...such as pulmonary infection, and
is one of the most common causes of nosocomial pneumonia in intensive care units. Female patients are less likely to develop secondary pneumonia after TBI, and pre-clinical studies have revealed a salutary role for estrogen after trauma. Therefore, we hypothesized that female mice would experience less mortality after post-TBI pneumonia with
. We employed a mouse model of TBI followed by
pneumonia. Male mice had greater mortality and impaired lung bacterial clearance after post-TBI pneumonia compared with female mice. This was confirmed as a difference in sex hormones, as oophorectomized wild-type mice had mortality and lung bacterial clearance similar to male mice. There were differences in tumor necrosis factor-α secretion in male and female alveolar macrophages after
infection. Finally, injection of male or oophorectomized wild-type female mice with estrogen restored lung bacterial clearance and prevented mortality. Our model of TBI followed by
pneumonia is among the first to reveal sex dimorphism in secondary, long-term TBI complications.
Slope was significantly non-zero for number of units (r2 = 0.91, p<0.001). https://doi.org/10.1371/journal.pmed.1002991.g001 In the Results, in the subsection “Heme levels in patients after TH and ...resuscitation”, there is an error in the fifth sentence of the first paragraph. While the absolute concentration of these mediators is important, the relative concentrations of hemoglobin and free heme, compared to Hp and Hpx respectively is likely of greater clinical significance; Hp and Hpx are the endogenous primary defense mechanisms protecting against hemolysis-dependent injury. (2018) Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study.
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Acute respiratory distress syndrome (ARDS) is a life‐threatening illness characterized by decreased alveolar‐capillary barrier function, pulmonary edema consisting of proteinaceous fluid, and ...inhibition of net alveolar fluid transport responsible for resolution of pulmonary edema. There is currently no pharmacotherapy that has proven useful to prevent or treat ARDS, and two trials using beta‐agonist therapy to treat ARDS demonstrated no effect. Prior studies indicated that IL‐8‐induced heterologous desensitization of the beta2‐adrenergic receptor (β2‐AR) led to decreased beta‐agonist‐induced mobilization of cyclic adenosine monophosphate (cAMP). Interestingly, phosphodiesterase (PDE) 4 inhibitors have been used in human airway diseases characterized by low intracellular cAMP levels and increases in specific cAMP hydrolyzing activity. Therefore, we hypothesized that PDE4 would mediate IL‐8‐induced heterologous internalization of the β2‐AR and that PDE4 inhibition would restore beta‐agonist‐induced functions. We determined that CINC‐1 (a functional IL‐8 analog in rats) induces internalization of β2‐AR from the cell surface, and arrestin‐2, PDE4, and β2‐AR form a complex during this process. Furthermore, we determined that cAMP associated with the plasma membrane was adversely affected by β2‐AR heterologous desensitization. Additionally, we determined that rolipram, a PDE4 inhibitor, reversed CINC‐1‐induced derangements of cAMP and also caused β2‐AR to successfully recycle back to the cell surface. Finally, we demonstrated that rolipram could reverse CINC‐1‐mediated inhibition of beta‐agonist‐induced alveolar fluid clearance in a murine model of trauma‐shock. These results indicate that PDE4 plays a role in CINC‐1‐induced heterologous internalization of the β2‐AR; PDE4 inhibition reverses these effects and may be a useful adjunct in particular ARDS patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives
Gender disparity exists in medicine, such as differences in pay and promotion opportunities. We hypothesize that there is also a gender difference in graduate medical education as ...manifested by operative case volume. This study compares surgical case volume by gender for graduating US otolaryngology residents.
Study Design
Cohort study.
Methods
With data use approval from the Accreditation Council for Graduate Medical Education, we evaluated the key indicator case log summaries of graduating otolaryngology residents from 2009–2017. Mean and standard deviation were used for all cases, and t‐tests were used to compare cases by resident gender. The Bonferroni method was used to adjust for multiple comparisons across years.
Results
Data from 1740 male and 804 female residents were evaluated. Across all years, the average number of key indicator cases reported was 778.8 and 813.6 by female and male residents, respectively, with an average difference of 34.8 cases per graduating year (95% confidence interval CI 19.4, 50.2; P < .001). When a resident self‐reported the role of resident surgeon/supervisor, the average number of key indicator cases reported was 602.6 and 643.9 by female and male residents, respectively, with an average difference of 41.3 cases per graduating year (95% CI, 28.0, 54.6; P < .001).
Conclusion
Gender‐based discrepancies in surgical case volume exist among graduating otolaryngology residents. This disparity is partially attributed to the self‐reported role in the surgery. This study has identified those discrepancies so that training programs can implement strategies to ensure improved gender parity.
Level of Evidence
2b Laryngoscope, 130:1651–1656, 2020
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Pulmonary edema associated with increased vascular permeability is a severe complication of Pseudomonas (P.) aeruginosa‐induced acute lung injury. The mechanisms underlying P aeruginosa‐induced ...vascular permeability are not well understood. In the present study, we investigated the role of neuronal Wiskott Aldrich syndrome protein (N‐WASP) in modulating P aeruginosa‐induced vascular permeability. Using lung microvascular endothelial and alveolar epithelial cells, we demonstrated that N‐WASP downregulation attenuated P aeruginosa‐induced actin stress fiber formation and prevented paracellular permeability. P aeruginosa‐induced dissociation between VE‐cadherin and β‐catenin, but increased association between N‐WASP and VE‐cadherin, suggesting a role for N‐WASP in promoting P aeruginosa‐induced adherens junction rupture. P aeruginosa increased N‐WASP‐Y256 phosphorylation, which required the activation of Rho GTPase and focal adhesion kinase. Increased N‐WASP‐Y256 phosphorylation promotes N‐WASP and integrin αVβ6 association as well as TGF‐β‐mediated permeability across alveolar epithelial cells. Inhibition of N‐WASP‐Y256 phosphorylation by N‐WASP‐Y256F overexpression blocked N‐WASP effects in P aeruginosa‐induced actin stress fiber formation and increased paracellular permeability. In vivo, N‐WASP knockdown attenuated the development of pulmonary edema and improved survival in a mouse model of P aeruginosa pneumonia. Together, our data demonstrate that N‐WASP plays an essential role in P aeruginosa‐induced vascular permeability and pulmonary edema through the modulation of actin cytoskeleton dynamics.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Study Design:
Prospective cohort.
Objectives:
Patient-Reported Outcome Measurement Information System (PROMIS) has been validated for lumbar spine. Use of patient-reported outcome (PRO) measures can ...improve clinical decision making and health literacy at the point of care. Use of PROMIS, however, has been limited in part because clinicians and patients lack plain language understanding of the meaning of scores and it remains unclear how best to use them at the point of care. The purpose was to develop plain language descriptions to apply to PROMIS Physical Function (PF) and Pain Interference (PI) scores and to assess patient understanding and preferences in presentation of their individualized PRO information.
Methods:
Retrospective analysis of prospectively collected PROMIS PF v1.2 and PI v1.1 for patients presenting to a tertiary spine center for back/lower extremity complaints was performed. Patients with missing scores, standard error >0.32, and assessments with <4 or >12 questions were excluded. Scores were categorized into score groups, specifically PROMIS PF groups were: <18, 20 ± 2, 25 ± 2, 30 ± 2, 35 ± 2, 40 ± 2, 45 ± 2, 50 ± 2, 55 ± 2, 60 ± 2, and >62; and PROMIS PI groups were: <48, 50 ± 2, 55 ± 2, 60 ± 2, 65 ± 2, 70 ± 2, 75 ± 2, 80 ± 2, and >82. Representative questions and answers from the PROMIS PI and PROMIS PF were selected for each score group, where questions with <25 assessments or representing <15% of assessments were excluded. Two fellowship-trained spine surgeons further trimmed the questions to create a streamlined clinical tool using a consensus process. Plain language descriptions for PROMIS PF were then used in a prospective assessment of 100 consecutive patients. Patient preference for consuming the score data was recorded and analyzed.
Results:
In total, 12 712 assessments/5524 unique patients were included for PF and 14 823 assessments/6582 unique patients for PI. More than 90% of assessments were completed in 4 questions. The number of assessments and patients per scoring group were normally distributed. The mean PF score was 37.2 ± 8.2 and the mean PI was 63.3 ± 7.4. Plain language descriptions and compact clinical tool was were generated. Prospectively 100 consecutive patients were surveyed for their preference in receiving their T-score versus plain language description versus graphical presentation. A total of 78% of patients found receiving personalized PRO data helpful, while only 1% found this specifically not helpful. Overall, 80% of patients found either graphical or plain language more helpful than T-score alone, and half of these preferred plain language and graphical descriptions together. In total, 89% of patients found the plain language descriptions to be accurate.
Conclusions:
Patients at the point of care are interested in receiving the results of their PRO measures. Plain language descriptions of PROMIS scores enhance patient understanding of PROMIS numerical scores. Patients preferred plain language and/or graphical representation rather than a numerical score alone. While PROs are commonly used for assessing outcomes in research, use at point of care is a growing interest and this study clarifies how they might be utilized in physician-patient communication.
Background
Understanding the variation in costs of endoscopic sinus surgery (ESS) is critical to defining value. Current published costs of ESS have not identified potential sources of variation. Our ...objective was to analyze ESS costs to identify sources of variance that could guide value‐improving decisions.
Methods
ESS cases (n = 1739) performed between 2008 and 2016 were identified from a database of 22 rural to tertiary facilities. Cost and time data were extracted from the database. Medical records were reviewed to confirm procedures. Three bilateral groupings were examined (n = 895 cases from 13 facilities): (1) full ESS (all sinuses); (2) intermediate ESS (total ethmoid, maxillary); and (3) anterior ESS (anterior ethmoid, maxillary). Cost and operative time were analyzed using multivariable gamma regression.
Results
Median costs for full, intermediate, and anterior ESS were $4281, $3716, and $2549 U.S. dollars (p < 0.001). Median durations were 87, 60, and 58 minutes (p < 0.001). Among patients with no additional procedures, those with full ESS had operative duration, total cost, and supply costs that were 1.37 (95% confidence interval CI, 1.17 to 1.61), 1.52 (95% CI, 1.32 to 1.75), and 2.40 (95% CI, 1.76 to 3.25) times greater than anterior ESS, respectively (all p < 0.001). Intermediate ESS duration at community urban facilities was 1.87 (95% CI, 1.74 to 2.02) times that of community rural facilities (p < 0.001).
Conclusion
Duration of surgery, extent of surgery, and location of surgery are sources of significant variation in the cost of ESS. These findings will assist healthcare policy makers, hospitals, and surgeons in optimizing the value of ESS.
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