Association of sex and aspirin use with postoperative bleeding in patients with lower extremity long bone fractures.

Objective: The perioperative management of patients on antiplatelet drugs is a rising challenge in orthopedic trauma because antiplatelet drugs are frequently encountered and carry an increased risk of hemorrhagic consequences. The study objective was to examine the effect of aspirin on bleeding outcomes for patients with lower extremity fractures. Methods: This retrospective study included patients requiring surgical fixation of traumatic hip, femur, and tibia fractures from January 1, 2018, to March 1, 2020. Patients were excluded if they had a significant head injury, were on chronic anticoagulant therapy, or they did not receive venous thromboembolism chemoprophylaxis. Comparisons between aspirin users (patients on aspirin therapy preinjury) and non-aspirin users were examined using χ2 tests, Cochran-Mantel-Haenszel tests, and multivariate logistic regression. The primary outcome was an overt, actionable bleed (eg, blood transfusion for surgical site hemorrhage) within 24 hours postoperative. Results: There were 864 patients with lower extremity long bone fractures and 24% were aspirin users. The incidence of postoperative bleeding was 8.8% and significantly differed for patients taking aspirin versus not (13.6% vs 7.3%, p=0.01). However, biological sex at birth (M/F) was a significant effect modifier (interaction p=0.04). Among women, there were significantly more postoperative bleeds for aspirin users (17.8% aspirin vs 7.4% no aspirin, adjusted OR (AOR): 2.48 (1.28-4.81), p=0.01). Among men, there were similar postoperative bleeding events by aspirin use (5.6% aspirin vs 7.2% no aspirin, AOR: 0.50 (0.14-1.82), p=0.30). Postoperative hemoglobin values <8 g/dL were more frequent among female aspirin users (21.5% aspirin vs 12.5% no aspirin, p=0.01), but this association was not observed in men (p=0.43). Conclusion: Women taking aspirin who suffer lower extremity fractures have greater than twofold greater odds of a postoperative bleeding event. These findings suggest adequate perioperative planning to ensure blood availability, and increased awareness to monitor closely for hemorrhage in the 24-hour postoperative window for women taking aspirin preinjury. Level of evidence: IV.

Epidemiology of C2 fractures and determinants of surgical management: analysis of a national registry.

Objective: Operative management of axis fractures (C2) usually depend on the stability and location of the break and individual patient characteristics. We sought to describe the epidemiology of C2 fractures and hypothesized that determinants for surgery would differ by fracture diagnosis. Methods: Patients with C2 fractures were identified from the US National Trauma Data Bank from January 1, 2017, to January 1, 2020. Patients were classified by C2 fracture diagnosis: odontoid type II, odontoid types I and III, and non-odontoid fracture (hangman's fracture or fractures through base of the axis). The primary comparison was C2 fracture surgery versus non-operative management. Multivariate logistic regression was used to identify independent associations with surgery. Decision tree-based models were developed to identify determinants for surgery. Results: There were 38 080 patients; 42.7% had an odontoid type II fracture; 16.5% had an odontoid type I/III fracture; and 40.8% had a non-odontoid fracture. All examined patient demographics, clinical characteristics, outcomes, and interventions differed by C2 fracture diagnosis. Overall, 5292 (13.9%) were surgically managed (17.5% odontoid type II, 11.0% odontoid type I/III, and 11.2% non-odontoid; p<0.001). The following covariates increased odds of surgery for all three fracture diagnoses: younger age, treatment at a level I trauma center, fracture displacement, cervical ligament sprain, and cervical subluxation. Determinants of surgery differed by fracture diagnosis: for odontoid type II, age ≤80 years, a displaced fracture, and cervical ligament sprain were determinants; for odontoid type I/III, age ≤85 years, a displaced fracture, and cervical subluxation were determinants; for non-odontoid fractures, cervical subluxation and cervical ligament sprain were the strongest determinants for surgery, by hierarchy. Conclusions: This is the largest published study of C2 fractures and current surgical management in the USA. Odontoid fractures, regardless of type, had age and fracture displacement as the strongest determinants for surgical management, whereas associated injuries were determinants of surgery for non-odontoid fractures. Level of evidence: III.

Factors associated with delays in medical and surgical open facial fracture management.

Objectives: Open fractures are at risk of infection because of exposure of bone and tissue to the environment. Facial fractures are often accompanied by other severe injuries, and therefore fracture management may be delayed until after stabilization. Previous studies in this area have examined timing of multiple facets of care but have tended to report on each in isolation (eg, antibiotic initiation). Methods: This was a retrospective study of adult patients admitted to five trauma centers from January 1, 2017 to March 31, 2021 with open facial fractures. Variables collected included demographics, injury mechanism, details on facial and non-facial injuries, facial fracture management (irrigation and debridement (I&D), irrigation without debridement, open reduction internal fixation (ORIF), antibiotics), and other hospital events. The study hypothesized that the presence of serious non-facial injuries would be associated with delays in facial fracture management. The primary aims were to describe open facial fracture management practices and examine factors associated with early versus delayed fracture management. A secondary aim was to describe infection rates. Early treatment was defined as within 24 hours of arrival for I&D, irrigation without debridement, and ORIF and within 1 hour for antibiotics. Results: A total of 256 patients were included. Twenty-seven percent had major trauma (Injury Severity Score ≥16). The presence of serious head injury/traumatic brain injury was associated with delayed I&D (ORearly=0.04, p<0.01), irrigation without debridement (ORearly=0.09, p<0.01), and ORIF (ORearly=0.10, p<0.01). Going to the OR within 24 hours was associated with early I&D (ORearly=377.26, p<0.01), irrigation without debridement (ORearly=13.54, p<0.01), and ORIF (ORearly=154.92, p<0.01). The infection rate was 4%. Conclusions: In this examination of multiple aspects of open facial fracture management, serious injuries to non-facial regions led to delays in surgical fracture management, consistent with the study hypothesis. Level of evidence: Level III, prognostic/epidemiological.

Characterization of peritoneal reactive ascites collected from acute appendicitis and small bowel obstruction patients.

BACKGROUND: Pathological abdominal adhesions can cause bowel obstructions. A history of appendectomy (appy) increases patient rehospitalization risk directly related to adhesions. To potentially identify strategies for adhesion treatment, we characterized reactive ascites (rA) collected during appy or adhesiolysis for small bowel obstruction (SBO). METHODS: This is a non-randomized, prospective observational study recruiting patients with non-perforated appendicitis or SBO from three Level 1 trauma centers in the United States. rA were analyzed via liquid chromatography-mass spectrometry (LC-MS) (n = 31), bead-based quantification cytokines and chemokines (n = 32) and soluble receptors (n = 30), and LC-MS metabolomics (n = 18). RESULTS: LC-MS showed that samples contained albumin, apolipoprotein A1, and transthyretin and that metabolites increased in SBO vs appy rA were biomarkers of oxidative stress. Multi-plex analyses showed levels of 17 cytokines/chemokines and 6 soluble receptors were significantly different in appy vs SBO rA. Top increased proteins in appy compared to SBO rA by 20.14-, 11.53-, and 8.18-fold were granulocyte-colony stimulating factor, C-X-C motif chemokine ligand 10, and interleukin-10, respectively. CONCLUSIONS: These data further define pro- and anti-inflammatory mediators and metabolites that may drive formation or perpetuate chronic abdominal adhesions. Future research is to further explore whether attenuation of these factors may decrease pathologic adhesion formation.

Hyperglycemia in nondiabetic adult trauma patients is associated with worse outcomes than diabetic patients: An analysis of 95,764 patients.

BACKGROUND: The adverse impact of acute hyperglycemia is well documented but its specific effects on nondiabetic trauma patients are unclear. The purpose of this study was to analyze the differential impact of hyperglycemia on outcomes between diabetic and nondiabetic trauma inpatients. METHODS: Adults admitted 2018 to 2019 to 46 Level I/II trauma centers with two or more blood glucose tests were analyzed. Diabetes status was determined from International Classification of Diseases-10th Rev.-Clinical Modification, trauma registry, and/or hemoglobin A1c greater than 6.5. Patients with and without one or more hyperglycemic result >180 mg/dL were compared. Logistic regression examined the effects of hyperglycemia and diabetes on outcomes, adjusting for age, sex, Injury Severity Score, and body mass index. RESULTS: There were 95,764 patients: 54% male; mean age, 61 years; mean Injury Severity Score, 10; diabetic, 21%. Patients with hyperglycemia had higher mortality and worse outcomes compared with those without hyperglycemia. Nondiabetic hyperglycemic patients had the highest odds of mortality (diabetic: adjusted odds ratio, 3.11; 95% confidence interval, 2.8-3.5; nondiabetics: adjusted odds ratio, 7.5; 95% confidence interval, 6.8-8.4). Hyperglycemic nondiabetics experienced worse outcomes on every measure when compared with nonhyperglycemic nondiabetics, with higher rates of sepsis (1.1 vs. 0.1%, p < 0.001), more SSIs (1.0 vs. 0.1%, p < 0.001), longer mean hospital length of stay (11.4 vs. 5.0, p < 0.001), longer mean intensive care unit length of stay (8.5 vs. 4.0, p < 0.001), higher rates of intensive care unit use (68.6% vs. 35.1), and more ventilator use (42.4% vs. 7.3%). CONCLUSION: Hyperglycemia is associated with increased odds of mortality in both diabetic and nondiabetic patients. Hyperglycemia during hospitalization in nondiabetics was associated with the worst outcomes and represents a potential opportunity for intervention in this high-risk group. LEVEL OF EVIDENCE: Therapeutic/care management; Level III.

The public health burden of geriatric trauma: Analysis of 2,688,008 hospitalizations from Centers for Medicare and Medicaid Services inpatient claims.

BACKGROUND: Geriatric trauma care (GTC) represents an increasing proportion of injury care, but associated public health research on outcomes and expenditures is limited. The purpose of this study was to describe GTC characteristics, location, diagnoses, and expenditures. METHODS: Patients at short-term nonfederal hospitals, 65 years or older, with ≥1 injury International Classification of Diseases, Tenth Revision, were selected from 2016 to 2019 Centers for Medicare and Medicaid Services Inpatient Standard Analytical Files. Trauma center levels were linked to Inpatient Standard Analytical Files data via American Hospital Association Hospital ID and fuzzy string matching. Demographics, care location, diagnoses, and expenditures were compared across groups. RESULTS: A total of 2,688,008 hospitalizations (62% female; 90% White; 71% falls; mean Injury Severity Score, 6.5) from 3,286 hospitals were included, comprising 8.5% of all Medicare inpatient hospitalizations. Level I centers encompassed 7.2% of the institutions (n = 236) but 21.2% of hospitalizations, while nontrauma centers represented 58.5% of institutions (n = 1,923) and 37.7% of hospitalizations. Compared with nontrauma centers, patients at Level I centers had higher Elixhauser scores (9.0 vs. 8.8) and Injury Severity Score (7.4 vs. 6.0; p < 0.0001). The most frequent primary diagnosis at all centers was hip/femur fracture (28.3%), followed by traumatic brain injury (10.1%). Expenditures totaled $32.9 billion for trauma-related hospitalizations, or 9.1% of total Medicare hospitalization expenditures and approximately 1.1% of the annual Medicare budget. The overall mortality rate was 3.5%. CONCLUSION: Geriatric trauma care accounts for 8.5% of all inpatient GTC and a similar percentage of expenditures, the most common injury being hip/femur fractures. The largest proportion of GTC occurs at nontrauma centers, emphasizing their vital role in trauma care. Public health prevention programs and GTC guidelines should be implemented by all hospitals, not just trauma centers. Further research is required to determine the optimal role of trauma systems in GTC, establish data-driven triage guidelines, and define the impact of trauma centers and nontrauma centers on GTC mortality. LEVEL OF EVIDENCE: Therapeutic/care management, Level III.

Examining trends in gun violence injuries before and during the COVID-19 pandemic across six trauma centers.

OBJECTIVES: The onset of the national stay-at-home orders accompanied by a surge in firearm sales has elevated the concerns of clinicians and public health authorities. The purpose of this study was to examine the impact of the stay-at-home orders among gunshot wound (GSW) trauma admissions. METHODS: This was a retrospective cohort study at six level I trauma centers across four states. Patients admitted after the onset of COVID-19 restrictions (March 16, 2020-June 30, 2020) were compared with those admitted during the same period in 2019. We compared (1) rate of patients with GSW and (2) characteristics of patients with GSW, by period using Χ2 tests or Fisher's exact tests, as appropriate. RESULTS: There were 6996 trauma admissions across the study period; 3707 (53%) in 2019 and 3289 (47%) in 2020. From 2019 to 2020, there was a significant increase in GSW admissions (4% vs. 6%, p=0.001); 4 weeks specifically had significant increases (March 16-March 23: 4%, April 1-April 8: 5%, April 9-April 16: 6%, and May 11-May 18: 5%). Of the 334 GSWs, there were significant increases in patients with mental illness (5% vs. 11%, p=0.03), alcohol use disorder (2% vs. 10%, p=0.003), substance use disorder (11% vs. 25%, p=0.001), and a significant decrease in mortality (14% vs. 7%, p=0.03) in 2020. No other significant differences between time periods were identified. CONCLUSION: Our data suggest that trauma centers admitted significantly more patients with GSW following the national guidelines, including an increase in those with mental illness and substance use-related disorders. This could be attributable to the stay-at-home orders. LEVEL OF EVIDENCE: Level III, retrospective study.

Are trauma research programs in academic and non-academic centers measured by equal standards? A survey of 137 level I trauma centers in the United States.

BACKGROUND: American College of Surgeons level I trauma center verification requires an active research program. This study investigated differences in the research programs of academic and non-academic trauma centers. METHODS: A 28-question survey was administered to ACS-verified level I trauma centers in 11/12/2020-1/7/2021. The survey included questions on center characteristics (patient volume, staff size), peer-reviewed publications, staff and resources dedicated to research, and funding sources. RESULTS: The survey had a 31% response rate: 137 invitations were successfully delivered via email, and 42 centers completed at least part of the survey. Responding level I trauma centers included 36 (86%) self-identified academic and 6 (14%) self-identified non-academic centers. Academic and non-academic centers reported similar annual trauma patient volume (2190 vs. 2450), number of beds (545 vs. 440), and years of ACS verification (20 vs. 14), respectively. Academic centers had more full-time trauma surgeons (median 8 vs 6 for non-academic centers) and general surgery residents (median 30 vs 7) than non-academic centers. Non-academic centers more frequently ranked trauma surgery (100% vs. 36% academic), basic science (50% vs. 6% academic), neurosurgery (50% vs. 14% academic), and nursing (33% vs. 0% academic) in the top three types of studies conducted. Academic centers were more likely to report non-profit status (86% academic, 50% non-academic) and utilized research funding from external governmental or non-profit grants more often (76% vs 17%). CONCLUSIONS: Survey results suggest that academic centers may have more physician, resident, and financial resources available to dedicate to trauma research, which may make fulfillment of ACS level I research requirements easier. Structural and institutional changes at non-academic centers, such as expansion of general surgery resident programs and increased pursuit of external grant funding, may help ensure that academic and non-academic sites are equally equipped to fulfill ACS research criteria.

Effect of the COVID-19 pandemic on the ability of level 1 trauma centers to meet American College of Surgeons research requirements.

INTRODUCTION: The COVID-19 pandemic has had major effects on hospitals' ability to perform scientific research while providing patient care and minimizing virus exposure and spread. Many non-COVID-19 research has been halted, and funding has been diverted to COVID-19 research and away from other areas. METHODS: A 28-question survey was administered to all level 1 trauma centers in the USA that included questions about how the pandemic affected the trauma centers' ability to fulfill the volume and research requirements of level 1 verification by the American College of Surgeons (ACS). RESULTS: The survey had a 29% response rate (40/137 successful invitations). Over half of respondents (52%) reported reduced trauma admissions during the pandemic, and 7% reported that their admissions dropped below the volume required for level 1 verification. Many centers diverted resources from research during the pandemic (44%), halted ongoing consenting studies (33%), and had difficulty fulfilling research requirements because of competing clinical priorities (40%). DISCUSSION: Results of this study show a need for flexibility in the ACS verification process during the COVID-19 pandemic, potentially including reduction of the required admissions and/or research publication volumes. LEVEL OF EVIDENCE: Level IV, cross-sectional study.

Effect of the COVID-19 pandemic on health insurance coverage among trauma patients: a study of six level I trauma centers.

BACKGROUND: Increased unemployment during the COVID-19 pandemic has likely led to widespread loss of employer-provided health insurance. This study examined trends in health insurance coverage among trauma patients during the COVID-19 pandemic, including differences in demographics and clinical characteristics by insurance type. METHODS: This was a retrospective study on adult patients admitted to six level 1 trauma centers between January 1, 2018 and June 30, 2020. The primary exposure was hospital admission date: January 1, 2018 to December 31, 2018 (Period 1), January 1, 2019 to March 15, 2020 (Period 2), and March 16, 2020 to June 30, 2020 (Period 3). Covariates included demographic and clinical variables. χ² tests examined whether the rates of patients covered by each insurance type differed between the pandemic and earlier periods. Mann-Whiney U and χ² tests investigated whether patient demographics or clinical characteristics differed within each insurance type across the study periods. RESULTS: A total of 31 225 trauma patients admitted between January 1, 2018 and June 30, 2019 were included. Forty-one per cent (n=12 651) were admitted in Period 1, 49% (n=15 258) were from Period 2, and 11% (n=3288) were from Period 3. Percentages of uninsured patients increased significantly across the three periods (Periods 1 to 3: 15%, 16%, 21%) (ptrend=0.02); however, there was no accompanying decrease in the percentages of commercial/privately insured patients (Periods 1 to 3: 40%, 39%, 39%) (ptrend=0.27). There was a significant decrease in the percentage of patients on Medicare during the pandemic period (Periods 1 to 3: 39%, 39%, 34%) (p<0.01). DISCUSSION: This study found that job loss during the COVID-19 pandemic resulted in increases of uninsured trauma patients. However, there was not a corresponding decrease in commercial/privately insured patients, as may have been expected; rather, a decrease in Medicare patients was observed. These findings may be attributable to a growing workforce during the study period, in combination with a younger overall patient population during the pandemic. LEVEL OF EVIDENCE: Retrospective, level III study.

Incorporating age improves the Glasgow Coma Scale score for predicting mortality from traumatic brain injury.

BACKGROUND: The Glasgow Coma Scale (GCS) score has been adapted into categories of severity (mild, moderate, and severe) and are ubiquitous in the trauma setting. This study sought to revise the GCS categories to account for an interaction by age and to determine the discrimination of the revised categories compared with the standard GCS categories. METHODS: The American College of Surgeons National Trauma Data Bank registry was used to identify patients with traumatic brain injury (TBI; ICD-9 codes 850-854.19) who were admitted to participating trauma centers from 2010 to 2015. The primary exposure variables were GCS score and age, categorized by decade (teens, 20s, 30s…, 80s). In-hospital mortality was the primary outcome for examining TBI severity/prognostication. Logistic regression was used to calculate the conditional probability of death by age decade and GCS in a development dataset (75% of patients). These probabilities were used to create a points-based revision of the GCS, categorized as low (mild), moderate, and high (severe). Performance of the revised versus standard GCS categories was compared in the validation dataset using area under the receiver operating characteristic (AUC) curves. RESULTS: The final population included 539,032 patients with TBI. Age modified the performance of the GCS, resulting in a novel categorization schema for each age decile. For patients in their 50s, performance of the revised GCS categories mirrored the standard GCS categorization (3-8, 9-12, 13-15); all other revised GCS categories were heavily modified by age. Model validation demonstrated the revised GCS categories statistically significantly outperformed the standard GCS categories at predicting mortality (AUC: 0.800 vs 0.755, p<0.001). The revised GCS categorization also outperformed the standard GCS categories for mortality within pre-specified subpopulations: blunt mechanism, isolated TBI, falls, non-transferred patients. DISCUSSION: We propose the revised age-adjusted GCS categories will improve severity assessment and provide a more uniform early prognostic indicator of mortality following traumatic brain injury. LEVEL OF EVIDENCE: III epidemiologic/prognostic.

The presence of S-sulfonated transthyretin in commercial human serum albumin solutions: Potential contribution to neuropathy.

BACKGROUND: Commercial solutions of human serum albumin (HSA) are administered to critically ill patients for the treatment of shock, restoration of blood volume, and the acute management of burns. Previously, conflicting results on the effects of HSA administration have been reported varying from a favorable increase in total plasma antioxidant capacity to a higher mortality rate in traumatic brain injury (TBI) patients. These results could be partially explained due to the known heterogeneity of HSA solutions. We report the discovery of S-sulfonated human transthyretin (hTTR) in HSA solutions. METHODS: Proteomics was performed on commercially available solutions of 5% HSA by LC-MS analysis. The MS charge envelope for hTTR was deconvolved to the uncharged native hTTR parent mass (13,762 Da). The parent mass was then integrated, and relative proportions of the 2 major species of hTTR, native and S-sulfonated hTTR (13,842 Da), were calculated. RESULTS: The majority of hTTR found in 5% commercial HSA solutions is in the S-sulfonated form regardless of the age of the HSA solution. S-sulfonation of hTTR at the free cysteine residue in position 10 appears to be the result of a mixed disulfide exchange possibly with S-cysteinylated hTTR or S-cysteinylated HSA. hTTR is a tetramer composed of four identical monomers each containing a reduced cysteine residue in position 10. S-sulfonation of hTTR at this cysteine residue can destabilize the hTTR tetramer, an important step in the formation of TTR-related amyloid fibrils. CONCLUSIONS: Administration of a commercial HSA solution that already contains S-sulfonated hTTR could potentially contribute to the development of amyloid-related/polyneuropathy in the critically ill.

Clinically relevant redifferentiation of fibroblast-like chondrocytes into functional chondrocytes by the low molecular weight fraction of human serum albumin.

OBJECTIVES: Traumatic joint injury induces chondrocyte dysfunction and progressive breakdown of articular cartilage, leading to post-traumatic osteoarthritis (PTOA). In this condition, dysfunctional fibroblast-like chondrocytes (FLCs) no longer express proteins required for cartilage maintenance, such as SOX9 and collagen-type II (COL2). Interleukin-6 (IL-6) has been demonstrated to downregulate expression of these two critical proteins in chondrocytes, and increased IL-6 levels have been measured in patients with PTOA. The <5kDa fraction of human serum albumin (LMWF5A) has been suggested to modulate this pathway, as decreased levels of IL-6 are secreted by immunostimulated LMWF5A-treated macrophages. Our objective was to determine whether LMWF5A induces an in vitro model of FLCs to redifferentiate into functional chondrocytes. METHODS: SOX9 and COL2 were monitored via western blot, and COL2 was detected with immunofluorescence. Aggrecan and IL-6 were quantified by ELISA. Glycosaminoglycan (GAG) levels were quantified with alcian blue. RESULTS: We found that LMWF5A significantly increases the principal cartilage transcription factor SOX9 and the SOX9 target protein COL2 in monolayer-cultured FLCs. Multiple LMWF5A treatments of 3-D pellet FLC cultures over 2wks resulted in a significant decrease in IL-6 and significant increases in the major players of articular cartilage mechanics, aggrecan and highly-sulfated GAGs. CONCLUSIONS: These data support the hypothesis and clinical outcomes of two phase III clinical trials that LMWF5A-treatment induces chondrogenesis and supports functional cartilage. We propose that LMWF5A could maintain articular cartilage integrity in all joints following traumatic injury.

Short-Course Antimicrobial Therapy Does Not Increase Treatment Failure Rate in Patients with Intra-Abdominal Infection Involving Fungal Organisms.

BACKGROUND: Fungi frequently are isolated in intra-abdominal infections (IAI). The Study to Optimize Peritoneal Infection Therapy (STOP-IT) recently suggested short-course treatment for patients with IAI. It remains unclear whether the presence of fungi in IAI affects the optimal duration of Antimicrobial therapy. We hypothesized that a shorter treatment course in IAI with fungal organisms would be associated with a higher rate of treatment failure. METHODS: Patients enrolled in the STOP-IT trial were stratified according to the presence or absence of a fungal isolate. They were analyzed as a subgroup based on original randomization to either the control group or an experimental group that received a four-day course of Antimicrobial therapy and by comparison with those without a fungal component to their infection. Descriptive comparisons were performed using a χ2, Fisher exact, or Kruskal-Wallis test as appropriate. The primary outcome was a composite of recurrent IAI, surgical site infection, and death. RESULTS: A total of 411 patients in the study (79%) had available culture data, of which 58 (14%) had positive fungal cultures. The most common organisms were Candida albicans and C. glabrata. The treatment failure rate was equivalent in the experimental and control arms (29.6% vs. 22.6%; p = 0.54). Patients with fungal isolates were more likely to have malignant disease (25.9% vs. 9.6%; p = 0.0004) and coronary artery disease (22% vs. 12%; p = 0.04), but were otherwise similar to those without fungal isolates. Patients with fungal isolates had more hospital days (median 10 vs. 7; p < 0.0001) and more days to resumption of enteral intake (median 5 vs. 3; p = 0.0006), but there was no difference in the composite outcome. CONCLUSIONS: Patients with IAI involving fungal organisms randomized to a shorter course of Antimicrobial therapy had no difference in the rate of treatment failure. These results suggest that the presence of fungi in IAI may not indicate independently the need for a longer course of Antimicrobial therapy.

Percutaneously drained intra-abdominal infections do not require longer duration of antimicrobial therapy.

BACKGROUND: The length of antimicrobial therapy in complicated intra-abdominal infections (CIAIs) is controversial. A recent prospective, multicenter, randomized controlled trial found that 4 days of antimicrobial therapy after source control of CIAI resulted in similar outcomes when compared with longer duration. We sought to examine whether outcomes remain similar in the subpopulation who received percutaneous drainage for source control of CIAI. METHODS: With the use of the STOP-IT database, patients with a CIAI who received percutaneous drainage were analyzed. Patients were randomized to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy or to receive a fixed course of antibiotics for 4 ± 1 days. Outcomes included incidence of and time to recurrent intra-abdominal infection, Clostridium difficile infection, and extra-abdominal infections as well as hospital days and mortality. RESULTS: Of 518 enrolled patients, 129 met inclusion criteria. Baseline characteristics, including demographics, comorbidities, and severity of illness, were similar. When comparing outcomes of the 4-day group (n = 72) with those of the longer group (n = 57), rates of recurrent intra-abdominal infection (9.7% vs. 10.5%, p = 1.00), C. difficile infection (0% vs. 1.8%, p = 0.442), and hospital days (4.0 [2.0-7.5] vs. 4.0 [3.0-8.0], p = 0.91) were similar. Time to recurrent infection was shorter in the 4-day group (12.7 [6.2] days vs. 21.3 [4.2] days, p = 0.015). There was no mortality. CONCLUSION: In this post hoc analysis of a prospective, multicenter, randomized trial, there was no difference in outcome between a shorter and longer duration of antimicrobial therapy in those with percutaneously drained source control of CIAI. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV.

Antioxidant oils and Salmonella enterica Typhimurium reduce tumor in an experimental model of hepatic metastasis.

Fruit seeds high in antioxidants have been shown to have anticancer properties and enhance host protection against microbial infection. Recently we showed that a single oral dose of Salmonella enterica serovar Typhimurium expressing a truncated human interleukin-2 gene (SalpIL2) is avirulent, immunogenic, and reduces hepatic metastases through increased natural killer cell populations in mice. To determine whether antioxidant compounds enhance the antitumor effect seen in SalpIL2-treated animals, we assayed black cumin (BC), black raspberry (BR), and milk thistle (MT) seed oils for the ability to reduce experimental hepatic metastases in mice. In animals without tumor, BC and BR oil diets altered the kinetics of the splenic lymphocyte response to SalpIL2. Consistent with previous reports, BR and BC seed oils demonstrated independent antitumor properties and moderate adjuvant potential with SalpIL2. MT oil, however, inhibited the efficacy of SalpIL2 in our model. Based on these data, we conclude that a diet high in antioxidant oils promoted a more robust immune response to SalpIL2, thus enhancing its antitumor efficacy.

Attenuated Salmonella typhimurium with interleukin 2 gene prevents the establishment of pulmonary metastases in a model of osteosarcoma.

PURPOSE: The current management of osteosarcoma (OS) entails an aggressive preoperative and postoperative chemotherapeutic regimen with limb salvage surgery. Despite these efforts, relapse-free survival is less than 60% in patients with classic OS, whereas most patients relapse with pulmonary metastases. In these studies, we sought to prevent the establishment of pulmonary metastases from OS with a single oral dose of SalpIL2. METHODS: Mice were administered attenuated Salmonella typhimurium with (SalpIL2) and without a gene for human interleukin 2 (Sal-NG) 7 days before challenge with 2 x 10(5) OS cells via tail vein. Three weeks after injection, mice were harvested for splenic lymphocytes and tumor enumeration. RESULTS: Prophylaxis with attenuated SalpIL2 significantly reduces pulmonary metastases in number and volume (P < .0001 and P < .0001) with respect to saline controls. Furthermore, splenic natural killer cell populations were increased 396% with SalpIL2 (P < .0007) and 426% with Sal-NG (P < .0003) compared to nontreated groups. CONCLUSIONS: Host natural killer response is greatly amplified and maybe partially responsible for the effective immune response against the formation of pulmonary metastases. A single oral dose of SalpIL2 may be a novel form of adjuvant therapy for patients after early detection of primary OS.

Attenuated Salmonella typhimurium with IL-2 gene reduces pulmonary metastases in murine osteosarcoma.

Historically, osteosarcoma has been a problematic metastatic disease, with 40-80% of patients developing pulmonary metastasis after primary tumor resection. Recent treatment advancements have reduced the occurrence of metastatic lesions to less than 30%. Using attenuated Salmonella typhimurium, we previously demonstrated regression in tumor burden in murine solid tumor and metastatic models. We established a murine model for metastatic osteosarcoma to determine the effect of treatment with a single oral dose of attenuated S. typhimurium with (SalpIL2) and without (Sal-NG) a gene for a truncated human interleukin-2. Female balb/c mice were administered 2 x 10(5) (ATCC K7M2) osteosarcoma cells via tail vein injection from culture and treated by oral gavage of Salmonella species 3 days later. Mice were harvested for splenic lymphocytes and tumor enumeration by intratracheal injection with India ink 21 days after injection. Treatment with attenuated SalpIL2 reduced pulmonary metastases in number and volume compared to saline controls. Furthermore, splenic natural killer cell populations were increased 93% with SalpIL2 and 114% with Sal-NG compared to nontreated groups. This pulmonary metastasis model demonstrates attenuated Salmonella typhimurium with human interleukin-2 reduced metastatic osteosarcoma in mice and confirm the need for further investigation into the immunologic properties of SalpIL2 as a possible treatment for metastatic osteosarcoma.

Sp1 elements regulate transcriptional activity within the murine Toll-like receptor 4 promoter.

BACKGROUND AND PURPOSE: Toll-like receptor 4 (TLR4) mediates the innate immune response to lipopolysaccharide (LPS) by a complex intracellular signaling pathway that activates the transcription factor nuclear factor (NF)-kappaB, with subsequent production of inflammatory cytokines. The precise mechanisms involved have not been delineated. We hypothesized that specific regulatory elements exist within the TLR4 promoter. METHODS: We cloned regions of the murine TLR4 promoter (0.25 kb to 2 kb; -2000 bp to +244 bp) into the pGL3-Basic plasmid containing the firefly luciferase gene and used the resulting constructs to transfect HEK293 or RAW 264.7 cells. After 24 h, we used LPS to stimulate RAW 264.7 cells. We quantified relative light units (RLUs) of cell lysates and secreted tumor necrosis factor (TNF)-alpha. For pairwise comparison, we used Student's t-test. Sequence analysis of the promoter revealed several putative Sp1 sites. We used two constructs showing increased promoter activity, TLR4-750/-1 and TLR4-500/-1, to transfect cells in the presence of a specific Sp1 inhibitor, mithramycin A. RESULTS: Of the six promoter constructs, four showed greater transcriptional activity (p < 0.05 vs. pGL3-Basic), as measured by luciferase activity. However, we did not observe differences in transcriptional activity of the promoter in five of those six constructs when we stimulated transfected RAW 264.7 cells with 10 ng of LPS. This finding suggests that transcriptional regulation of the promoter is unaffected by cellular changes caused by LPS. Both TLR4-750/-1 and TLR4-500/-1 showed dose-dependent reductions in transcriptional activity in the presence of increasing concentrations of the specific Sp1 inhibitor mithramycin A in both HEK293 and RAW 264.7 cells (p < 0.05 vs. no mithramycin A). CONCLUSION: At least one Sp1 transcriptional regulatory element is present within the murine TLR4 promoter (range -750 bp to -250 bp). This finding holds promise for manipulating this fundamental inflammatory response.

Postoperative severe microangiopathic hemolytic anemia associated with a giant hepatic cavernous hemangioma.

Complications related to liver hemangioma are rare. We herein describe the case of a patient with three giant cavernous hemangiomas of the liver, of which two were resected for symptoms. A significant microangiopathic hemolytic anemia occurred in the early postoperative period, leading to acute renal failure and necessitating blood transfusions. The systematic evaluation of hemolytic processes in the postoperative patient is described. Surgeons should be aware of the potential for hemolytic complications after major surgery when giant hepatic hemangiomas are present.