Impact of sternal fixation on patient outcomes: A case matched review.

INTRODUCTION: Sternal fractures are debilitating injuries often resulting in severe pain and respiratory compromise. Surgical fixation of sternal fractures is gaining popularity as a treatment modality for sternal fractures. Unfortunately, little literature exists on this topic. This study looks to further examine the benefits of sternal fixation (SF), hypothesizing SF results in improved pain, improved respiratory function, and decreased opioid use. METHODS: Retrospective review was performed between patients with sternal fractures who underwent nonoperative management (NOM) versus operative SF. Case matching was used to construct an artificial control group matched on age and Injury Severity Score using a 1:1 ratio of treatment to control. Exclusion criteria were age younger than 18 years. Outcomes of interest included mean pain score, total opioid requirements (in morphine milliequivalents) within 24 hours of discharge, intensive care unit and hospital length of stay (LOS), and incentive spirometry percent predicted value at discharge. Dependent variables were analyzed using t test, and Injury Severity Score was analyzed using the sign test. Statistical significance was set at p < 0.05. RESULTS: Fifty-eight patients from the SF cohort were matched with 58 patients from the NOM cohort. The average age was 59.8 years for the SF group and 62.2 years for the NOM group. Injury Severity Score was matched at 9 for both cohorts. Although pain scores were similar for both cohorts, the SF group required significantly less opioids at discharge (62.1 vs. 92.2 morphine milliequivalents; p = 0.007). In addition, the SF cohort demonstrated significantly improved respiratory function per incentive spirometry percent predicted value at discharge (75.5% vs. 59.9%; p < 0.001). Intensive care unit LOS and hospital LOS were similar between cohorts. CONCLUSION: Despite similarities in pain scores, intensive care unit LOS, and hospital LOS, SF was associated with decreased opioid requirements and improved respiratory function at discharge in this study. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Finite element analysis for better evaluation of rib fractures: A pilot study.

INTRODUCTION: Modeling rib fracture stability is challenging. Computer-generated finite element analysis (FEA) is an option for assessment of chest wall stability (CWS). The objective is to explore FEA as a means to assess CWS, hypothesizing it is a reliable approach to better understand rib fracture pathophysiology. METHODS: Thoracic anatomy was generated from standardized skeletal models with internal/external organs, soft tissue and muscles using Digital Imaging and Communications in Medicine data. Material properties were assigned to bone, cartilage, skin and viscera. Simulation was performed using ANSYS Workbench (2020 R2, Canonsburg, PA). Meshing the model was completed identifying 1.3 and 2.1 million elements and nodes. An implicit solver was used for a linear/static FEA with all bony contacts identified and applied. All material behavior was modeled as isotropic/linear elastic. Six load cases were evaluated from a musculoskeletal AnyBody model; forward flexion, right/left lateral bending, right/left axial rotation and 5-kg weight arm lifting. Standard application points, directions of muscle forces, and joint positions were applied. Ten fracture cases (unilateral and bilateral) were defined and 66 model variations were simulated. Forty-three points were applied to each rib in the mid/anterior axillary lines to assess thoracic stability. Three assessment criteria were used to quantify thoracic motion: normalized mean absolute error, normalized root mean square error, and normalized interfragmentary motion. RESULTS: All three analyses demonstrated similar findings that rib fracture deformation and loss of CWS was highest for left/right axial rotation. Increased number of ribs fracture demonstrated more fracture deformation and more loss of CWS compared with a flail chest segment involving less ribs. A single rib fracture is associated with ~3% loss of CWS. Normalized interfragmentary motion deformation can increases by 230%. Chest wall stability can decrease by over 50% depending on fracture patterns. CONCLUSION: Finite element analysis is a promising technology for analyzing CWS. Future studies need to focus on clinical relevance and application of this technology. LEVEL OF EVIDENCE: Diagnostic Tests or Criteria; Level IV.

Mobilization of Resources and Emergency Response on the National Scale.

Mass casualty incidents are increasingly common. They are defined by large numbers of patients arriving nearly simultaneously, overwhelming available resources needed for optimal care. They require rapid mobilization of resources to provide optimal outcomes and limit disability and death. Because the mechanism of injury in a mass casualty incident is often traumatic in nature, surgeons should be aware of the critical role they play in planning and response. The coronavirus disease 2019 pandemic is a notable, resulting in a sustained surge of critically ill patients. Initial response requires local mobilization of resources; large-scale events potentially require a national response.

Discrepancies in rib fracture severity between radiologist and surgeon: A retrospective review.

BACKGROUND: Chest computed tomography (CT) scans are important for the management of rib fracture patients, especially when determining indications for surgical stabilization of rib fractures (SSRFs). Chest CTs describe the number, patterns, and severity of rib fracture displacement, driving patient management and SSRF indications. Literature is scarce comparing radiologist versus surgeon rib fracture description. We hypothesize there is significant discrepancy between how radiologists and surgeons describe rib fractures. METHODS: This was an institutional review board-approved, retrospective study conducted at a Level I academic center from December 2016 to December 2017. Adult patients (≥18 years of age) suffering rib fractures with a CT chest where included. Basic demographics were obtained. Outcomes included the difference between radiologist versus surgeon description of rib fractures and differences in the number of fractures identified. Rib fracture description was based on current literature: 1, nondisplaced; 2, minimally displaced (<50% rib width); 3, severely displaced (≥50% rib width); 4, bicortically displaced; 5, other. Descriptive analysis was used for demographics and paired t test for statistical analysis. Significance was set at p = 0.05. RESULTS: Four hundred and ten patients and 2,337 rib fractures were analyzed. Average age was 55.6(±20.6); 70.5% were male; median Injury Severity Score was 16 (interquartile range, 9-22) and chest Abbreviated Injury Scale score was 3 (interquartile range, 3-3). For all descriptive categories, radiologists consistently underappreciated the severity of rib fracture displacement compared with surgeon assessment and severity of displacement was not mentioned for 35% of rib fractures. The mean score provided by the radiologist was 1.58 (±0.63) versus 1.78 (±0.51) by the surgeon (p < 0.001). Radiologists missed 138 (5.9%) rib fractures on initial CT. The sensitivity of the radiologist to identify a severely displaced rib fracture was 54.9% with specificity of 79.9%. CONCLUSION: Discrepancy exists between radiologist and surgeon regarding rib fracture description on chest CT as radiologists routinely underappreciate fracture severity. Surgeons need to evaluate CT scans themselves to appropriately decide management strategies and SSRF indications. LEVEL OF EVIDENCE: Prognostic/Diagnostic Test, level III.

Surgical Simulation: Markers of Proficiency.

OBJECTIVE: Surgical simulation has become an integral component of surgical training. Simulation proficiency determination has been traditionally based upon time to completion of various simulated tasks. We aimed to determine objective markers of proficiency in surgical simulation by comparing novel assessments with conventional evaluations of technical skill. DESIGN: Categorical general surgery residents completed 10 laparoscopic cholecystectomy modules using a high-fidelity simulator. We recorded and analyzed simulation task times, as well as number of hand movements, instrument path length, instrument acceleration, and participant affective engagement during each simulation. Comparisons were made to Objective Structured Assessment of Technical Skill (OSATS) and Accreditation Council for Graduate Medical Education Milestones, as well as previous laparoscopic experience, duration of laparoscopic cholecystectomies performed by participants, and postgraduate year. Comparisons were also made to Fundamentals of Laparoscopic Surgery task times. Spearman's rho was utilized for comparisons, significance set at >0.50. SETTING: University of Missouri, Columbia, Missouri, an academic tertiary care facility. PARTICIPANTS: Fourteen categorical general surgery residents (postgraduate year 1-5) were prospectively enrolled. RESULTS: One hundred forty simulations were included. The number of hand movements and instrument path lengths strongly correlated with simulation task times (ρ 0.62-0.87, p < 0.0001), FLS task completion times (ρ 0.50-0.53, p < 0.0001), and prior real-world laparoscopic cholecystectomy experience (ρ -0.51 to -0.53, p < 0.0001). No significant correlations were identified between any of the studied markers with Accreditation Council for Graduate Medical Education Milestones, Objective Structured Assessment of Technical Skill evaluations, total previous laparoscopic experience, or postgraduate year level. Neither instrument acceleration nor participant engagement showed significant correlation with any of the conventional markers of real-world or simulation skill proficiency. CONCLUSIONS: Simulation proficiency, measured by instrument and hand motion, is more representative of simulation skill than simulation task time, instrument acceleration, or participant engagement.

Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.

Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.

Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI.

Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ray structure of lead mannosides and then designed mannosides with improved drug-like properties. We show that cyclizing the carboxamide onto the biphenyl B-ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2-methyl-4-(1-oxo-1,2-dihydroisoquinolin-7-yl)phenyl α-d-mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N-Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22, as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria-mediated hemagglutination and prevent biofilm formation by UPEC with single-digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.

Human esophageal myofibroblasts secrete proinflammatory cytokines in response to acid and Toll-like receptor 4 ligands.

The pathophysiology of esophageal injury, repair, and inflammation in gastroesophageal reflux-disease (GERD) is complex. Whereas most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that subepithelial esophageal myofibroblasts in GERD secrete proinflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts [-smooth muscle actin (-SMA)+vimentin+CD31-] in the subepithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed -SMA coimmunostaining with IL-6 and p65. We established and characterized primary cultures of -SMA+vimentin+CD31-CD45- human esophageal myofibroblasts (HuEso MFs). We modeled GERD by treatment with pH 4.5-acidified media and Toll-like receptor 4 (TLR4) ligands, LPS and high-mobility group box 1 protein (HMGB1), and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate that spindle-shaped cell myofibroblasts are located near the basement membrane of stratified squamous epithelium in normal esophagus. We identify an increase in subepithelial myofibroblasts and activation of proinflammatory pathways in patients with GERD. Primary cultures of stromal cells obtained from normal esophagus retain myofibroblast morphology and express the acid receptor transient receptor potential channel vanilloid subfamily 1 (TRPV1) and TLR4. HuEso MFs stimulated with acid and TLR4 agonists LPS and HMGB1 increase IL-6 and IL-8 secretion via TRPV1 and NF-B activation. Our work implicates a role for human subepithelial stromal cells in the pathogenesis of GERD-related esophageal injury. Findings of this study can be extended to the investigation of epithelial-stromal interactions in inflammatory esophageal mucosal disorders.

Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection.

Urinary tract infections (UTIs) are among the most common bacterial infections, causing considerable morbidity in females. Infection is highly recurrent despite appropriate antibiotic treatment. Uropathogenic Escherichia coli (UPEC), the most common causative agent of UTIs, invades bladder epithelial cells (BECs) and develops into clonal intracellular bacterial communities (IBCs). Upon maturation, IBCs disperse, with bacteria spreading to neighboring BECs to repeat this cycle. This process allows UPEC to gain a foothold in the face of innate defense mechanisms, including micturition, epithelial exfoliation, and the influx of polymorphonuclear leukocytes. Here, we investigated the mechanism and dynamics of urothelial exfoliation in the early acute stages of infection. We show that UPEC α-hemolysin (HlyA) induces Caspase-1/Caspase-4-dependent inflammatory cell death in human urothelial cells, and we demonstrate that the response regulator (CpxR)-sensor kinase (CpxA) two-component system (CpxRA), which regulates virulence gene expression in response to environmental signals, is critical for fine-tuning HlyA cytotoxicity. Deletion of the cpxR transcriptional response regulator derepresses hlyA expression, leading to enhanced Caspase-1/Caspase-4- and NOD-like receptor family, pyrin domain containing 3-dependent inflammatory cell death in human urothelial cells. In vivo, overexpression of HlyA during acute bladder infection induces more rapid and extensive exfoliation and reduced bladder bacterial burdens. Bladder fitness is restored fully by inhibition of Caspase-1 and Caspase-11, the murine homolog of Caspase-4. Thus, we have discovered that fine-tuning of HlyA expression by the CpxRA system is critical for enhancing UPEC fitness in the urinary bladder. These results have significant implications for our understanding of how UPEC establishes persistent colonization.

Epimorphin(-/-) mice are protected, in part, from acute colitis via decreased interleukin 6 signaling.

Epimorphin (Epim), a member of the syntaxin family of membrane-bound, intracellular vesicle-docking proteins, is expressed in intestinal myofibroblasts and macrophages. We demonstrated previously that Epimorphin(-/-)(Epim(-/-)) mice are protected, in part, from dextran sodium sulfate (DSS)-induced colitis. Although interleukin (IL)-6/p-Stat3 signaling has been implicated in the pathogenesis of colitis, the myofibroblast contribution to IL-6 signaling in colitis remains unexplored. Our aim was to investigate the IL-6 pathway in Epim(-/-) mice in the DSS colitis model. Whole colonic tissue, epithelium, and stroma of WT and congenic Epim(-/-) mice treated with 5% DSS for 7 days were analyzed for IL-6 and a downstream effector, p-Stat3, by immunostaining and immunoblot. Colonic myofibroblast and peritoneal macrophage IL-6 secretion were evaluated by enzyme-linked immunosorbent assay. IL-6 and p-Stat3 expression were decreased in Epim(-/-) vs WT colon. A relative increase in stromal vs epithelial p-Stat3 expression was observed in WT mice but not in Epim(-/-) mice. Epim deletion abrogates IL-6 secretion from colonic myofibroblasts treated with IL-1ß and decreases IL-6 secretion from peritoneal macrophages in a subset of DSS-treated mice. Epim deletion inhibits IL-6 secretion most profoundly from colonic myofibroblasts. Distribution of Stat3 activation is altered in DSS-treated Epim(-/-) mice. Our findings support the notion that myofibroblasts modulate IL-6/p-Stat3 signaling in DSS-treated Epim(-/-) mice.

Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis.

The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs). Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection. Here we discovered soluble biomarkers engaged in myeloid cell development and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of young women with UTI. Translation of these findings revealed that temperance of the neutrophil response early during UTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition of cyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladder epithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome and drugs targeting cyclooxygenase-2 could prevent recurrent UTI.

Stromal cells participate in the murine esophageal mucosal injury response.

We identified α-smooth muscle actin (α-SMA)- and vimentin-expressing spindle-shaped esophageal mesenchymal cells in the adult and neonate murine esophageal lamina propria. We hypothesized that these esophageal mesenchymal cells express and secrete signaling and inflammatory mediators in response to injury. We established primary cultures of esophageal mesenchymal cells using mechanical and enzymatic digestion. We demonstrate that these primary cultures are nonhematopoietic, nonendothelial, stromal cells with myofibroblast-like features. These cells increase secretion of IL-6 in response to treatment with acidified media and IL-1ß. They also increase bone morphogenetic protein (Bmp)-4 secretion in response to sonic hedgehog. The location of these cells and their biological functions demonstrate their potential role in regulating esophageal epithelial responses to injury and repair.

Current physical and SDS extraction methods do not efficiently remove exosporium proteins from Bacillus anthracis spores.

Biochemical studies of the outermost spore layers of the Bacillus cereus family are hindered by difficulties in efficient dispersal of the external spore layers and difficulties in dissociating protein complexes that comprise the exosporium layer. Detergent and physical methods have been utilized to disrupt the exosporium layer. Herein we compare commonly used SDS extraction buffers used to extract spore proteins and demonstrate the incomplete extractability of the exosporium layer by these methods. Sonication and bead beating methods for exosporium layer removal were also examined. A combination of genetic and physical methods is the most effective for isolating proteins found in the spore exosporium.