Pharmacological Inhibition of Epidermal Growth Factor Receptor Prevents Intracranial Aneurysm Rupture by Reducing Endoplasmic Reticulum Stress.

BACKGROUND: Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress. METHODS: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture. RESULTS: Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture. CONCLUSIONS: Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage.

Green Synthesis of Halogenated Thiophenes, Selenophenes and Benzo[b]selenophenes Using Sodium Halides as a Source of Electrophilic Halogens.

Herein, we report the first synthesis of chlorinated benzo[b]selenophenes via environmentally friendly electrophilic chlorocyclization reaction using "table salt" as a source of "electrophilic chlorine" and ethanol as a solvent. In addition, the synthesis of diverse halogenated heterocycles, including 3-chloro, 3-bromo and 3-iodo thiophenes, selenophenes, and benzo[b]selenophenes was successfully accomplished under the same environmentally benign reaction conditions. This methodology has several advantages over other previously reported reactions as it employs simple starting compounds, an environmentally friendly solvent, ethanol, and non-toxic inorganic reagents under mild reaction conditions, resulting in the high product yields.

PROMIS Physical Function Computer Adaptive Test Compared With Other Upper Extremity Outcome Measures in the Evaluation of Proximal Humerus Fractures in Patients Older Than 60 Years.

OBJECTIVES: To compare the PROMIS Physical Function Computer Adaptive Test (PROMIS PF CAT) to commonly used traditional PF measures for the evaluation of patients with proximal humerus fractures. DESIGN: Prospective. SETTING: Two Level I trauma centers. PATIENTS/PARTICIPANTS: Forty-seven patients older than 60 years with displaced proximal humerus fractures treated between 2006 and 2009. INTERVENTION: Evaluation included completion of the PROMIS PF CAT, the Constant Shoulder Score, the Disabilities of the Arm, Shoulder, and Hand (DASH) and the Short Musculoskeletal Functional Assessment (SMFA). MAIN OUTCOME MEASUREMENT: Observed correlations among the administered PF outcome measures. RESULTS: On average, patients responded to 86 outcome-related items for this study: 4 for the PROMIS PF CAT (range: 4-8 items), 6 for the Constant Shoulder Score, 30 for the DASH, and 46 for the SMFA. Time to complete the PROMIS PF CAT (median completion time = 98 seconds) was significantly less than that for the DASH (median completion time = 336 seconds, P < 0.001) and for the SMFA (median completion time = 482 seconds, P < 0.001). PROMIS PF CAT scores correlated statistically significantly and were of moderate-to-high magnitude with all other PF outcome measure scores administered. CONCLUSIONS: This study suggests using the PROMIS PF CAT as a sole PF outcome measure can yield an assessment of upper extremity function similar to those provided by traditional PF measures, while substantially reducing patient assessment time.

Comparison of locked plate fixation and nonoperative management for displaced proximal humerus fractures in elderly patients.

Use of locked plate fixation for proximal humerus fractures in elderly patients has increased markedly in recent years. We conducted a study to compare outcomes of operative (locked plate fixation) and nonoperative management of these fractures. From our database, we identified 207 displaced proximal humerus fractures that met all inclusion and exclusion criteria. For patients who accepted our invitation to return for evaluation, clinical outcome was assessed using several questionnaires: Constant; DASH (Disabilities of the Arm, Shoulder, and Hand); SMFA (Short Musculoskeletal Functional Assessment); and Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function Computer Adaptive Test. Of the 207 patients, 61 were managed operatively and 146 nonoperatively. Operative patients had lower rates of malunion but higher rates of complications, which included screw perforation, loss of fixation, infection, and secondary surgical procedures. Forty-seven patients (a mix of operative and nonoperative) accepted our invitation to return for clinical evaluation at a mean follow-up of 3.3 years. The 2 groups' clinical outcomes were similar.

Effect of surgical treatment on mortality after acetabular fracture in the elderly: a multicenter study of 454 patients.

OBJECTIVES: Controversy exists regarding the effect of operative treatment on mortality after acetabular fracture in elderly patients. Our hypothesis was that operative treatment would confer a mortality benefit compared with nonoperative treatment even after adjusting for comorbidities associated with death. DESIGN: Retrospective study. SETTING: Three University Level I Trauma Centers. PATIENTS/PARTICIPANTS: All patients aged 60 years and older with acetabular fractures treated from 2002 to 2009 were included in the study. Four hundred fifty-four patients were identified with an average age of 74 years. Sixty-seven percent of the study group was male and 33% female. INTERVENTION: One of 4 treatments: nonoperative management with early mobilization, percutaneous reduction and fixation, open reduction and internal fixation, acute total hip arthroplasty. MAIN OUTCOME MEASUREMENTS: Kaplan-Meier survival curves were created, and Cox proportional hazards models were used to calculate unadjusted and adjusted hazard ratios (HRs) for covariates of interest. RESULTS: In contrast to previous smaller studies, the overall mortality was relatively low at 16% at 1 year [95% confidence interval (CI), 13-19]. Unadjusted survivorship curves suggested higher 1-year mortality rates for nonoperatively treated patients (21% vs. 13%, P < 0.001); however, nonoperative treatment was associated with other risk factors for higher mortality. By accounting for these patient risk factors, our final multivariate model of survival demonstrated no significant difference in hazard of death for nonoperative treatment (0.92, P = 0.6) nor for any of the 3 operative treatment subgroups (P range, 0.4-0.8). As expected, we did find a significantly increased hazard for factors such as the Charlson comorbidity index [HR, 1.25 per point (95% CI, 1.16-1.34)] and age [HR, 1.08 per year of age more than 70 years (95% CI, 1.05-1.11)]. In addition, associated fracture patterns (compared with elementary patterns) significantly increased the hazard of death with a ratio of 1.51 (95% CI, 1.10-2.06). CONCLUSIONS: The operative treatment of acetabular fractures does not increase or decrease mortality, once comorbidities are taken into account. The reasons for this are unknown. Regardless of the causes, the decision for operative versus nonoperative treatment of geriatric acetabular fractures should not be justified based on the concern for increased or decreased mortality alone. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Unrecognized chronic hepatitis C virus infection among baby boomers in the emergency department.

UNLABELLED: The Centers for Disease Control and Prevention and U.S. Preventive Services Task Force have highlighted public screening as an essential strategy for increasing hepatitis C virus (HCV) detection in persons born between 1945 and 1965 ("baby boomers"). Because earlier HCV screening efforts have not targeted emergency department (ED) baby boomer patients, we describe early experience with integrated opt-out HCV antibody (Ab) screening of medically stable baby boomers presenting to an urban academic ED. We performed HCV Ab testing 24 hours per day and confirmed positive test results using polymerase chain reaction (PCR). The primary outcome was prevalence of unrecognized HCV infection. Among 2,325 unique HCV-unaware baby boomers, 289 (12.7%) opted out of HCV screening. We performed HCV Ab tests on 1,529 individuals, of which 170 (11.1%) were reactive. Among Ab reactive cases, follow-up PCR was performed on 150 (88.2%), of which 102 (68.0%) were confirmed RNA positive. HCV Ab reactivity was more likely in males compared to females (14.7% vs. 7.4%; P<0.001), African Americans compared to whites (13.3% vs. 8.8%; P=0.010), and underinsured/ uninsured patients compared to insured patients (16.8%/16.9% vs. 5.0%; P=0.001). Linkage-to-care service activities were recorded for 100 of the 102 confirmed cases. Overall, 54 (54%) RNA-positive individuals were successfully contacted by phone within five call-back attempts. We confirmed initial follow-up appointments for 38 (70.4%) RNA-positive individuals successfully contacted, and 21 (55.3%) individuals with confirmed appointments attended their initial visit with a liver specialist; 3 (7.9%) are awaiting an upcoming scheduled appointment. CONCLUSION: We observed high prevalence of unrecognized chronic HCV infection in this series of baby boomers presenting to the ED, highlighting the ED as an important venue for high-impact HCV screening and linkage to care.

Delayed Primary Closure of Fasciotomy Incisions in the Lower Leg: Do We Need to Change Our Strategy?

OBJECTIVES: The primary purpose of this study is to determine whether a strategy of bringing patients back to the operating room for successive debridements allows for the eventual delayed primary closure (DPC) of fasciotomy wounds. DESIGN: Retrospective cohort study. Data were collected from medical records and radiographs. SETTING: Two urban level 1 trauma centers. PATIENTS: One hundred four adult patients with acute compartment syndrome in the setting of a tibia fracture (open or closed). INTERVENTION: All patients underwent decompressive fasciotomies with closure by either DPC or split-thickness skin grafting (STSG) during a subsequent surgical procedure. MAIN OUTCOME MEASURE: Number of fasciotomy wounds closed by DPC after the initial fasciotomy procedure. RESULTS: Of the 104 patients brought to the operating room for their first debridement after their fasciotomies, 19 patients (18%) were treated with DPC, whereas 42 patients (40%) were closed with STSG because they were believed to be too swollen to allow for primary closure by the treating surgeon. Three of the remaining 43 patients were treated with DPC during their second debridement. No patients who underwent more than 2 washouts could be treated with DPC. No patients who sustained open fractures were able to be closed by DPC (P = 0.02). Patients who underwent STSG on their first postfasciotomy procedure had a significantly shorter hospital stay than patients who underwent additional procedures before closure (12.2 vs. 17.4 days; P = 0.005). CONCLUSIONS: Fasciotomy wounds that are not able to be primarily closed during their first postfasciotomy surgical procedure are rarely closed through DPC techniques. Early skin grafting of these wounds should be considered, especially in the clinical setting of an open injury, because it significantly decreases the length of hospital stay. Other techniques that avoid repeated debridements and attempted closures might also help reduce hospital stay. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Does fluoroscopy improve acetabular component placement in total hip arthroplasty?

BACKGROUND: The success of THA largely depends on correct placement of the individual components. Traditionally, these have been placed freehand using anatomic landmarks, but studies have shown poor accuracy with this method. QUESTIONS/PURPOSES: Specifically, we asked (1) does using fluoroscopy lead to more accurate and greater likelihood of cup placement with the Lewinnek safe zone than does freehand cup placement; (2) is there a learning curve associated with the use of fluoroscopy for cup placement; (3) does the use of fluoroscopy increase operative time; and (4) is there a difference in leg length discrepancy between freehand and fluoroscopic techniques? METHODS: This series consisted of 109 consecutive patients undergoing primary THA, conversion of a previous hip surgery to THA, and revision THA during a 24-month period. No patients were excluded from analysis during this time. The first 52 patients had cups placed freehand, and then the next 57 patients had acetabular components placed using fluoroscopy; the analysis began with the first patient treated using fluoroscopy, to include our initial experience with the technique. The abduction, version, and limb length discrepancy were measured on 6-week postoperative pelvic radiographs obtained with the patient in the supine position. Operative time, sex, age, BMI, diagnosis, operative side, and femoral head size were recorded as possible confounders. RESULTS: Cups inserted freehand were placed in the ideal range of abduction (30°-45°) and anteversion (5°-25°) 44% of the time. With fluoroscopy, placement in the Lewinnek safe zone for both measures significantly increased to 65%. The odds of placing the cup in the Lewinnek safe zone for abduction and version were 2.3 times greater with the use of fluoroscopy (95% CI, 1.2-5.0; p = 0.03). Patients undergoing primary THAs (32 freehand, 35 C-arm) had cup placement in the safe zone for abduction and version 44% of the time freehand and 57% of the time with fluoroscopy, which failed to reach statistical significance. There was no difference in operative time, patient age, sex, operative side, diagnosis, limb length discrepancy, or femoral head size between the two groups. CONCLUSIONS: The use of fluoroscopy to directly observe pelvic position and acetabular component placement increased the success of placement in the Lewinnek safe zone in this cohort of patients having complex and primary THAs. This is a simple, low-cost, and quick method for increasing successful acetabular component alignment. The study population included a large proportion of patients having complex THAs, and further validation of this technique in patients undergoing straightforward, primary THAs needs to be done to understand if similar gains in accuracy for component placement can be expected in that group. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Automated electronic medical record sepsis detection in the emergency department.

Background. While often first treated in the emergency department (ED), identification of sepsis is difficult. Electronic medical record (EMR) clinical decision tools offer a novel strategy for identifying patients with sepsis. The objective of this study was to test the accuracy of an EMR-based, automated sepsis identification system. Methods. We tested an EMR-based sepsis identification tool at a major academic, urban ED with 64,000 annual visits. The EMR system collected vital sign and laboratory test information on all ED patients, triggering a "sepsis alert" for those with ≥2 SIRS (systemic inflammatory response syndrome) criteria (fever, tachycardia, tachypnea, leukocytosis) plus ≥1 major organ dysfunction (SBP ≤ 90 mm Hg, lactic acid ≥2.0 mg/dL). We confirmed the presence of sepsis through manual review of physician, nursing, and laboratory records. We also reviewed a random selection of ED cases that did not trigger a sepsis alert. We evaluated the diagnostic accuracy of the sepsis identification tool. Results. From January 1 through March 31, 2012, there were 795 automated sepsis alerts. We randomly selected 300 cases without a sepsis alert from the same period. The true prevalence of sepsis was 355/795 (44.7%) among alerts and 0/300 (0%) among non-alerts. The positive predictive value of the sepsis alert was 44.7% (95% CI [41.2-48.2%]). Pneumonia and respiratory infections (38%) and urinary tract infection (32.7%) were the most common infections among the 355 patients with true sepsis (true positives). Among false-positive sepsis alerts, the most common medical conditions were gastrointestinal (26.1%), traumatic (25.7%), and cardiovascular (20.0%) conditions. Rates of hospital admission were: true-positive sepsis alert 91.0%, false-positive alert 83.0%, no sepsis alert 5.7%. Conclusions. This ED EMR-based automated sepsis identification system was able to detect cases with sepsis. Automated EMR-based detection may provide a viable strategy for identifying sepsis in the ED.

Predictive factors of distal femoral fracture nonunion after lateral locked plating: a retrospective multicenter case-control study of 283 fractures.

INTRODUCTION: Reported initial success rates after lateral locked plating (LLP) of distal femur fractures have led to more concerning outcomes with reported nonunion rates now ranging from 0 to 21%. Reported factors associated with nonunion include comorbidities such as obesity, age and diabetes. In this study, our goal was to identify patient comorbidities, injury and construct characteristics that are independent predictors of nonunion risk in LLP of distal femur fractures; and to develop a predictive algorithm of nonunion risk, irrespective of institutional criteria for clinical intervention variability. PATIENTS AND METHODS: A retrospective review of 283 distal femoral fractures in 278 consecutive patients treated with LLP at three Level1 academic trauma centers. Nonunion was liberally defined as need for secondary procedure to manage poor healing based on unrestricted surgeon criteria. Patient demographics (age, gender), comorbidities (obesity, smoking, diabetes, chronic steroid use, dialysis), injury characteristics (AO type, periprosthetic fracture, open fracture, infection), and management factors (institution, reason for intervention, time to intervention, plate length, screw density, and plate material) were obtained for all participants. Multivariable analysis was performed using logistic regression to control for confounding in order to identify independent risk factors for nonunion. RESULTS: 28 of the 283 fractures were treated for nonunion, 13 were referred to us from other institutions. Obesity (BMI>30), open fracture, occurrence of infection, and use of stainless steel plate were significant independent risk factors (P<0.01). A predictive algorithm demonstrates that when none of these variables are present (titanium instead of stainless steel) the risk of nonunion requiring intervention is 4%, but increases to 96% with all factors present. When a stainless plate is used, obesity alone carries a risk of 44% while infection alone a risk of 66%. While Chi-square testing suggested no institutional differences in nonunion rates, the time to intervention for nonunion varied inversely with nonunion rates between institutions, indicating varying trends in management approach. DISCUSSION: Obesity, open fracture, occurrence of infection, and the use of stainless steel are prognostic risk factors of nonunion in distal femoral fractures treated with LLP independent of differing trends in how surgeons intervene in the management of nonunion.

Short versus long cephalomedullary nails for the treatment of intertrochanteric hip fractures in patients older than 65 years.

OBJECTIVES: To compare failure rates between short and long cephalomedullary nails used for the treatment of intertrochanteric hip fractures in patients over 65 years of age. DESIGN: Retrospective cohort study. Data were collected from medical records and radiographs. SETTING: Three level 1 trauma centers. PATIENTS/PARTICIPANTS: Patients aged 65 years or older who underwent treatment of an intertrochanteric hip fracture with a cephalomedullary nail between January 2004 and December 2010. INTERVENTION: Open reduction and internal fixation of intertrochanteric hip fracture with either short or long cephalomedullary nail. MAIN OUTCOME MEASUREMENT: Postoperative treatment failure rate, defined as periprosthetic fracture or reoperation requiring removal or revision of nail, including conversion to arthroplasty. RESULTS: Incidence of treatment failure (periprosthetic fracture and reoperation requiring removal of nail) was 30 of 559 (5.4%) for the entire cohort; 13 of 219 (5.9%) occurred after placement of a short nail compared with 17 of 340 (5.0%) after placement of a long nail (P = 0.70). There were 11 of 559 (2.0%) patients who sustained a periprosthetic fracture after nailing, 6 of 219 (2.7%) after short nails and 5 of 340 (1.5%) after long nails (P = 0.35). The remaining 19 treatment failures were major reoperations requiring removal of nail, 7 of 219 (3.2%) after short nails and 12 of 340 (3.5%) after long nails (P = 0.81). The reasons for these 19 revision procedures were: screw/helical blade cutout (16), progressive arthritis with conversion to arthroplasty (1), avascular necrosis of femoral head with conversion to arthroplasty (1), and symptomatic leg length discrepancy with conversion to arthroplasty (1). Median follow-up period for patients living at least 1 year postoperatively was 30 months (range, 12-85 months). Overall, 175 of 698 (25%) patients died within 1 year after index surgery. CONCLUSIONS: When using contemporary cephalomedullary implants, short and long nails exhibit similar treatment failure rates. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Transient osteoporosis of pregnancy.

Transient osteoporosis of pregnancy (TOP) is a rare yet perhaps under-reported condition that has affected otherwise healthy pregnancies throughout the world. The condition presents suddenly in the third trimester of a usually uneventful pregnancy and progressively immobilizes the mother. Radiographic studies detect drastic loss of bone mass, elevated rates of turnover in the bone, and oedema in the affected portion. Weakness of the bone can lead to fractures during delivery and other complications for the mother. Then, within weeks of labour, symptoms and radiological findings resolve. Aetiology is currently unknown, although neural, vascular, haematological, endocrine, nutrient-deficiency, and other etiologies have been proposed. Several treatments have also been explored, including simple bed rest, steroids, bisphosphonates, calcitonin, induced termination of pregnancy, and surgical intervention. The orthopedist plays an essential role in monitoring the condition (and potential complications) as well as ensuring satisfactory outcomes for both the mother and newborn.