Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice

BACKGROUND: The posttraumatic response to traumatic brain injury (TBI) is characterized, in part, by activation of the innate immune response, including the complement system. We have recently shown that mice devoid of a functional alternative pathway of complement activation (factor B-/- mice) are protected from complement-mediated neuroinflammation and neuropathology after TBI. In the present study, we extrapolated this knowledge from studies in genetically engineered mice to a pharmacological approach using a monoclonal anti-factor B antibody. This neutralizing antibody represents a specific and potent inhibitor of the alternative complement pathway in mice. METHODS: A focal trauma was applied to the left hemisphere of C57BL/6 mice (n = 89) using a standardized electric weight-drop model. Animals were randomly assigned to two treatment groups: (1) Systemic injection of 1 mg monoclonal anti-factor B antibody (mAb 1379) in 400 μl phosphate-buffered saline (PBS) at 1 hour and 24 hours after trauma; (2) Systemic injection of vehicle only (400 μl PBS), as placebo control, at identical time-points after trauma. Sham-operated and untreated mice served as additional negative controls. Evaluation of neurological scores and analysis of brain tissue specimens and serum samples was performed at defined time-points for up to 1 week. Complement activation in serum was assessed by zymosan assay and by murine C5a ELISA. Brain samples were analyzed by immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) histochemistry, and real-time RT-PCR. RESULTS: The mAb 1379 leads to a significant inhibition of alternative pathway complement activity and to significantly attenuated C5a levels in serum, as compared to head-injured placebo-treated control mice. TBI induced histomorphological signs of neuroinflammation and neuronal apoptosis in the injured brain hemisphere of placebo-treated control mice for up to 7 days. In contrast, the systemic administration of an inhibitory anti-factor B antibody led to a substantial attenuation of cerebral tissue damage and neuronal cell death. In addition, the posttraumatic administration of the mAb 1379 induced a neuroprotective pattern of intracerebral gene expression. CONCLUSION: Inhibition of the alternative complement pathway by posttraumatic administration of a neutralizing anti-factor B antibody appears to represent a new promising avenue for pharmacological attenuation of the complement-mediated neuroinflammatory response after head injury

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Factors predicting secondary displacement after non-operative treatment of undisplaced femoral neck fractures

Introduction We quantified the risk and the time of occurrence of secondary fracture displacement in non-operatively treated femoral neck fractures in our clinic, as well as investigated potential predicting patient- and fracture-related factors. Methods The records of 593 patients with femoral neck fractures from January 2000 to December 2009 were reviewed. Sixty-one patients [mean age 83.0 years (SD 9.9)] with undisplaced femoral neck fractures initially received non-operative treatment. The occurrence and the time of secondary fracture displacement were documented, as well as demographics and radiological parameters. Radiographs were evaluated independently by two surgeons. Multivariable regression and Kaplan–Meier survival analyses were used. Results Thirty-four (55.7 %) fractures showed secondary displacement occurring within the first 12 weeks after initiation of non-operative treatment. Twenty (38 %) fractures originally classified as Garden I were found to be Garden II. The risk of secondary displacement was three times higher (RR = 2.8; 95 % CI 1.7–4.8, p < 0.001) for these fractures in comparison with those confirmed as Garden I. Patients with a history of previously diagnosed osteoporosis were at a higher risk of secondary displacement as well (RR = 1.3; 95 % CI 1.0–1.5). Conclusions Non-operative treatment of femoral neck fractures is a treatment option, but only in well-selected cases. The majority of secondary displacements were associated with initial misdiagnosis using the Garden classification. For Garden II, primary surgical treatment is likely a better option, and therefore careful application of the Garden classification in this context is essential

Factors predicting secondary displacement after non-operative treatment of undisplaced femoral neck fractures

Introduction: We quantified the risk and the time of occurrence of secondary fracture displacement in non-operatively treated femoral neck fractures in our clinic, as well as investigated potential predicting patient- and fracture-related factors. Methods: The records of 593 patients with femoral neck fractures from January 2000 to December 2009 were reviewed. Sixty-one patients [mean age 83.0years (SD 9.9)] with undisplaced femoral neck fractures initially received non-operative treatment. The occurrence and the time of secondary fracture displacement were documented, as well as demographics and radiological parameters. Radiographs were evaluated independently by two surgeons. Multivariable regression and Kaplan-Meier survival analyses were used. Results: Thirty-four (55.7%) fractures showed secondary displacement occurring within the first 12weeks after initiation of non-operative treatment. Twenty (38%) fractures originally classified as Garden I were found to be Garden II. The risk of secondary displacement was three times higher (RR=2.8; 95% CI 1.7-4.8, p<0.001) for these fractures in comparison with those confirmed as Garden I. Patients with a history of previously diagnosed osteoporosis were at a higher risk of secondary displacement as well (RR=1.3; 95% CI 1.0-1.5). Conclusions: Non-operative treatment of femoral neck fractures is a treatment option, but only in well-selected cases. The majority of secondary displacements were associated with initial misdiagnosis using the Garden classification. For Garden II, primary surgical treatment is likely a better option, and therefore careful application of the Garden classification in this context is essential

Prognostic value of blood glucose levels in diabetic patients upon admission and its outcomes in patients with acute coronary syndrome

Background: Coronary heart disease (CHD) is the main leading cause of morbidity and mortality in patients with diabetes mellitus. Hyperglycemia on admission was associated with a worse outcome for all patients admitted with ACS. Aim: To correlate the relationship between hyperglycemia with acute coronary syndrome and poor outcome. Methodology: Clinical evaluation of the patients were carried out on arrival to Emergency Department regarding: Initial assessment of patient general condition either stable or not through; ABCDE (air way and cervical spine control, breathing, circulation, neurological dysfunction and exposure). Then determine the characters and types of chest pain. Assess the condition of the patients either stable or unstable which will determine the needed investigations and plane of management. Results: the mortality was higher in patients with RBG more than 300 mg/dl (68.4 %), (10.5 %) of the patients had ranged from 250 ─ < 300 mg/dl, and the patients had ranged from 200 ─ < 250 mg/dl were (10.5 %). The patients had ranged from 160 ─ < 200 mg/dl were (5.3) and there were (5.3) of the patients had ranged from 70 ─ < 160mg/dl. Conclusions: The data from this study have shown that hyperglycemia on admission was associated with a worse outcome for all patients admitted with ACS

A single dose of tranexamic acid reduces blood loss after reverse and anatomic shoulder arthroplasty: a randomized controlled trial

Hematoma formation and the need for blood transfusions are commonly reported complications after shoulder arthroplasty. Tranexamic acid (TXA) has been widely used in hip and knee arthroplasty to decrease perioperative blood loss. The role of TXA is still being established in shoulder arthroplasty

A Biomechanical Comparison of Different Suture Materials Used for Arthroscopic Shoulder Procedures

PURPOSE: To evaluate the viscoelastic properties of 4 commercially available cord-like sutures and 2 commercially available suture tapes when subjected to physiological loads, as well as to compare them with each other and to identify the clinically most desirable combination of suture material properties. METHODS: Six suture materials (Ethibond, FiberWire, FiberTape, Orthocord, Ultrabraid, and Ultratape) underwent creep testing (n = 7, 60 N, 10 minutes) to determine specimen stiffness, initial elongation at 60 N of load, static creep (during 10 minutes of loading), and relaxed elongation (material recovery 3 minutes after removal of load). Furthermore, cyclic testing (n = 7, 10-45 N, 0.5 Hz, 500 cycles) was carried out to determine dynamic creep, peak-to-peak displacement, and relaxed elongation. Mechanical testing was conducted on a material testing machine in 37°C phosphate-buffered saline solution. RESULTS: FiberTape showed the greatest stiffness (23.9 ± 3.2 N/mm, P < .001), the smallest amounts of static (0.38 ± 0.10 mm, P < .001) and dynamic (0.16 ± 0.09 mm, P = .003) creep, and the smallest peak-to-peak displacement (0.20 ± 0.02 mm, P < .001). FiberTape and FiberWire showed the smallest initial elongation (1.17 ± 0.17 mm and 1.63 ± 0.25 mm, respectively; P < .001). Ultrabraid showed the greatest relaxed elongation, both statically (4.73 ± 0.73 mm, P < .001) and dynamically (4.18 ± 0.83 mm, P = .002). CONCLUSIONS: FiberTape consistently displayed less creep, greater stiffness, and less extensibility than the other suture types. Ultrabraid showed the largest amount of relaxed elongation on both static and dynamic testing. CLINICAL RELEVANCE: When considering high stiffness in combination with low initial extension and low static creep to be ideal parameters to achieve optimal initial construct stability and considering low dynamic creep in combination with low peak-to-peak displacement to be ideal conditions for the repetitive loading of the construct during the healing process, tapes seem to be superior to cord-like sutures for performing rotator cuff repair

Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation

<p>Abstract</p> <p>Background</p> <p>Neuroprotective strategies for prevention of the neuropathological sequelae of traumatic brain injury (TBI) have largely failed in translation to clinical treatment. Thus, there is a substantial need for further understanding the molecular mechanisms and pathways which lead to secondary neuronal cell death in the injured brain. The intracerebral activation of the complement cascade was shown to mediate inflammation and tissue destruction after TBI. However, the exact pathways of complement activation involved in the induction of posttraumatic neurodegeneration have not yet been assessed. In the present study, we investigated the role of the alternative complement activation pathway in contributing to neuronal cell death, based on a standardized TBI model in mice with targeted deletion of the factor B gene (<it>fB</it>-/-), a "key" component required for activation of the alternative complement pathway.</p> <p>Results</p> <p>After experimental TBI in wild-type (<it>fB</it>+/+) mice, there was a massive time-dependent systemic complement activation, as determined by enhanced C5a serum levels for up to 7 days. In contrast, the extent of systemic complement activation was significantly attenuated in <it>fB</it>-/- mice (<it>P </it>< 0.05,<it>fB</it>-/- <it>vs</it>. <it>fB</it>+/+; <it>t </it>= 4 h, 24 h, and 7 days after TBI). TUNEL histochemistry experiments revealed that posttraumatic neuronal cell death was clearly reduced for up to 7 days in the injured brain hemispheres of <it>fB</it>-/- mice, compared to <it>fB</it>+/+ littermates. Furthermore, a strong upregulation of the anti-apoptotic mediator Bcl-2 and downregulation of the pro-apoptotic Fas receptor was detected in brain homogenates of head-injured <it>fB</it>-/- vs. <it>fB</it>+/+ mice by Western blot analysis.</p> <p>Conclusion</p> <p>The alternative pathway of complement activation appears to play a more crucial role in the pathophysiology of TBI than previously appreciated. This notion is based on the findings of (<it>a</it>) the significant attenuation of overall complement activation in head-injured <it>fB</it>-/- mice, as determined by a reduction of serum C5a concentrations to constitutive levels in normal mice, and (<it>b</it>) by a dramatic reduction of TUNEL-positive neurons in conjunction with an upregulation of Bcl-2 and downregulation of the Fas receptor in head-injured <it>fB</it>-/- mice, compared to <it>fB</it>+/+ littermates. Pharmacological targeting of the alternative complement pathway during the "time-window of opportunity" after TBI may represent a promising new strategy to be pursued in future studies.</p