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Study objective The transfusion of older packed RBCs may be harmful in critically ill patients. We seek to determine the association between packed RBC age and mortality among trauma patients requiring massive packed RBC transfusion. Methods We analyzed data from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. Subjects in the parent trial included critically injured adult patients admitted to 1 of 12 North American Level I trauma centers who received at least 1 unit of packed RBCs and were predicted to require massive blood transfusion. The primary exposure was volume of packed RBC units transfused during the first 24 hours of hospitalization, stratified by packed RBC age category: 0 to 7 days, 8 to 14 days, 15 to 21 days, and greater than or equal to 22 days. The primary outcome was 24-hour mortality. We evaluated the association between transfused volume of each packed RBC age category and 24-hour survival, using random-effects logistic regression, adjusting for total packed RBC volume, patient age, sex, race, mechanism of injury, Injury Severity Score, Revised Trauma Score, clinical site, and trial treatment group. Results The 678 patients included in the analysis received a total of 8,830 packed RBC units. One hundred patients (14.8%) died within the first 24 hours. On multivariable analysis, the number of packed RBCs greater than or equal to 22 days old was independently associated with increased 24-hour mortality (adjusted odds ratio [OR] 1.05 per packed RBC unit; 95% confidence interval [CI] 1.01 to 1.08): OR 0.97 for 0 to 7 days old (95% CI 0.88 to 1.08), OR 1.04 for 8 to 14 days old (95% CI 0.99 to 1.09), and OR 1.02 for 15 to 21 days old (95% CI 0.98 to 1.06). Results of sensitivity analyses were similar only among patients who received greater than or equal to 10 packed RBC units. Conclusion Increasing quantities of older packed RBCs are associated with increased likelihood of 24-hour mortality in trauma patients receiving massive packed RBC transfusion (≥10 units), but not in those who receive fewer than 10 units.

Glutaredoxin 2 (GRX2), a mitochondrial glutathione-dependent oxidoreductase, is central to glutathione homeostasis and mitochondrial redox, which is crucial in highly metabolic tissues like the heart. Previous research showed that absence of Grx2, leads to impaired mitochondrial complex I function, hypertension and cardiac hypertrophy in mice but the impact on mitochondrial structure and function in intact cardiomyocytes and in humans has not been explored. We hypothesized that Grx2 controls cardiac mitochondrial dynamics and function in cellular and mouse models, and that low expression is associated with human cardiac dysfunction. Here we show that Grx2 absence impairs mitochondrial fusion, ultrastructure and energetics in primary cardiomyocytes and cardiac tissue. Moreover, provision of the glutathione precursor, N-acetylcysteine (NAC) to Grx2-/- mice did not restore glutathione redox or prevent impairments. Using genetic and histopathological data from the human Genotype-Tissue Expression consortium we demonstrate that low GRX2 is associated with fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, GRX2 is important in the control of cardiac mitochondrial structure and function, and protects against human cardiac pathologies., Graphical abstract fx1

With no approved pharmacological treatment, nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in Western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here, we show that a high‐fat high‐sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic nicotinamide adenine dinucleotide (NAD+) levels driving reductions in hepatic mitochondrial content, function, and adenosine triphosphate (ATP) levels, in conjunction with robust increases in hepatic weight, lipid content, and peroxidation in C57BL/6J mice. To assess the effect of NAD+ repletion on the development of steatosis in mice, nicotinamide riboside, a precursor of NAD+ biosynthesis, was added to the HFHS diet, either as a preventive strategy or as a therapeutic intervention. We demonstrate that NR prevents and reverts NAFLD by inducing a sirtuin (SIRT)1‐ and SIRT3‐dependent mitochondrial unfolded protein response, triggering an adaptive mitohormetic pathway to increase hepatic β‐oxidation and mitochondrial complex content and activity. The cell‐autonomous beneficial component of NR treatment was revealed in liver‐specific Sirt1 knockout mice (Sirt1hep−/−), whereas apolipoprotein E‐deficient mice (Apoe −/−) challenged with a high‐fat high‐cholesterol diet affirmed the use of NR in other independent models of NAFLD. Conclusion: Our data warrant the future evaluation of NAD+ boosting strategies to manage the development or progression of NAFLD. (Hepatology 2016;63:1190–1204)

New findings What is the central question of this study? Does exercise, independent of random error and within-subject variability, contribute to the variability in gene expression responses to an acute bout of resistance exercise? What is the main finding and its importance? A reanalysis of publicly available microarray data revealed that variability in observed gene expression responses for a subset of genes could be partially attributable to an effect of acute resistance exercise. These finding support the notion that individual responsiveness explains a portion of the variability in observed gene expression responses to acute resistance exercise. Abstract The purpose of this study was to use publicly available transcriptomic data to determine whether variability in gene expression responses to an acute bout of acute resistance exercise (ARE) can be attributable to an effect of ARE per se. We examined microarray data from a previous study that collected skeletal muscle biopsies before and 24 h after ARE or a no-exercise time-matched control period (CTL). By subtracting the standard deviation in the observed responses to CTL from ARE, we determined that ARE contributed to the variability in the observed gene expression responses for many (∼31,000), but not all, transcripts included on the Affymetrix Human Genome chips. ARE had a large effect on variability in the observed gene expression responses in 1290 genes that was not attributed to any technical/biological variability associated with repeated measurements. Pathway analysis using WebGestalt revealed that several of these 1290 genes are involved in pathways known to regulate skeletal muscle adaptations to chronic resistance training. These results suggest that variability in the observed gene expression responses for a subset of genes could be partially attributable to an effect of ARE.

Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis.We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a value of p0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites.We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL [IQR 67 to 336 ng/dL] in those who did (p0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, Injury Severity Score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis.Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis.

BACKGROUND: The classic definition of massive transfusion, 10 or more units of red blood cells (RBCs) in 24 hours, has never been demonstrated as a valid surrogate for severe hemorrhage and can introduce survival bias. In addition, the definition fails to capture other products that the clinician may have immediately available, and may use, during the initial resuscitation. Assuming that units of resuscitative fluids reflect patient illness, our objective was to identify a rate of resuscitation intensity (RI) that could serve as an early surrogate of sickness for patients with substantial bleeding after injury. METHODS: Adult patients surviving at least 30 minutes after admission and receiving one or more RBCs within 6 hours of admission from 10 US Level 1 trauma centers were enrolled in the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Total fluid units were calculated as the sum of the number of crystalloid units (1 L = 1 U), colloids (0.5 L = 1 U), and blood products (1 RBC = 1 U, 1 plasma = 1 U, 6 pack platelets = 1 U). Univariable and multivariable logistic regressions were used to evaluate associations between RI and 6-hour mortality, adjusting for age, center, penetrating injury, weighted Revised Trauma Score (RTS), and Injury Severity Score (ISS). RESULTS: A total of 1,096 eligible patients received resuscitative fluids within 30 minutes, including 620 transfused with blood products. Despite varying products used, the total fluid RI was similar across all sites (3.2T 2.5 U). Patients who received four or more units of any resuscitative fluid had a 6-hour mortality rate of 14.4% versus 4.5% in patients who received less than 4 U. The adjusted odds ratio of 6-hour mortality for patients receiving 4 U or more within 30 minutes was 2.1 (95% confidence interval, 1.2Y3.5). CONCLUSION: Resuscitation with four or more units of any fluid was significantly associated with 6-hour mortality. This study suggests that early RI regardless of fluid type can be used as a surrogate for sickness and mortality in severely bleeding patients. ( JT rauma Acute Care Surg. 2013;74: S16YS23. Copyright * 2013 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III.

Hypertonic saline (HS) has been investigated as an immune modulator following hemorrhagic shock and sepsis. The polymorphonuclear neutrophil (PMN) response to HS is regulated by the release of ATP, which is converted to adenosine and activates adenosine receptors. Binding to A3 adenosine receptors promotes PMN activation, and inhibition of A3 receptors improves the efficacy of HS resuscitation. A3 receptor expression of PMNs has not been previously evaluated in injured patients. Whole blood was obtained from 10 healthy volunteers and 60 injured patients within 2 h of injury. Inclusion criteria were blunt or penetrating injury with evidence of hypovolemic shock (systolic blood pressure [SBP] ≤90 mmHg and base deficit ≥6 mEq/L or need for blood transfusion) or evidence of severe traumatic brain injury including initial Glasgow Coma Scale score of 8 or less or evidence of traumatic brain injury on head computed tomography scan (head Abbreviated Injury Score ≥3) or intubation in the field or emergency department. A3 receptor expression was assessed by flow cytometry. Polymorphonuclear neutrophils were also exposed to fMLP or HS (20-40 mM) in vitro. Clinical data were collected including admission physiology, injury severity (Injury Severity Score [ISS]), development of multiple organ failure, and survival. In normal volunteers, less than 1% of PMNs expressed A3 receptors on the cell surface. A3 receptor expression was significantly higher in injured patients, and the level of expression correlated with the severity of injury (ISS ≥25: A3 positive PMN 36.6% vs. ISS25: 16.2%; P = 0.019) and degree of hypovolemic shock (SBP ≤90 mmHg: A3 positive PMN 43.8% vs. SBP90 mmHg: 20.6%; P = 0.008). Stimulation with fMLP or HS increased A3 expression in normal volunteers, but only in patients with ISS of less than 25 or without hypovolemic shock. A3 receptor expression on the surface of PMNs is upregulated by injury, and increased expression levels are associated with greater injury severity and hypovolemic shock. Hypertonic saline increases A3 expression of PMNs from healthy volunteers and less severely injured patients.

We reported similar rates of ventilator-associated pneumonia (VAP) previously in trauma patients intubated either in a pre-hospital (PH) venue or the emergency department. A subset of PH intubations with continuous quality assessment was re-examined to identify the intubation factors associated with VAP.The subgroup was derived from an existing data set of consecutive adult trauma patients intubated prior to Level I trauma center admission July 2007-July 2008. Intubation details recorded included bag-valve mask ventilation (BVM) and the presence of material in the airway. The diagnosis of VAP was made preferentially by quantitative bronchoalveolar lavage (BAL) cultures (≥ 10⁴ colony-forming units indicating infection). Baseline data, injury characteristics, and circumstances of intubation of patients with and without VAP were compared by univariable analysis.Detailed data were available for 197 patients; 32 (16.2%) developed VAP, on average 6.0±0.7 days after admission. Baseline characteristics were similar in the groups, but diabetes mellitus was more common in the VAP group (4 [12.5%] vs. 5 [3.0%]; p=0.02). There was a higher rate of blunt injury in the VAP patients (28 [87.5%] vs. 106 [64.2%]; p=0.01) and higher injury severity scores (33.1±2.8 vs. 23.0±1.0; p=0.0002) and chest Abbreviated Injury Scores (2.6±0.3 vs. 1.5±0.1; p=0.002). Lower Glasgow Coma Scale scores (7.9±0.9 vs. 9.9±0.4; p=0.04) and greater use of BVM (18 [56.3%] vs. 56 [34.0%]; p=0.02) were observed in patients who developed VAP. Among aspirations, 10 (31.3%) of patients with emesis developed VAP compared with only 4 (12.5%) with blood in the airway (p=0.003).Aspiration, along with depressed consciousness and greater injury severity, may predispose trauma patients to VAP. Prospective studies should focus on the quality and timing of aspiration relative to intubation to determine if novel interventions can prevent aspiration or decrease the risk of VAP after aspiration.

Pressure ulcers are estimated to be present in more than one-third of patients with spinal cord injury. The rate of recurrence after flap surgery over last 50 years has ranged between 3 and 82 percent, with no trend toward improvement. This study seeks to identify and evaluate patient and operative characteristics associated with flap dehiscence and ulcer recurrence.A retrospective chart review of all patients who underwent pressure ulcer flap coverage between 1993 and 2008 was performed. Thirty-one demographic and operative variables were collected. Multivariate logistic regression with generalized estimating equation was used to evaluate the effect of significant variables. The primary outcome was recurrence of pressure ulcer at the operative site. Secondary outcomes included flap line dehiscence and the need for operative revision.There were 88 recurrences of pressure ulcers after flap surgery (39 percent) of 227 operations performed on 135 patients. Thirty-six flaps (16 percent) had dehiscences necessitating return to the operating room. Hemoglobin A1c less than 6 percent and previous same-site flap failure were associated with both dehiscence and recurrence (odds ratios, 2.15 and 3.84; and odds ratios, 6.51 and 3.27). Younger age and albumin less than 3.5 were associated with early flap failure (odds ratios, 5.95 and 2.45). Ischial wound location correlated with late recurrence (odds ratio, 4.01). Patients with multiple risk factors had operative success rates that approached zero.Confirmation of adequate nutritional status and strict preoperative management of blood glucose may improve operative success rates. The authors propose that operative management should be approached with trepidation, if at all, in young patients with recurrent ischial ulcers.

Cardiac muscle undergoes significant remodeling with aging. This may be partly due to the progressive impairment of mitochondrial biogenesis and function. Our purpose was to examine how aging affects the subcellular localization of apoptogenic factors involved in mitochondrially mediated cell death in cardiac muscle. Employing 6- and 36-month-old Fischer 344xBN animals, we assessed markers of organelle content and function, as well as the mitochondrial and cytosolic compartmentalization of proteins implicated in apoptosis. Aging was associated with decrements in cardiac mitochondrial content and respiratory function. These changes were accompanied by a greater cytosolic accumulation of cytochrome c and AIF, as well as a higher mitochondrial Bax and a faster rate of permeability transition pore opening. Mitochondria from aged hearts demonstrated a greater enrichment of p66Shc and p46Shc providing further evidence of enhanced apoptogenic signaling. Opa1 was greater in the senescent myocardium, while Drp1 was higher in the mitochondrial fraction of aged, compared to the young animals. Furthermore, the level of fragmented DNA was greater in the hearts of senescent animals. Thus, the specific compartmentalization of apoptogenic proteins implies that mitochondrially mediated cell death signaling is highly active in the aged myocardium, which may contribute to progressive cardiac pathophysiology.

The role of prehospital endotracheal intubation (ETI) remains controversial, with significant national variability in practice. The purpose of this project was to evaluate ETI management in a system of advanced life support (ALS) providers experienced in ETI and other advanced airway techniques, and describe management and outcomes of patients with a "difficult airway." Data were collected prospectively for all ETIs performed by the fire department over a 4-year period (2001-2005), and included demographics, number of laryngoscopy attempts, airway procedures, complications, and outcomes. Of 80,501 ALS patient contacts, 4091 (5.1%) underwent attempted oral ETI, with a 96.8% success rate in four or fewer attempts. The difficult airway cohort included 130 patients (3.2%), whose airway management consisted of oral ETI after more than four attempts (46%), bag-valve-mask ventilation (33%), cricothyroidotomy (8%), retrograde ETI (5%), and digital ETI (1%). Procedural success rates ranged from 14% (digital ETI) to 91% (cricothyroidotomy). Nine patients (7%) had failed airway management, of whom 5 were found in cardiac arrest. The two most common reasons subjectively reported by ALS providers for airway difficulty were anterior trachea (39%) and small mouth (30%). Overall mortality for the difficult airway cohort was 44%. Prehospital ETI can be performed with a high success rate by experienced ALS providers, but may still require advanced airway techniques in a small subset of patients. Patient anatomy is a primary factor in failed ETI. Among the advanced procedures, cricothyroidotomy had the highest success rate and should not be delayed by other interventions.

An arterial CO2 (Paco2) of 30 mm Hg to 39 mm Hg has been shown to be the ideal target range for early ventilation in trauma patients; however, this requires serial arterial blood gases. The use of end-tidal capnography (EtCO2) has been recommended as a surrogate measure of ventilation in the prehospital arena. This is based on the observation of close EtCO2 Pa(CO2) correlation in healthy patients, yet trauma patients frequently suffer from impaired pulmonary ventilation/perfusion. Thus, we hypothesize that EtCO2 will demonstrate a poor reflection of actual ventilation status after severe injury.Prospective observational study on consecutive intubated trauma patients treated in our emergency department (ED) during 9 months. Arterial blood gas values and concomitant EtCO2 levels were recorded. Regression was used to determine the strength of correlation among all trauma patients and subgroups based on injury severity (Abbreviated Injury Score and Injury Severity Score) and physiologic markers of perfusion status (lactate, shock index, and arterial base deficit).During 9 months, 180 patients were evaluated. The EtCO2 Paco2 correlation was poor at R2 = 0.277. Patients ventilated in the recommended EtCO2 (range, 35 to 40) were likely to be under ventilated (Pa(CO2)40 mm Hg) 80% of the time, and severely under ventilated (Pa(CO2)50 mm Hg) 30% of the time. Correlation was best for patients with isolated traumatic brain injury and worst for those with evidence of poor tissue perfusion.EtCO2 has low correlation with Pa(CO2), and therefore should not be used to guide ventilation in intubated trauma patients in the ED. Better strategies for guiding prehospital and ED ventilation are needed.

Background Damage-control laparotomy has become increasingly common after operative resuscitation of severe hemorrhagic shock after injury. Despite increased use, uncertainty exists about the safety and timing of enteral nutrition. The purpose of this study was to determine the safety and effect of immediate enteral nutrition. Study Design Data were obtained from a multicenter prospective cohort study evaluating clinical outcomes in adults with hemorrhagic shock after injury and were limited to patients with an open abdomen and no hollow viscus injury. The immediate enteral nutrition cohort was defined as initiation of enteral feeds within 36 hours after acute resuscitation completion. Multivariate stepwise logistic regression was used to evaluate factors associated with immediate enteral nutrition. Results One hundred subjects met inclusion criteria; 32 immediate enteral nutrition and 68 nonimmediate enteral nutrition. Nearly all patients underwent fascial closure (93.8% immediate enteral nutrition versus 94.1% nonimmediate enteral nutrition), with an average closure day of 6.47 ± 0.83 with immediate enteral nutrition and 8.55 ± 0.85 with nonimmediate enteral nutrition (p = 0.129). No significant difference in multiorgan dyfunction syndrome, length of ventilator days, ICU days, hospital days, or mortality was seen between groups. The rate of pneumonia was significantly different: 14 (43.8%) in immediate enteral nutrition and 49 (72.1%) in nonimmediate enteral nutrition (p = 0.008). Immediate enteral nutrition remained independently associated with a reduction in pneumonia within our stepwise regression (odds ratio=0.32; 95% CI, 0.13 to 0.79). Conclusions Immediate enteral nutrition after damage control appears safe, with no effect on abdominal closure rate. In addition, the reduction in pneumonia associated with immediate enteral nutrition suggests a tangible benefit. Immediate enteral nutrition should be considered in patients with open abdomens after severe trauma.

Little is known about the dermoscopic features of scalp tumours. Objective To determine the dermoscopic features of scalp tumours. METHODS: Retrospective analysis of dermoscopic images of histopathologically diagnosed scalp tumours from International Dermoscopy Society members. RESULTS: A total of 323 tumours of the scalp from 315 patients (mean age: 52 years; range 3-88 years) were analysed. Scalp nevi were significantly associated with young age (65 years and sun damage. Atypical network and regression were predictive for thin (≤1 mm) melanomas, whereas advanced melanomas (tumour thickness > 1 mm) revealed blue white veil, unspecific patterns and irregular black blotches or dots. CONCLUSIONS: The data collected provide a new knowledge regarding the clinical and dermoscopy features of pigmented scalp tumours

Item does not contain fulltext We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.

BACKGROUND: Prediction of outcome after injury is fraught with uncertainty and statistically beset by misspecified models. Single-time point regression only gives prediction and inference at one time, of dubious value for continuous prediction of ongoing bleeding. New statistical machine learning techniques such as SuperLearner (SL) exist to make superior prediction at iterative time points while evaluating the changing relative importance of each measured variable on an outcome. This then can provide continuously changing prediction of outcome and evaluation of which clinical variables likely drive a particular outcome. METHODS: PROMMTT data were evaluated using both naive (standard stepwise logistic regression) and SL techniques to develop a time-dependent prediction of future mortality within discrete time intervals. We avoided both underfitting and overfitting using cross validation to select an optimal combination of predictors among candidate predictors/machine learning algorithms. SL was also used to produce interval-specific robust measures of variable importance measures (VIM resulting in an ordered list of variables, by time point) that have the strongest impact on future mortality. RESULTS: Nine hundred eighty patients had complete clinical and outcome data and were included in the analysis. The prediction of ongoing transfusion with SL was superior to the naive approach for all time intervals (correlations of cross-validated predictions with the outcome were 0.819, 0.789, 0.792 for time intervals 30-90, 90-180, 180-360, >360 minutes). The estimated VIM of mortality also changed significantly at each time point. CONCLUSION: The SL technique for prediction of outcome from a complex dynamic multivariate data set is superior at each time interval to standard models. In addition, the SLVIM at each time point provides insight into the time-specific drivers of future outcome, patient trajectory, and targets for clinical intervention. Thus, this automated approach mimics clinical practice, changing form and content through time to optimize the accuracy of the prognosis based on the evolving trajectory of the patient. (Copyright (C) 2013 by Lippincott Williams & Wilkins)

Acute traumatic coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity, and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma.Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data.There were 1,198 patients with laboratory results, of whom 41.6% were coagulopathic. Using international normalized ratio of 1.3 or greater, 41.6% of patients (448) were coagulopathic, while 20.5% (214) were coagulopathic using partial thromboplastin time of 35 or greater. Coagulopathy was primarily associated with a combination of an Injury Severity Score (ISS) of greater than 15 and a base deficit (BD) of less than -6 (p0.05). Regression modeling for international normalized ratio-based coagulopathy shows that prehospital crystalloid (odds ratio [OR], 1.05), ISS (OR, 1.03), Glasgow Coma Scale (GCS) score (OR, 0.93), heart rate (OR, 1.08), systolic blood pressure (OR, 0.96), BD (OR, 0.92), and temperature (OR, 0.84) were significant predictors of coagulopathy (all p0.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all p0.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p0.04). Similar results were found for partial thromboplastin time-defined coagulopathy.ATC is associated with the depletion of factors I, II, V, VII, VIII, IX, and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of ATC and the effects of resuscitation can guide factor-guided resuscitation and correction of coagulopathy after injury.

BACKGROUND: Because randomized clinical trials in trauma outcomes research are expensive and complex, they have rarely been the basis for the clinical care of trauma patients. Most published findings are derived from retrospective and occasionally prospective observational studies that may be particularly susceptible to bias. The sources of bias include some common to other clinical domains, such as heterogeneous patient populations with competing and interdependent short- and long-term outcomes. Other sources of bias are unique to trauma, such as rapidly changing multisystem responses to injury that necessitate highly dynamic treatment regimens such as blood product transfusion. The standard research design and analysis strategies applied in published observational studies are often inadequate to address these biases. METHODS: Drawing on recent experience in the design, data collection, monitoring, and analysis of the 10-site observational PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, 7 common and sometimes overlapping biases are described through examples and resolution strategies. RESULTS: Sources of bias in trauma research include ignoring (1) variation in patients' indications for treatment (indication bias), (2) the dependency of intervention delivery on patient survival (survival bias), (3) time-varying treatment, (4) time-dependent confounding, (5) nonuniform intervention effects over time, (6) nonrandom missing data mechanisms, and (7) imperfectly defined variables. This list is not exhaustive. CONCLUSION: The mitigation strategies to overcome these threats to validity require epidemiologic and statistical vigilance. Minimizing the highlighted types of bias in trauma research will facilitate clinical translation of more accurate and reproducible findings and improve the evidence-base that clinicians apply in their care of injured patients. Language: en

Cardiolipin (CL) is a phospholipid that maintains the integrity of mitochondrial membranes. We previously demonstrated that CL content increases with chronic muscle use, and decreases with denervation-induced disuse. To investigate the underlying mechanisms, we measured the mRNA expression of 1) CL synthesis enzymes cardiolipin synthase (CLS) and CTP:PA-cytidylyltransferase-1 (CDS-1); 2) remodeling enzymes tafazzin and acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1); and 3) outer membrane CL enzymes, mitochondrial phospholipase D and phospholipid scramblase 3 (Plscr3), during chronic contractile activity (CCA)-induced mitochondrial biogenesis and denervation. With CCA, CDS-1 expression increased by 128%, parelleling CL levels. Surprisingly, denervation also led to large increases in CDS-1 and CLS, despite a decrease in mitochondria, possibly due to a compensatory mechanism to restore lost CL. ALCAT1 decreased by 32% with CCA, but increased by 290% following denervation, indicating that both CCA and denervation alter CL remodeling. CCA and denervation also elicited 60–90% increases in Plscr3, likely to facilitate CL movement to the outer membrane. The expression of these genes was not affected by aging, but changes due to CCA and denervation were attenuated compared with young animals. The absence of PPARγ coactivator-1α in knockout animals led to a decrease in CDS-1 and an increase in ALCAT1 mRNA levels, implicating PGC-1α in regulating both CL synthesis and remodeling. These data suggest that chronic muscle use and disuse modify the expression of mRNAs encoding CL metabolism enzymes. Our data also illustrate, for the first time, that PPARγ coactivator-1α regulates the CL metabolism pathway in muscle.

BACKGROUND: Nonphysician advanced life support (ALS) providers often perform tracheal intubation (TI) for cardiac arrest or other life-threatening indications in the prehospital setting, where airway assessment and airway management tools are limited. However, the frequency of difficult TI in obese patients in this setting is unclear. In this study we determined factors associated with TI success, and determined TI difficulty as a function of body mass index (BMI) in a system of ALS providers experienced in TI, to guide future prehospital education efforts. METHODS: A retrospective review was performed of all patients ≥15 years of age who underwent prehospital TI by paramedics in the Seattle Medic One system over a 4-year period, and were transported to the regional level 1 trauma center (Harborview Medical Center). Data were abstracted from a prospectively collected prehospital airway management database and from the hospital medical records, including demographic information, number of TI attempts, TI success or failure, and body weight/height (BMI). Descriptive statistics and multivariable logistic regression were calculated, with the primary end point being difficult TI (defined as ≥4 TI attempts or the need to use an alternative airway management technique). RESULTS: Of 80,501 patient contacts in whom 4114 TIs were attempted during the 4-year study period, 823 met study entry criteria (including a calculable BMI). The overall TI success rate in the study population was 98.5% (811 out of 823), with 6.8% (56 out of 823) meeting the predetermined definition for difficult TI. There was no significant association between difficult TI and patient age, gender, use of succinylcholine, or medical diagnosis (trauma vs. nontrauma). In comparison with the lean patient subgroup (BMI 40 kg/m 2 ) had a significant association with difficult TI (odds ratio 3.68; confidence interval [CI] 1.27-10.59), whereas those with class I/II obesity (BMI ≥30 kg/m 2 and

International audience; Sirt1 is a NAD(+)-dependent histone deacetylase that interacts with the regulatory protein of mitochondrial biogenesis PGC-1 alpha and is sensitive to metabolic alterations. We assessed whether a strict relationship between the expression of Sirt1, mitochondrial proteins, and PGC-1 alpha existed across tissues possessing a wide range of oxidative capabilities, as well as in skeletal muscle subject to chronic use (voluntary wheel running or electrical stimulation for 7 days, 10 Hz; 3 h/day) or disuse (denervation for up to 21 days) in which organelle biogenesis is altered. PGC-1 alpha levels were not closely associated with the expression of Sirt1, measured using immunoblotting or via enzymatic deacetylase activity. The mitochondrial protein cytochrome c increased by 70-90% in soleus and plantaris muscles of running animals, whereas Sirt1 activity remained unchanged. In chronically stimulated muscle, cytochrome c was increased by 30% compared with nonstimulated muscle, whereas Sirt1 activity was increased modestly by 20-25%. In contrast, in denervated muscle, these markers of mitochondrial content were decreased by 30-50% compared with the control muscle, whereas Sirt1 activity was increased by 75-80%. Our data suggest that Sirt1 and PGC-1 alpha expression are independently regulated and that, although Sirt1 activity may be involved in mitochondrial biogenesis, its expression is not closely correlated to changes in mitochondrial proteins during conditions of chronic muscle use and disuse.

Background: Etomidate is an induction agent used for the rapid sequence intubation (RSI) of trauma patients because of its favorable hemodynamic profile and rapid onset. However, recent studies have shown etomidate to decrease circulating cortisol concentrations, potentially influencing inflammation. We hypothesized that etomidate may alter the occurrence of acute respiratory distress syndrome (ARDS) in injury victims. Methods: We analyzed data collected prospectively from a clinical trial of prehospital hypertonic saline administration. Post hoc, patients were grouped according to whether they did or did not receive etomidate for prehospital airway management. The incidence of ARDS was compared between the two groups by Fisher's exact test. Logistic regression was used to adjust for the effects of other known risk factors for ARDS. Results: Over a 2-year period, 94 study patients underwent RSI, of which 35 received etomidate (37%). There were no significant differences in demographic, physiology, anatomic injury scores, or use of hypertonic saline resuscitation between the groups. After adjusting for physiology, injury severity, and transfusion, etomidate use remained associated with ARDS (aOR = 3.9, 95% CI = 1.24―12.0). Conclusion: Single-dose etomidate for RSI in severely injured trauma patients is associated with increased ARDS and multiple organ dysfunction syndrome, in part, because of an effect of etomidate on the inflammatory response.

Background The leading cause of late mortality after trauma is multiple organ failure syndrome, due to a dysfunctional inflammatory response early after injury. Preclinical studies demonstrate that hypertonicity alters the activation of inflammatory cells, leading to reduction in organ injury. The purpose of this study was to evaluate the effect of hypertonicity on organ injury after blunt trauma. Design Double-blind, randomized controlled trial from October 1, 2003, to August 31, 2005. Setting Prehospital enrollment at a single level I trauma center. Patients Patients older than 17 years with blunt trauma and prehospital hypotension (systolic blood pressure, ≤ 90 mm Hg). Interventions Treatment with 250 mL of 7.5% hypertonic saline and 6% dextran 70 (HSD) vs lactated Ringer solution (LRS). Main Outcome Measures The primary end point was survival without acute respiratory distress syndrome (ARDS) at 28 days. Cox proportional hazards regression was used to adjust for confounding factors. A preplanned subset analysis was performed for patients requiring 10 U or more of packed red blood cells in the first 24 hours. Results A total of 209 patients were enrolled (110 in the HSD group and 99 in the LRS group). The study was stopped for futility after the second interim analysis. Intent-to-treat analysis demonstrated no significant difference in ARDS-free survival (hazard ratio, 1.01; 95% confidence interval, 0.63-1.60). There was improved ARDS-free survival in the subset (19% of the population) requiring 10 U or more of packed red blood cells (hazard ratio, 2.18; 95% confidence interval, 1.09-4.36). Conclusions Although no significant difference in ARDS-free survival was demonstrated overall, there was benefit in the subgroup of patients requiring 10 U or more of packed red blood cells in the first 24 hours. Massive transfusion may be a better predictor of ARDS than prehospital hypotension. The use of HSD may offer maximum benefit in patients at highest risk of ARDS. Trial Registration clinicaltrials.gov Identifier:NCT00113685

International audience; During aging, skeletal muscle undergoes sarcopenia, a condition characterized by a loss of muscle cell mass and alterations in contractile function. The origin of these decrements is unknown, but evidence suggests that they can be partly attributed to mitochondrial dysfunction. To characterize the nature of this dysfunction, we investigated skeletal muscle contractile properties, subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial biogenesis and function, as well as apoptotic susceptibility in young (6 months old) and senescent (36 months old) Fischer 344 Brown Norway rats. Muscle mass and maximal force production were significantly lower in the 36-month group, which is indicative of a sarcopenic phenotype. Furthermore, contractile activity in situ revealed greater fatigability in the 36-month compared to the 6-month animals. This decrement could be partially accounted for by a 30% lower mitochondrial content in fast-twitch muscle from 36-month animals, as well as lower protein levels of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha. Enzyme activities and glutamate-induced oxygen consumption rates in isolated SS and IMF mitochondria were similar between age groups. However, mitochondrial reactive oxygen species (ROS) production during state 3 respiration was similar to 1.7-fold greater in mitochondria isolated from 36-month compared to 6-month animals, and was accompanied by a 1.8-fold increase in the DNA repair enzyme 8-oxoguanine glycosylase 1 in fast-twitch muscle. Basal rates of release of cytochrome c and endonuclease G in SS mitochondria were 3.5- to 7-fold higher from senescent animals. These data suggest that the age-related sarcopenia and muscle fatigability are associated with enhanced ROS production, increased mitochondrial apoptotic susceptibility and reduced transcriptional drive for mitochondrial biogenesis.

Prehospital intubation has been challenged on the grounds that it predisposes to hyperventilation, which is detrimental after traumatic brain injury (TBI), and impairs venous return in patients with hypovolemia. We sought to determine the incidence of hyperventilation among a cohort of trauma patients undergoing prehospital intubation and the impact of ventilation on outcome after severe TBI.Data were prospectively collected for all intubated trauma patients transported directly from the field for a period of 14 months (n = 574). An arrival Pco230 mm Hg was termed severe hypocapnea and considered a marker of hyperventilation. Patients with a Pco245 mm Hg were considered severely hypercapneic. Targeted ventilation was defined as a Pco2 between 30 and 35 mm Hg based on the Brain Trauma Foundation guidelines.The rate of severe hypocapnea was 18% and women were more likely to be hyperventilated (p0.05). Patients with severe hypercapnia had higher Injury Severity Scores and were more likely hypotensive, hypoxic, and acidodic (p0.05). Patients in the targeted ventilation range were less likely to die than were those outside the range even after excluding the severe hypercapnea group (odds ratio, 0.57; 95% confidence interval, 0.33-0.99). This effect was even greater among patients with isolated TBI (odds ratio, 0.31; 95% confidence interval, 0.10-0.96).Targeted prehospital ventilation is associated with lower mortality after severe TBI.

The advent and incorporation of the air bag into motor vehicles has resulted in the mitigation of many head and truncal injuries in motor vehicle collisions. However, air bag deployment is not risk free. We present a case of sodium azide-induced laryngospasm after air bag deployment. An unrestrained male driver was in a moderate-speed motor vehicle collision with air bag deployment. Medics found him awake, gasping for air with stridorous respirations and guarding his neck. The patient had no external signs of trauma and was presumed to have tracheal injury. The patient was greeted by the Anesthesiology service, which intubated him using glidescope-assisted laryngoscopy. The patient was admitted for overnight observation and treatment of alkaline ocular injury and laryngospasm. Although air bags represent an important advance in automobile safety, their use is not without risk. Bruising and tracheal rupture secondary to air bag deployment have been reported in out-of-position occupants. Additionally, alkaline by-products from the combustion of sodium azide in air bags have been implicated in ocular injury and facial burns. Laryngospasm after sodium azide exposure presents another diagnostic challenge for providers. Therefore, it is incumbent to maintain vigilance in the physical examination and diagnosis of occult injuries after air bag deployment.

Apoptosis can be evoked by reactive oxygen species (ROS)-induced mitochondrial release of the proapoptotic factors cytochrome c and apoptosis-inducing factor (AIF). Because skeletal muscle is composed of two mitochondrial subfractions that reside in distinct subcellular regions, we investigated the apoptotic susceptibility of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. SS and IMF mitochondria exhibited a dose-dependent release of protein in response to H2O2(0, 25, 50, and 100 μM). However, IMF mitochondria were more sensitive to H2O2and released a 2.5-fold and 10-fold greater amount of cytochrome c and AIF, respectively, compared with SS mitochondria. This finding coincided with a 44% ( P < 0.05) greater rate of opening (maximum rate of absorbance decrease, Vmax) of the protein release channel, the mitochondrial permeability transition pore (mtPTP), in IMF mitochondria. IMF mitochondria also exhibited a 47% ( P < 0.05) and 60% (0.05 < P < 0.1) greater expression of the key mtPTP component voltage-dependent anion channel and cyclophilin D, respectively, along with a threefold greater cytochrome c content, but similar levels of AIF compared with SS mitochondria. Despite a lower susceptibility to H2O2-induced release, SS mitochondria possessed a 10-fold greater Bax-to-Bcl-2 ratio ( P < 0.05), a 2.7-fold greater rate of ROS production, and an approximately twofold greater membrane potential compared with IMF mitochondria. The expression of the antioxidant enzyme Mn2+-superoxide dismutase was similar between subfractions. Thus the divergent protein composition and function of the mtPTP between SS and IMF mitochondria contributes to a differential release of cytochrome c and AIF in response to ROS. Given the relatively high proportion of IMF mitochondria within a muscle fiber, this subfraction is likely most important in inducing apoptosis when presented with apoptotic stimuli, ultimately leading to myonuclear decay and muscle fiber atrophy.

In an emergency medical system with established rapid-sequence intubation protocols, prehospital (PH) intubation of patients with trauma is not associated with a higher rate of ventilator-associated pneumonia (VAP) than emergency department (ED) intubation.Retrospective observational cohort.Level I trauma center.Adult patients with trauma intubated in a PH or an ED setting from July 1, 2007, through July 31, 2008.Diagnosis of VAP by means of bronchoscopic alveolar lavage or clinical assessment when bronchoscopic alveolar lavage was impossible. Secondary outcomes included time to VAP, length of hospitalization, and in-hospital mortality.Of 572 patients, 412 (72.0%) underwent PH intubation. The ED group was older than the PH group (mean ages, 46.4 vs 39.1 years; P.001) and had a higher incidence of blunt injury (142 [88.8%] vs 322 [78.2%]; P = .002). The mean (SD) lowest recorded ED systolic blood pressure was lower in the ED group (102.8 [1.9] vs 111.4 [1.2] mm Hg; P.001), despite similar mean injury severity scores in both groups (27.2 [0.7] vs 27.0 [1.1]; P = .94). There was no difference in the mean rate of VAP (30 [18.8%] vs 71 [17.2%]; P = .66) or mean time to diagnosis (8.1 [1.2] vs 7.8 [1.0] days; P = .89). Logistic regression analysis identified history of drug abuse, lowest recorded ED systolic blood pressure, and injury severity score as 3 independent factors predictive of VAP.Prehospital intubation of patients with trauma is not associated with higher risk of VAP. Further investigation of intubation factors and the incidence and timing of aspiration is required to identify potentially modifiable factors to prevent VAP.

Background: Little is known about the dermoscopic features of keratinocyte skin cancer. Objective: We sought to determine the dermoscopic features of facial actinic keratosis (AK), intraepidermal carcinoma (IEC), moderately to poorly differentiated invasive squamous cell carcinoma (SCC), and well-differentiated SCC of the keratoacanthoma type. Methods: This was a retrospective analysis of dermoscopic images of histopathologically diagnosed keratinocyte skin cancer. Results: A total of 243 (70 AK, 71 IEC, 78 SCC, and 24 keratoacanthomas) tumors of the face from 243 patients (mean age: 71.1 years; range: 44-94 years) were analyzed. The majority of patients had a fair skin type, history of melanoma or nonmelanoma skin cancer, and multiple AK. A red pseudonetwork was significantly associated with AK (P < .001), whereas dotted/glomerular vessels, diffuse yellow opaque scales, and microerosions were significantly more prevalent among IEC (P < .001). Hairpin vessels, linear-irregular vessels, targetoid hair follicles, white structureless areas, a central mass of keratin, and ulceration were significantly associated with invasive SCC (P < .001 for all criteria). Similar patterns as in SCC were observed among keratoacanthomas. Limitations: The retrospective design of our study and the lack of assessment of sensitivity and specificity of the dermoscopic criteria are limitations. Conclusions: Based on our findings we propose a progression model of facial AK developing into IEC and invasive SCC. (J Am Acad Dermatol 2012;66:589-97.)