Introduction
Flail chest is considered a highly morbid condition with reported mortality ranging from 10 to 20%. It is often associated with other severe injuries, which may complicate management and ...interpretation of outcomes. The physiologic impact and prognosis of isolated flail chest injury is poorly defined.
Methods
This is a National Trauma Databank study. All patients from 1/2007 to 12/2014 admitted with flail chest were extracted. Patients with head or abdominal AIS ≥3, dead on arrival, or transferred, were excluded. Primary outcome was mortality; secondary outcomes were need for mechanical ventilation and pneumonia.
Results
Of the 1,047,519 patients with blunt chest injury, 14,718 (1.4%) patients presented with flail chest, and 8098 (0.77%) met inclusion criteria. The most commonly associated intrathoracic injuries were hemothorax (57.9%) and lung contusions (63.0%), while sternal fracture (8.8%) and cardiac contusion (2.5%) were less common. In total, 29.8% of patients required mechanical ventilation, and 11.2% developed pneumonia. Overall mortality was 5.6%. On multivariable analysis, age >65 and need for mechanical ventilation were independent risk factors for mortality (OR 6.02, 3.75, respectively,
p
< 0.001). Independent predictors for mechanical ventilation included cardiac or pulmonary contusion and sternal fractures (OR 3.78, 2.38, 2.29, respectively,
p
< 0.001). Need for mechanical ventilation was an independent predictor of pneumonia (OR 13.18,
p
< 0.001).
Conclusions
Mortality in isolated flail chest is much lower than previously reported. Fewer than 30% of patients require mechanical ventilation. Need for mechanical ventilation, however, is independently associated with mortality and pneumonia. Age >65 is an independent risk factor for adverse outcomes, and these patients may benefit by more aggressive monitoring and treatment.
Background For critically injured patients requiring a massive transfusion, the optimal plasma fibrinogen level is unknown. The purpose of this study was to examine the impact of the fibrinogen level ...on mortality. We hypothesized that decreasing fibrinogen levels are associated with worse outcomes. Study Design All patients undergoing a massive transfusion from January 2000 through December 2011 were retrospectively identified. Those with a fibrinogen level measured on admission to the surgical ICU were analyzed according to their fibrinogen level (normal ≥180 mg/dL, abnormal ≥101 to <180 mg/dL, and critical ≤100 mg/dL). Primary outcome was death. Multivariate analysis evaluated the impact of fibrinogen on survival. Results There were 260 patients who met inclusion criteria. Ninety-two patients had normal admission fibrinogen levels, 114 had abnormal levels, and 54 patients had critical levels. Patients with a critical fibrinogen level had significantly higher mortality at 24 hours compared with patients with abnormal (31.5% vs 5.3%; adj. p < 0.001) and normal fibrinogen levels (31.5% vs 4.3%; adjusted p < 0.001). Patients with a critical fibrinogen level had significantly higher in-hospital mortality compared with patients with abnormal (51.9% vs 25.4%; adjusted p = 0.013) and normal fibrinogen levels (51.9% vs 18.5%; adjusted p < 0.001). A critical fibrinogen level was the most important independent predictor of mortality (p = 0.012). Conclusions For patients undergoing a massive transfusion after injury, as the fibrinogen level increased, a stepwise improvement in survival was noted. A fibrinogen level ≤100 mg/dL was a strong independent risk factor for death. The impact of an aggressive fibrinogen replacement strategy using readily available products warrants further prospective evaluation.
Coupling of thiol and urea-type -NHC(double bond, length as m-dashX)NH2 (X = O or NH) groups is effective in promoting oxidative protein folding. In particular, a thiol compound coupled with a ...guanidyl (X = NH) group significantly accelerates the rates of folding processes and enhances the yields of native proteins.
Proteins have evolved by incorporating several structural units within a single polypeptide. As a result, multidomain proteins constitute a large fraction of all proteomes. Their domains often fold ...to their native structures individually and vectorially as each domain emerges from the ribosome or the protein translocation channel, leading to the decreased risk of interdomain misfolding. However, some multidomain proteins fold in the endoplasmic reticulum (ER) nonvectorially via intermediates with nonnative disulfide bonds, which were believed to be shuffled to native ones slowly after synthesis. Yet, the mechanism by which they fold nonvectorially remains unclear. Using two-dimensional (2D) gel electrophoresis and a conformation-specific antibody that recognizes a correctly folded domain, we show here that shuffling of nonnative disulfide bonds to native ones in the most N-terminal region of LDL receptor (LDLR) started at a specific timing during synthesis. Deletion analysis identified a region on LDLR that assisted with disulfide shuffling in the upstream domain, thereby promoting its cotranslational folding. Thus, a plasma membranebound multidomain protein has evolved a sequence that promotes the nonvectorial folding of its upstream domains. These findings demonstrate that nonvectorial folding of a multidomain protein in the ER of mammalian cells is more coordinated and elaborated than previously thought. Thus, our findings alter our current view of how a multidomain protein folds nonvectorially in the ER of living cells.
Abstract Introduction The Brain Trauma Foundation (BTF) recently updated recommendations for intracranial pressure (ICP) monitoring in severe traumatic brain injury (TBI). The effect of ICP ...monitoring on outcomes is controversial, and compliance with BTF guidelines is variable. The purpose of this study was to assess both compliance and outcomes at level I trauma centers. Materials and methods The American College of Surgeons Trauma Quality Improvement Program database was queried for all patients admitted to level I trauma centers with isolated blunt severe TBI (AIS > 3, GCS < 9) who met criteria for ICP monitoring. Patients who had severe extracranial injuries, craniectomy, or death in the first 24 hours were excluded. Comparison between groups with and without ICP monitoring was made, analysing demographics, comorbidities, mechanism of injury, head Abbreviated Injury Scale (AIS), vital signs on admission, head CT scan findings. Outcomes included in-hospital mortality, mechanical ventilation days, Intensive Care Unit (ICU) length of stay, hospital length of stay, systemic complications, and functional independence at discharge. Multivariable analysis was used to identify independent risk factors for each of the outcomes. Results Overall, 4880 patients were included. ICP monitoring was used in 529 patients (10.8%). Stepwise logistic regression analysis identified ICP monitor placement as an independent risk factor for mortality (OR 1.63; 95% CI, 1.1.28-2.07; p < 0.001), mechanical ventilation (OR 5.74 95% CI 4.42-7.46; p < 0.001), ICU length of stay (OR 4.03; 95% CI, 2.94-5.52; p < 0.001), systemic complications (OR 2.78; 95% CI, 2.29-3.37; p < 0.001), and decreased functional independence at discharge (OR 1.71 95% CI 1.29-2.26; p < 0.001). Subgroup analysis of patients with head AIS 3, 4, and 5 confirmed that ICP monitors remained an independent risk factor for mortality in both head AIS 4 and 5. Conclusions Compliance with BTF guidelines for ICP monitoring is low, even at level I trauma centers. In this study, ICP monitoring was associated with poor outcomes, and was found to be an independent risk factor for mortality. Further studies are needed to determine the optimal role of ICP monitoring in the management of severe TBI.
Many secretory enzymes acquire essential zinc ions (Zn
) in the Golgi complex. ERp44, a chaperone operating in the early secretory pathway, also binds Zn
to regulate its client binding and release ...for the control of protein traffic and homeostasis. Notably, three membrane transporter complexes, ZnT4, ZnT5/ZnT6 and ZnT7, import Zn
into the Golgi lumen in exchange with protons. To identify their specific roles, we here perform quantitative Zn
imaging using super-resolution microscopy and Zn
-probes targeted in specific Golgi subregions. Systematic ZnT-knockdowns reveal that ZnT4, ZnT5/ZnT6 and ZnT7 regulate labile Zn
concentration at the distal, medial, and proximal Golgi, respectively, consistent with their localization. Time-course imaging of cells undergoing synchronized secretory protein traffic and functional assays demonstrates that ZnT-mediated Zn
fluxes tune the localization, trafficking, and client-retrieval activity of ERp44. Altogether, this study provides deep mechanistic insights into how ZnTs control Zn
homeostasis and ERp44-mediated proteostasis along the early secretory pathway.
Background
Hypocalcemia is cited as a complication of massive transfusion. However, this is not well studied as a primary outcome in trauma patients. Our primary outcome was to determine if ...transfusion of packed red blood cells (pRBC) was an independent predictor of severe hypocalcemia (ionized calcium ≤ 3.6 mg/dL).
Methods
Retrospective, single-center study (01/2004–12/2014) including all trauma patients ≥ 18 yo presenting to the ED with an ionized calcium (iCa) level drawn. Variables extracted included demographics, interventions, outcomes, and iCa. Regression models identified independent risk factors for severe hypocalcemia (SH).
Results
Seven thousand four hundred and thirty-one included subjects, 716 (9.8%) developed SH within 48 h of admission. Median age: 39 (Range: 18–102), systolic blood pressure: 131 (IQR: 114–150), median Glasgow Coma Scale (GCS): 15 (IQR: 10–15), Injury Severity Score (ISS): 14 (IQR: 9–24). SH patients were more likely to have depressed GCS (13 vs 15,
p
< 0.0001), hypotension (23.2% vs 5.1%,
p
< 0.0001) and tachycardia (57.0% vs 41.9%,
p
< 0.0001) compared to non-SH patients. They also had higher emergency operative rate (71.8% vs 29%,
p
< 0.0001) and higher blood administration prior to minimum iCa pRBC: (8 vs 0,
p
< 0.0001), FFP: (4 vs 0,
p
< 0.0001), platelet: (1 vs 0,
p
< 0.0001). Multivariable analysis revealed penetrating mechanism (AOR: 1.706), increased ISS (AOR: 1.029), and higher pRBC (AOR: 1.343) or FFP administered (AOR: 1.097) were independent predictors of SH. SH was an independent predictor of mortality (AOR: 2.658). Regression analysis identified a significantly higher risk of SH at pRBC + FFP administration of 4 units (AOR: 18.706, AUC:. 897 (0.884–0.909).
Conclusion
Transfusion of pRBC is an independent predictor of SH and is associated with increased mortality. The predicted probability of SH increases as pRBC + FFP administration increases.
Calcium ion (Ca2+) is an important second messenger that regulates numerous cellular functions. Intracellular Ca2+ concentration (Ca2+i) is strictly controlled by Ca2+ channels and pumps on the ...endoplasmic reticulum (ER) and plasma membranes. The ER calcium pump, sarco/endoplasmic reticulum calcium ATPase (SERCA), imports Ca2+ from the cytosol into the ER in an ATPase activity-dependent manner. The activity of SERCA2b, the ubiquitous isoform of SERCA, is negatively regulated by disulfide bond formation between two luminal cysteines. Here, we show that ERdj5, a mammalian ER disulfide reductase, which we reported to be involved in the ER-associated degradation of misfolded proteins, activates the pump function of SERCA2b by reducing its luminal disulfide bond. Notably, ERdj5 activated SERCA2b at a lower ER luminal Ca2+ (Ca2+ER), whereas a higher Ca2+ER induced ERdj5 to form oligomers that were no longer able to interact with the pump, suggesting Ca2+ER-dependent regulation. Binding Ig protein, an ER-resident molecular chaperone, exerted a regulatory role in the oligomerization by binding to the J domain of ERdj5. These results identify ERdj5 as one of the master regulators of ER calcium homeostasis and thus shed light on the importance of cross talk among redox, Ca2+, and protein homeostasis in the ER.
All organisms possess specific cellular machinery that introduces disulfide bonds into proteins newly synthesized and transported out of the cytosol. In
E. coli, the membrane-integrated DsbB protein ...cooperates with ubiquinone to generate a disulfide bond, which is transferred to DsbA, a periplasmic dithiol oxido-reductase that serves as the direct disulfide bond donor to proteins folding oxidatively in this compartment. Despite the extensive accumulation of knowledge on this oxidation system, molecular details of the DsbB reaction mechanisms had been controversial due partly to the lack of structural information until our recent determination of the crystal structure of a DsbA–DsbB–ubiquinone complex. In this review we discuss the structural and chemical nature of reaction intermediates in the DsbB catalysis and the illuminated molecular mechanisms that account for the de novo formation of a disulfide bond and its donation to DsbA. It is suggested that DsbB gains the ability to oxidize its specific substrate, DsbA, having very high redox potential, by undergoing a DsbA-induced rearrangement of cysteine residues. One of the DsbB cysteines that are now reduced then interacts with ubiquinone to form a charge transfer complex, leading to the regeneration of a disulfide at the DsbB active site, and the cycle can begin anew.
Abstract Background Recent literature suggests that obesity is protective in critically illness. This study addresses the effect of BMI on outcomes after emergency abdominal surgery (EAS). Methods ...Retrospective, ACS-NSQIP analysis. All patients that underwent EAS were included. The study population was divided into five groups based on BMI; regression models were used to evaluate the role of obesity in morbidity and mortality. Results 101,078 patients underwent EAS; morbidity and mortality were 19.5% and 4.5%, respectively. Adjusted mortality was higher in underweight patients (AOR 1.92), but significantly lower in all obesity groups (AOR's 0.73, 0.66, 0.70, 0.70 respectively). Underweight and class III obesity was associated with increased complications (AOR 1.47 and 1.30), while mild obesity was protective (AOR 0.92). Conclusions Underweight patients undergoing EAS have increased morbidity and mortality. Although class III obesity is associated with increased morbidity, overweight and class I obesity were protective. All grades of obesity may be protective against mortality after EAS relative to normal weight patients.
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