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Background: Albeit low survival rates, resuscitative thoracotomy (RT) is considered standard for selected trauma patients. Because it has potential for rapid cardiopulmonary rescue, extracorporeal membrane oxygenation (ECMO) may augment RT. The aim of this study was to identify the impact of ECMO on trauma patients that recently underwent RT after injury.Study Design: All patients who underwent RT were identified from the National Trauma Data Bank (2007-2017). Patients were excluded if they died within 60 minutes, underwent delayed ECMO, and/or had missing data. Delayed ECMO group was defined as those patients undergoing ECMO after 1 hour following RT.Results: Out of 8 694 272 injured patients, 10 106 (.1%) underwent RT. Median age was 31 years [23-45], 86% male. Penetrating injury was the dominant mechanism (62%). Of these, .6% (23) underwent immediate ECMO. Extracorporeal membrane oxygenation patients were significantly younger (23[17-33] vs. 31[23-46], p .003) and had significantly higher chest abbreviated injury scale scores (5[4-5] vs. 3[3-4], P < .001). Extracorporeal membrane oxygenation patients achieved significantly higher rate of return of spontaneous circulation (96% vs. 70%, p .007) and had nonsignificant trend of improved mortality (52% vs. 63%, p .260).Conclusion: Immediate ECMO may be a useful therapeutic modality after RT. It achieves higher ROSC rates with opportunity for improved survival. Future prospective study is warranted. [ABSTRACT FROM AUTHOR]

Focused assessment with Sonography for trauma (FAST) examination is essential to trauma triage. We sought to determine whether FASTs completed early in sequencing portend worse outcomes. A two-year review (2014-2015) of all trauma activations at our Level I trauma center was performed. Patients were matched at baseline and FAST times were compared. Outcomes included resuscitation time (RESUS-h), ventilation days (d), hospital length of stay (HLOS-d), ICU length of stay (LOS-d), survival (%), nosocomial infection rate (%), and venous thromboembolism complication rate (%). ED interventions included transfusions, crystalloid, antibiotics, central line placement, intubation, thoracostomy, thoracotomy, pelvic X-ray, and binder. One thousand, three hundred and twelve patients were included for analysis (mean age = 38 ± 19 years, mean Injury Severity Score = 12 ± 11, 21% penetrating). Compared with FASTs completed after the primary survey, early FASTs led to significantly more ventilation days (P < 0.01), longer ICU length of stay (P < 0.01), and a greater incidence of nosocomial infections (P = 0.03). In the ED, early FASTs led to significantly more intubations (P < 0.01) and transfusions (P < 0.01) compared with late FASTs. FASTs completed before primary survey portend worse outcomes, with more ED interventions and equivocal results. FAST as a true adjunct to primary survey is recommended. [ABSTRACT FROM AUTHOR]

Angioembolization versus open control of traumatic pelvic hemorrhage is debated. We sought to compare outcomes between angioembolization and open internal iliac artery occlusion. A 14-year retrospective review (2004-2017) was performed at our academic Level I trauma center. All pelvic hemorrhage patients who underwent internal iliac artery angioembolization or silastic loop ligation via laparotomy were compared for outcomes. Patient demographics included vital signs, mechanism, and injury severity score (ISS). Outcomes included mortality (%), operating room visits, reoperation for hemorrhage (%), transfusion burden (units), and infection (%). A total of 163 trauma patients matched for age, ISS, mechanism, and cavitary involvement were included for analysis. Compared with silastic loop ligation (n = 51, mean ISS = 32 ± 14), patients who underwent angioembolization (n = 112, mean ISS = 30 ± 8.9) demonstrated decreased mortality (23% vs 57%, P < 0.01), made fewer operating room trips (mean = 2.2 vs 3.6 trips, P < 0.01), made fewer trips for pelvic (2.8 vs 11%, P = 0.05) and nonpelvic-related bleeding (3.6 vs 22%, P < 0.01), used fewer blood products [packed red blood cells, fresh-frozen plasma, platelets, and cryoprecipitate] (P < 0.01 for all), and indicated a trend toward fewer infections (5.7% vs 14%, P = 0.07). Internal iliac artery angioembolization demonstrates lower mortality, lower reoperation rates, decreased transfusion burden, and a trend toward fewer infections compared with silastic loop ligation. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the survival outcome associated with large-volume blood transfusion after trauma. This was a retrospective study at a Level I trauma center from January 2000 to December 2014 that included trauma patients who received ≥25 units packed red blood cell (pRBC) within the first 24 hours of hospital admission. Univariate and multivariable logistic regressions identified risk factors for mortality. Receiver operating characteristic curve analysis evaluated the ability of pRBC volume to predict mortality. Among 74,065 adults (≥18 years old), 178 patients (0.24%) received ≥25 units of pRBC in the first 24 hours, of which 142 (79.8%) received 25 to 49 units, 28 (15.7%) received 50 to 74 units, and 8 (4.5%) received ≥75 units. Overall, 92.2 per cent were male, mean age 33.9 (±14.0), mean Injury Severity Score 28.9 (±14.3), and median Glasgow Coma Scale score 12 (3-15). The overall mortality was 65.2 per cent and 64.1 per cent for those receiving 25 to 49 units, 64.3 per cent for 50 to 74 units, and 87.5 per cent for ≥75 units. In univariate analysis, female gender was associated with lower mortality [odds ratio (OR) 0.24, P = 0.025]. Decreasing Glasgow Coma Scale (OR 0.82, P < 0.001), increasing Injury Severity Score (OR 1.07, P < 0.001), and thoracotomy (OR 3.91, P < 0.001) were associated with higher mortality. There was no transfusion cutoff that was significantly associated with higher mortality. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the frequency and cause of preventable and potentially preventable complications on an emergency nontrauma surgical service. The study is a retrospective review conducted at an academic teaching hospital. All patients were assessed (January 2010-June 2012) for emergency general surgical conditions, excluding trauma. The main outcome measures were preventable and potentially preventable complications and deaths, treatments, loop closure mechanisms, and impact on outcomes. The results showed that of 9078 nontrauma emergency surgical admissions and consultations, 194 patients (2.1%) had 261 complications. One hundred and ten (42.1% of total complications) were preventable. The most common causes of preventable complications were delay in management or diagnosis (n = 45, 41% of all preventable complications), technical/iatrogenic (n = 28, 25%), and infectious (n = 18, 16%). The most common nonpreventable complication was infectious (n = 84, 82% of all complications). The most common diagnoses associated with preventable complications were acute cholecystitis (n = 27, 25%), acute appendicitis (n = 25, 23%), and small bowel obstruction (n = 7, 6%). Preventable complications changed management in 80 per cent of cases. Of three (0.01%) mortalities, two were preventable. The mortality rate in emergency nontrauma surgery is low. A significant burden of complications remains. A large proportion are preventable or potentially preventable, with many changing management. These preventable errors are important targets for quality improvement efforts as the specialty of acute care surgery evolves. [ABSTRACT FROM AUTHOR]

BACKGROUND: Falls are a leading cause of unintentional injury among adults, especially those over 65 years of age. With increasing longevity and improving access to health care, falls are affecting a more mobile senior citizen population that does not fit the typical profile. We set out to evaluate the current nature of these falls in the elderly. METHODS: This is a 2-year retrospective chart review of all falls in patients 65 years or older at an urban Level I trauma center. Demographics, location and height of fall, associated injuries, and outcomes were obtained from chart review. RESULTS: There were 400 patients meeting inclusion criteria. The cohort had a mean age of 78.3 ± 8.8 years, 50% were male, and 72.5% had at least 1 comorbidity. Non-ground level falls (Non-GLF) were recorded in 56 patients (14%). These patients suffered a significantly higher injury burden. Non-GLF were associated with significantly higher intensive care unit length of stay (2.6 ± 5.6 vs 4.6 ± 6.7 days, P = .016) and a trend toward higher mortality than GLF. CONCLUSIONS: Falls remain a source of considerable healthcare expenditure, especially among the elderly. Non-GLF account for 14% of cases and are associated with a significantly higher burden of injury and morbidity. Fall prevention strategies should include these active older individuals at risk of high-level falls. [ABSTRACT FROM AUTHOR]

Background: Bile duct injury (BDI) is one of the most severe complications during cholecystectomy. Early identification of risk factors for BDI may permit risk reduction strategies and inform patient consent. Objective: This study aimed to define patient, provider, and systemic factors associated with BDI; BDI incidence; and short-term outcomes of BDI after urgent cholecystectomy. Methods: Patients who underwent urgent cholecystectomy for acute cholecystitis were retrospectively screened (2020-2022). All patients who sustained BDI were included without exclusions. Demographics, clinical data, and outcomes were collected and compared with descriptive statistics. Results: During the study period, BDI occurred in 4 (0.5%) of 728 patients who underwent urgent cholecystectomy for acute cholecystitis. Most BDI cases (75%) took place overnight or during the weekend. The attending surgeon was almost exclusively (75%) in their first year of practice. BDI was recognized during index operation in 2 cases (50%). Hepatobiliary surgery performed the bile duct repair in all 4 cases. Two complications occurred (50%). All patients were followed by hepatobiliary surgery in the outpatient setting and returned to their baseline level of function within 2 months of hospital discharge. Conclusion: Most BDI occurred in procedures attended by first-year faculty during after hours cholecystectomies, suggesting a role for increased proctorship in early career attendings in addition to in-hours cholecystectomy for acute cholecystitis. The timely return to baseline function experienced by these patients emphasizes the favorable outcomes associated with early recognition of BDI and involvement of hepatobiliary surgery. Further examination with multicenter evaluation would be beneficial to validate these study findings. [ABSTRACT FROM AUTHOR]

Our careers as surgeons are some of the busiest and perhaps most sought after in existence.We have all put in countless years of tenacious effort, at times blood, frequent sweat, and occasional tears, to have the privilege to care for others and correct their ailments. Many of us are like freight trains rolling down the tracks indefinitely. But all too often we finish our training and head down those tracks without considering what stops we should make along the way, which forks in the tracks we should consider taking, and perhaps most often, we do not consider how we are going to eventually stop the train. Most of us have been witness to colleagues who keep working beyond their prime, be it for lack of alternative opportunities, lack of hobbies to retire to, or for lack of insight into their own decline. From these observations was born this presidential panel. As you can see, it is a collection of past presidents of So Cal ACS, with the exception for Dr Freischlag (who we all know would have served as president at some point had she never relocated away from Southern California). Each of these speakers has unique experience from their own careers that they will share with us so we can take pause and consider their insights and wisdom for how to navigate a successful and satisfying career. [ABSTRACT FROM AUTHOR]

Background: The unhoused population is at high risk for traumatic injuries and faces unique challenges in accessing follow-up care. However, there is scarce data regarding differences in Emergency Department (ED) return rates and reasons for return between unhoused and housed patients. Methods: We conducted a 3-year retrospective cohort study at a level-1 trauma center in a large metropolitan area. All patients who presented to the ED with traumatic injuries and were discharged without hospital admission were included in the study. The primary outcome was ED returns for trauma-related complications or new traumatic events <6 months after discharge. Patient characteristics and study outcomes were compared between housed and unhoused groups. Results: A total of 4184 patients were identified, of which 20.3% were unhoused. Compared to housed, unhoused patients were more likely to return to the ED (18.8% vs 13.9%, P < .001), more likely to return for trauma-related complications (4.6% vs 3.1%, P = .045), more likely to return with new trauma (7.1% vs 2.8%, P < .001), and less likely to return for scheduled wound checks (2.5% vs 4.3%, P = .012). Of the patients who returned with trauma-related complications, unhoused patients had a higher proportion of wound infection (20.5% vs 5.7%, P = .008). In the regression analysis, unhoused status was associated with increased odds of ED return with new trauma and decreased odds of return for scheduled wound checks. Conclusions: This study observed significant disparities between unhoused and housed patients after trauma. Our results suggest that inadequate follow-up in unhoused patients may contribute to further ED return. [ABSTRACT FROM AUTHOR]

Introduction: Intimate partner violence (IPV) is the leading cause of death in pregnant women. Although it can be difficult to identify patients experiencing IPV, injuries to the head, neck, or face due to an assault are known to correlate with intentional injury. The objective of this study is to assess the contemporary burden of IPV in pregnancy and describe the patient characteristics. Methods: The National Inpatient Sample was queried for all pregnant women between January 2016 and December 2019. Patients were divided into two groups: suspected IPV (SIPV) and no-SIPV groups.We defined SIPV as any pregnant patient with an identified head, neck, or face injuries categorized as intentional assault. Multivariable logistic regression analysis was performed to assess the association between SIPV and variables of interest. Results: A total of 28,540 pregnant patients presented with traumatic injuries with 530 (.02%) identified as SIPV. Suspected IPV patients were younger (25 vs 27 years, P = .012), more likely to be of Black race (46% vs 28%, P = .002), more likely to be in the lowest income quartile (51% vs 38%, P = .031), less likely to have private insurance (12% vs 34%, P < .001), and have higher rates of substance use disorder (35% vs 18%, P < .001). Black race and history of substance use disorder were associated with increased odds of SIPV-related injuries (odds ratio [OR]: 2.01, interquartile range [IQR]: 1.27-3.16, P = .003 and OR: 2.30, IQR 1.54-3.43, P < .001, respectively). Conclusions: Our results suggest that there are significant racial and socioeconomic disparities in potential risk for IPV during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Disruption score (DS) is a novel bibliometric created to identify research that shifts paradigms, which may be overlooked by citation count (CC). We analyzed the most disruptive, compared to the most cited, literature in vascular surgery, and hypothesized that DS and CC would not correlate. Methods: A PubMed search identified vascular surgery publications from 1954 to 2014. The publications were linked to the iCite NIH tool and DS algorithm to identify the top 100 studies by CC and DS, respectively. The publications were reviewed for study focus, design, and contribution, and subsequently compared. Results: A total of 56,640 publications were identified. The top 100 DS papers were frequently published in J Vasc Sur (43%) and Eur J Vasc Endovasc Surg (13%). The top 100 CC paperswere frequently published in N Engl J Med (32%) and J Vasc Sur (20%). The most cited article is the fifth most disruptive; the most disruptive article is not in the top 100 cited papers. The DS papers had a higher mean DS than the CC papers (.17 vs .0001, P < .0001). The CC papers had a higher mean CC than the DS papers (866 vs 188, P < .0001). DS and CC are weakly correlated metrics (r = .22, P = .03). Discussion: DS was weakly correlated with CC and captured a unique subset of literature that created paradigm shifts in vascular surgery. DS should be utilized as an adjunct to CC to avoid overlooking impactful research and influential researchers, and to measure true academic productivity. [ABSTRACT FROM AUTHOR]

BACKGROUND: The optimal management of pediatric patients with high-grade blunt pancreatic injury (BPI) involving the main pancreatic duct remains controversial. This study aimed to assess the nationwide trends in the management of pediatric high-grade BPI at pediatric (PTC), mixed (MTC), and adult trauma centers (ATC). STUDY DESIGN: This is a retrospective observational study of the National Trauma Data Bank. We included pediatric patients (age 16 years or less) sustaining high-grade BPI (Abbreviated Injury Scale 3 or more) from 2011 to 2021. Patients who did not undergo pancreatic operation were categorized into the nonoperative management (NOM) group. Trauma centers were defined as PTC (level I/II pediatric only), MTC (level I/II adult and pediatric), and ATC (level I/II adult only). Primary outcome was the proportion of patients undergoing NOM, and secondary outcomes included the use of ERCP and in-hospital mortality. A Cochran-Armitage test was used to analyze the trend. RESULTS: A total of 811 patients were analyzed. The median age was 9 years (interquartile range 6 to 13), 64% were male patients, and the median injury severity score was 17 (interquartile range 10 to 25). During the study period, there was a significant upward linear trend in the use of NOM and ERCP among the overall cohort (range 48% to 66%; ptrend = 0.033, range 6.1% to 19%; ptrend = 0.030, respectively). The significant upward trend for NOM was maintained in the subgroup of patients at PTC and MTC (ptrend = 0.037), whereas no significant trend was observed at ATC (ptrend = 0.61). There was no significant trend in in-hospital mortality (ptrend = 0.38). CONCLUSIONS: For the management of pediatric patients with high-grade BPI, this study found a significant trend toward increasing use of NOM and ERCP without mortality deterioration, especially at PTC and MTC. [ABSTRACT FROM AUTHOR]

Background: We sought to develop a novel Prehospital Injury Mortality Score (PIMS) to predict blunt trauma mortality using only prehospital variables.Study Design: The 2017 Trauma Quality Improvement Program database was queried and divided into two equal sized sets at random (derivation and validation sets). Multiple logistic regression models were created to determine the risk of mortality using age, sex, mechanism, and trauma activation criterion. The PIMS was derived using the weighted average of each independent predictor. The discriminative power of the scoring tool was assessed by calculating the area under the receiver operating characteristics (AUROC) curve. The PIMS ability to predict mortality was then assessed by using the validation cohort. The score was compared to the Revised Trauma Score (RTS) using the AUROC curve, including a subgroup of patients with normal vital signs.Results: The derivation and validation groups each consisted of 163 694 patients. Seven independent predictors of mortality were identified, and the PIMS was derived with scores ranging from 0 to 20. The mortality rate increased from 1.4% to 43.9% and then 100% at scores of 1, 10, and 19, respectively. The model had very good discrimination with an AUROC of .79 in both the derivation and validation groups. When compared to the RTS, the AUROC were similar (.79 vs. .78). On subgroup analysis of patients with normal prehospital vital signs, the PIMS was superior to the RTS (.73 vs. .56).Conclusion: The PIMS is a novel scoring tool to predict mortality in blunt trauma patients using prehospital variables. It had improved discriminatory power in blunt trauma patients with normal vital signs compared to the RTS. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER)-associated degradation (ERAD) is a protein quality control process that eliminates misfolded proteins from the ER. DnaJ homolog subfamily C member 10 (ERdj5) is a protein disulfide isomerase family member that accelerates ERAD by reducing disulfide bonds of aberrant proteins with the help of an ER-resident chaperone BiP. However, the detailed mechanisms by which ERdj5 acts in concert with BiP are poorly understood. In this study, we reconstituted an in vitro system that monitors ERdj5-mediated reduction of disulfide-linked J-chain oligomers, known to be physiological ERAD substrates. Biochemical analyses using purified proteins revealed that J-chain oligomers were reduced to monomers by ERdj5 in a stepwise manner via trimeric and dimeric intermediates, and BiP synergistically enhanced this action in an ATP-dependent manner. Single-molecule observations of ERdj5-catalyzed J-chain disaggregation using highspeed atomic force microscopy, demonstrated the stochastic release of small J-chain oligomers through repeated actions of ERdj5 on peripheral and flexible regions of large J-chain aggregates. Using systematic mutational analyses, ERAD substrate disaggregation mediated by ERdj5 and BiP was dissected at the molecular level. [ABSTRACT FROM AUTHOR]

Background: Computed tomography (CT) has emerged as the diagnostic modality of choice in trauma patients. Recent studies suggest its use in hemodynamically unstable patients is safe and potentially lifesaving; however, the incidence of adverse events (AE) during the trauma CT scanning process remains unknown.Study Design: Over a 6-month period at a Level 1 trauma center, data on patients undergoing trauma CT (whole-body CT (WBCT) +/- additional CT studies) were prospectively collected. All patients requiring a trauma team activation (TTA) were included. Adverse events and specific time intervals were recorded from the time of TTA notification to the time of return to the resuscitation bay from the CT suite.Results: Of the 94 consecutive patients included in the study, 47.9% experienced 1 or more AE. Median duration away from the resuscitation bay for all patients was 24 minutes. Patients with AE spent a significantly longer time away from the resuscitation bay and had longer scan times. Vasopressor support and ongoing transfusion requirement at the time of CT scanning were associated with AE.Conclusion: Adverse events of varying clinical significance occur frequently in patients undergoing emergent trauma CT. A standard trauma CT protocol could improve the efficiency and safety of the scanning process. [ABSTRACT FROM AUTHOR]

Background: As the number of households with dogs in the United States has increased, so has the incidence of dog bites. Contemporary analysis of nationwide epidemiological data regarding such injuries is scarce. The purpose of this study is to describe dog bite injury patterns and related surgical interventions with a focus on differences between pediatric and adult age groups.Study Design: This is a retrospective study (2015-2017) using the National Trauma Data Bank. 10 569 patients were included.Results: Of these, 4729 (44.7%) qualified as pediatric (age ≤ 12 years) and 5840 (55.3%) qualified as adults (age ≥ 13 years). Pediatric patients were more frequently admitted with facial injuries (78.1% vs. 29.3%, P < .01) and facial fractures (4.8% vs. 2.5%, P < .01), and had a higher incidence of facial bone surgical procedures (1.3% vs. .5%, P < .01). Adult patients were more frequently admitted with upper extremity injuries (65.8% vs. 21.2%, P < .01) and upper extremity vascular arterial injuries (2.3% vs. .2%, P < .01) with a higher incidence of upper extremity arterial procedures (1.3% vs. .2%, P < .01).Conclusion: This study demonstrates the contrast in injury patterns from dog bite between adults and children. These findings can dictate injury prevention policies and prepare clinicians to treat dog bite victims. [ABSTRACT FROM AUTHOR]

Background: The impact of body mass index (BMI) on trauma severity after ground-level falls (GLF) is currently unclear. This study aimed to examine the associations between BMI, injuries, and outcomes after GLF.Study Design: All patients ≥16 years of age injured by GLF were queried from the TQIP database (2013-2017). Exclusions were transfers, emergency department death, AIS 6 in any region, and missing data. Body mass index defined study groups: Underweight (BMI<18.5), Normal (BMI 18.5-24.9), Overweight (25.0-29.9), and Obese (≥30).Results: After exclusions, 131 570 patients remained for analysis. Most patients had a normal BMI (n = 58 503, 44%). Median ISS was 9 [IQR 9-10] in all groups. The Obese group had significantly lower rates of fractures than the Normal group, particularly femur fractures (53% vs. 64%, P < .001), but required orthopedic surgical intervention more frequently (45% vs. 41%, P < .001). On multivariate analysis, being overweight was protective against mortality (OR .881, P = .005), while obesity was not associated with mortality (OR 1.012, P = .821).Conclusion: Increasing BMI may be protective against both fracture risk and mortality after GLF. However, obese patients require operative fixation more frequently. Particularly as fracture diagnosis may be more challenging in the obese, special care should be taken during their tertiary surveys after GLF to ensure injuries are not missed. [ABSTRACT FROM AUTHOR]

Background: Glycemic control is an important aspect of critical care because derangements are associated with morbidity and mortality. Patients at highest risk for hypoglycemia in the surgical intensive care unit (SICU) are incompletely described by existing literature. Our objective was to delineate this high-risk patient population in our SICU.Study Design: In this single-center, retrospective, observational study, SICU patients admitted from June 1, 2019 to July 31, 2020 with ≥1 episode of hypoglycemia (blood glucose <60 mg/dL) were included.Results: There were 41 hypoglycemic events in 27 patients, comprising an incidence of 1.5% among SICU patients. The most common admission diagnoses were cirrhosis (n = 13, 48%), polytrauma (n = 12, 44%), multisystem organ failure (n = 11, 41%), diabetes mellitus (n = 9, 33%), and soft tissue infection (n = 8, 30%). Four high-risk populations were identified: patients in multisystem organ failure (MSOF) (n = 11, 41%); those who were nil per os (NPO) (n = 10, 37%); patients receiving long acting subcutaneous insulin, for example, Lantus (n = 3, 11%); and those on continuous intravenous insulin infusions (n = 3, 11%). After multi-disciplinary peer review, most hypoglycemic events (n = 16, 59%) were deemed iatrogenic.Conclusions: Hypoglycemia is rare in surgical critical care. When it does occur, patients are typically in MSOF, NPO, on long acting subcutaneous insulin or continuous insulin infusions, have soft tissue infections, or have acute or chronic liver failure. Increased vigilance with frequent blood glucose monitoring in these high-risk patients may reduce the risk of hypoglycemia in the SICU. [ABSTRACT FROM AUTHOR]

Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical studies have suggested that olanzapine-induced hyperglycemia in certain patients cannot be explained by such a generalized mechanism. Here, we focused on the effects of olanzapine on insulin biosynthesis and secretion by mouse insulinoma MIN6 cells. Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This was due to olanzapine's impairment of proper disulfide bond formation in proinsulin, although direct targets of olanzapine remain undetermined. Olanzapine-induced proinsulin misfolding and subsequent decrease also occurred at the mouse level. This mechanism of olanzapine-induced b-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine. [ABSTRACT FROM AUTHOR]

Oxidative protein folding occurs primarily in the mammalian endoplasmic reticulum, enabled by a diverse network comprising more than 20 members of the protein disulfide isomerase (PDI) family and more than five PDI oxidases. Although the canonical disulfide bond formation pathway involving Ero1α and PDI has been well-studied so far, the physiological roles of the newly identified PDI oxidases, glutathione peroxidase-7 (GPx7) and -8 (GPx8), are only poorly understood. We here demonstrated that human GPx7 has much higher reactivity with H2O2 and hence greater PDI oxidation activity than human GPx8. The high reactivity of GPx7 is due to the presence of a catalytic tetrad at the redox-active site, which stabilizes the sulfenylated species generated upon the reaction with H2O2. Although it was previously postulated that GPx7 catalysis involved a highly reactive peroxidatic cysteine that can be sulfenylated by H2O2, we revealed that a resolving cysteine instead regulates the PDI oxidation activity of GPx7. We also determined that GPx7 formed complexes preferentially with PDI and P5 in H2O2-treated cells. Altogether, these results suggest that human GPx7 functions as an H2O2-dependent PDI oxidase in cells, whereas PDI oxidation may not be the central physiological role of human GPx8. [ABSTRACT FROM AUTHOR]

The article offers information on the role in conformational regulation in Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). It mentions that crystal structures of a series of reaction intermediates and transition states stabilized with appropriate ligands or analogs. It mentions that Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail.

Introduction: Patients with trauma-induced coagulopathies may benefit from the use of antifibrinolytic agents, such as tranexamic acid (TXA). This study evaluated the safety and efficacy of TXA in civilian adults hospitalized with traumatic hemorrhagic shock. Methods: Patients who sustained blunt or penetrating trauma with signs of hemorrhagic shock from June 2014 through July 2018 were considered for TXA treatment. A retrospective control group was formed from patients seen in the same past five years who were not administered TXA and matched based on age, gender, Injury Severity Score (ISS), and mechanism of injury (blunt vs penetrating trauma). The primary outcome of this study was mortality measured at 24 hours, 48 hours, and 28 days. Secondary outcomes included total blood products transfused, hospital length of stay (LOS), intensive care unit LOS, and adverse events. We conducted three prespecified subgroup analyses to assess outcomes of patients, including (1) those who were severely injured (ISS >15), (2) those who sustained significant blood loss (≥10 units of total blood products transfused), and (3) those who sustained blunt vs penetrating trauma. Results: Propensity matching yielded two cohorts: the hospital TXA group (n = 280) and a control group (n = 280). The hospital TXA group had statistically lower mortality at 28 days (1.1% vs 5%, odds ratio [OR] [0.21], (95% confidence interval [CI], 0.06, 0.72)) and used fewer units of blood products (median = 4 units, interquartile range (IQR) = [1, 10] vs median=7 units, IQR = [2, 12.5] for the hospital TXA and control groups, respectively, (95% CI for the difference in median, -3 to -1). There were no statistically significant differences between groups with regard to 24-hour mortality (1.1% vs 1.1%, OR = 1, 95% CI, 0.20, 5.00), 48-hour mortality (1.1% vs 1.4%, OR [0.74], 95% CI, 0.17, 3.37), hospital LOS (median= 9 days, IQR = (5, 16) vs median =12 days IQR = (6, 22.5) for the hospital TXA and control groups, respectively, 95% CI for the difference in median = (-5 to 0)), and incidence of thromboembolic events (eg, deep vein thrombosis, pulmonary embolism) during hospital stay (0.7% vs 0.7% for the hospital TXA and control group, respectively, OR [1], 95% CI, 0.14 to 7.15). We conducted subgroup analyses on patients with ISS>15, patients transfused with ≥10 units of blood products, and blunt vs penetrating trauma. The results indicated lower 28-day mortality for ISS>15 (1.8% vs 7.1%, OR [0.23], 95% CI, 0.06 to 0.81) and blunt trauma (0.6% vs 6.3%, OR [0.09], 95% CI, 0.01 to 0.75); fewer units of blood products for penetrating trauma (median = 2 units, IQR = (1, 8) vs median = 8 units, IQR = (5, 15) for the hospital TXA and control groups, respectively, 95% CI for the difference in median = (-6 to -3)), and ISS>15 (median = 7 units, IQR = (2, 14) vs median = 8.5 units, IQR = (4, 16) for the hospital TXA and control groups, respectively, 95% CI for the difference in median, -3 to 0). Conclusion: The current study demonstrates a statistically significant reduction in mortality after TXA administration at 28 days, but not at 24 and 48 hours, in patients with traumatic hemorrhagic shock. [ABSTRACT FROM AUTHOR]

About 20 members of the protein-disulfide isomerase (PDI) family are present in the endoplasmic reticulum of mammalian cells. They are thought to catalyze thiol-disulfide exchange reactions within secretory or membrane proteins to assist in their folding or to regulate their functions. PDIp is a PDI family member highly expressed in the pancreas and known to bind estrogen in vivo and in vitro. However, the physiological functions of PDIp remained unclear. In this study, we set out to identify its physiological substrates. By combining acid quenching and thiol alkylation, we stabilized and purified the complexes formed between endogenous PDIp and its target proteins from the mouse pancreas. MS analysis of these complexes helped identify the disulfide-linked PDIp targets in vivo, revealing that PDIp interacts directly with a number of pancreatic digestive enzymes. Interestingly, when pancreatic elastase, one of the identified proteins, was expressed alone in cultured cells, its proenzyme formed disulfide-linked aggregates within cells. However, when pancreatic elastase was co-expressed with PDIp, the latter prevented the formation of these aggregates and enhanced the production and secretion of proelastase in a form that could be converted to an active enzyme upon trypsin treatment. These findings indicate that the main targets of PDIp are digestive enzymes and that PDIp plays an important role in the biosynthesis of a digestive enzyme by assisting with the proper folding of the proenzyme within cells. [ABSTRACT FROM AUTHOR]

Draining the chest cavity with two chest tubes after thoracotomy for trauma is controversial. This article aims to determine whether using two tubes after thoracotomy for trauma is more effective than using a single tube. A 9-year retrospective review (2007-2015) was performed at our academic level I trauma center. All patients who underwent trauma thoracotomy (unilateral and bilateral) were included for analysis (n = 99). Patients with incomplete data, pediatric patients (age < 18), pregnant patients, and early deaths (<24 hours) were excluded. When analyzed by chest cavity, dual tubes have increased drainage bilaterally (P = 0.008) and require more days to clear the right chest (P = 0.002). Patients with dual tubes bilaterally are associated with increased intensive care unit length of stay (P = 0.05) and ventilator days (P = 0.04). Although dual chest tube insertion achieves greater drainage, it comes at the cost of increased time to clear the chest and is associated with worse outcomes in bilateral injuries. One chest tube may be sufficient post-trauma thoracotomy; routine placement of two chest tubes is not recommended. [ABSTRACT FROM AUTHOR]

Equivocal focused abdominal sonography for trauma (FAST) examinations confound decision-making for trauma surgeons. We sought to determine whether the equivocal FAST (defined as any nonconcordant result) has a deleterious effect on trauma outcomes. A 2-year review (2014-2015) of all trauma activations at our Level I trauma center was performed. Patients were matched at baseline and FAST results were compared. Outcomes included resuscitation time (h), ventilation days (d), hospital length of stay (HLOS-d), ICU length-of-stay, and survival (%). In addition, skill level of the sonographer was stratified by novice (postgraduate year (PGY) years 1-3) or expert skill levels (PGY-4/fellow or attending). A total of 1,027 patients were included. Compared with concordant FAST examinations, equivocal FASTs were associated with increased HLOS (14.1 vs 10.6, P = 0.05), higher mortality (9.8 vs 3.7%, P = 0.02), decreased positive predictive value in the right upper quadrant (RUQ) (55 vs 79%, P = 0.02) and left upper quadrant (LUQ) (50 vs 83%, P < 0.01) and significantly decreased specificity in the thoracic (83 vs 98%), RUQ (80 vs 98%), LUQ (86 vs 99%), and pelvic (88 vs 98%) windows (P < 0.01 for all). A trend of greater positive predictive value in the thoracic window (100 vs 81%, P = 0.09) among PGY-4/fellow and attending providers compared with PGY levels 1-3 was observed. Equivocal FASTs portend worse outcomes than concordant FASTs because of high false-negative rates, specifically in the thoracic region and the upper quadrants. Lower thresholds for intervention are recommended. [ABSTRACT FROM AUTHOR]

Shock Index (SI = heart rate/systolic blood pressure) predicts outcomes among trauma patients. Studies have also shown that the change in SI between the field and Emergency Department (ED) arrival (Delta SI) predicts mortality in trauma. Given the lack of reliable prehospital data, Delta SI may more accurately prognosticate if used within the ED. All trauma patients arriving to our Level I trauma center in 2014 were reviewed. Patients were matched for age, gender, mechanism of injury, and injury severity score. SI and ED Delta SI were calculated. ED Delta SI >0.1 and ≤0.1 defined the study groups. Pregnant patients, pediatric patients, and patients with incomplete data were excluded. Outcomes included intensive care unit (ICU) length of stay, blood products, and mortality. A total of 2591 patients were identified (n = 1294 patients analyzed). After matching, patients with ED Delta SI >0.1 had greater mortality (6.6 vs 2.6%, P = 0.010), need for blood transfusion (1764 vs 565 cc, P < 0.001), and ICU length of stay (5.6 vs 3.8 days, P = 0.014) compared with patients with ED Delta SI ≤0.1. In conclusion, ED Delta SI >0.1 is associated with increased mortality, need for blood transfusion, and ICU length of stay. Delta SI may be superior to traditional SI for trauma outcome prognostication. [ABSTRACT FROM AUTHOR]

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 24h were excluded. Comparison between groups with and without ICP monitoring was made, analyzing 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 1.28-2.07; 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. [ABSTRACT FROM AUTHOR]

ERp44 retrieves some endoplasmic reticulum (ER)-resident enzymes and immature oligomers of secretory proteins from the Golgi. Association of ERp44 with its clients is regulated by pH-dependent mechanisms, but the molecular details are not fully understood. Here we report high-resolution crystal structures of human ERp44 at neutral and weakly acidic pH. These structures reveal key regions in the C-terminal tail (C tail) missing in the original crystal structure, including a regulatory histidine-rich region and a subsequent extended loop. The former region forms a short α-helix (α16), generating a histidine-clustered site (His cluster). At low pH, the three Trx-like domains of ERp44 ("a," "b," and "b'") undergo significant rearrangements, likely induced by protonation of His157 located at the interface between the a and b domains. The α16-helix is partially unwound and the extended loop is disordered in weakly acidic conditions, probably due to electrostatic repulsion between the protonated histidines in the His cluster. Molecular dynamics simulations indicated that helix unwinding enhances the flexibility of the C tail, disrupting its normal hydrogen-bonding pattern. The observed pH-dependent conformational changes significantly enlarge the positively charged regions around the client-binding site of ERp44 at low pH. Mutational analyses showed that ERp44 forms mixed disulfides with specific cysteines residing on negatively charged loop regions of Ero1α. We propose that the protonation states of the essential histidines regulate the ERp44--client interaction by altering the C-tail dynamics and surface electrostatic potential of ERp44. [ABSTRACT FROM AUTHOR]

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 activitydependent 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. [ABSTRACT FROM AUTHOR]

The membrane topology of vitamin K epoxide reductase (VKOR) is controversial with data supporting both a three transmembrane and a four transmembrane model. The positioning of the transmembrane domains and the loops between these domains is critical if we are to understand the mechanism of vitamin K oxidation and its recycling by members of the thioredoxin family of proteins and the mechanism of action of warfarin, an inhibitor of VKOR. Here we show that both mammalian VKOR isoforms adopt the same topology, with the large loop between transmembrane one and two facing the lumen of the endoplasmic reticulum (ER). We used a redox sensitive green fluorescent protein (GFP) fused to the N- or C-terminus to show that these regions face the cytosol, and introduction of glycosylation sites along with mixed disulfide formation with thioredoxin-like transmembrane protein (TMX) to demonstrate ER localization of the major loop. The topology is identical with the bacterial homologue from Synechococcus sp., for which the structure and mechanism of recycling has been characterized. Our results provide a resolution to the membrane topology controversy and support previous results suggesting a role for members of the ER protein disulfide isomerase (PDI) family in recycling VKOR. [ABSTRACT FROM AUTHOR]

The Ni atom at the catalytic center of [NiFe] hydrogenases is incorporated by a Ni-metallochaperone, HypA, and a GTPase/ATPase, HypB. We report the crystal structures of the transient complex formed between HypA and ATPase-type HypB (HypBAT) with Ni ions. Transient association between HypA and HypBAT is controlled by the ATP hydrolysis cycle of HypBAT, which is accelerated by HypA. Only the ATP-bound form of HypBAT can interact with HypA and induces drastic conformational changes of HypA. Consequently, upon complex formation, a conserved His residue of HypA comes close to the N-terminal conserved motif of HypA and forms a Ni-binding site, to which a Ni ion is bound with a nearly square-planar geometry. The Ni binding site in the HypABAT complex has a nanomolar affinity (Kd = 7 nM), which is in contrast to the micromolar affinity (Kd = 4 μM) observed with the isolated HypA. The ATP hydrolysis and Ni binding cause conformational changes of HypBAT, affecting its association with HypA. These findings indicate that HypA and HypBAT constitute an ATP-dependent Ni acquisition cycle for [NiFe]-hydrogenase maturation, wherein HypBAT functions as a metallochaperone enhancer and considerably increases the Ni-binding affinity of HypA. [ABSTRACT FROM AUTHOR]

BACKGROUND: The effect of diabetes and the role of laparoscopic surgery on outcomes following appendectomy for acute appendicitis are not known. METHODS: National Surgical Quality Improvement Program study, including patients with acute appendicitis and no significant comorbidities (American Society of Anesthesiologists grade I or II) who underwent appendectomy. Diabetic patients were matched (1:3) with nondiabetic patients. The primary outcomes were 30-day mortality, surgical site infections (SSIs), and systemic infectious complications. RESULTS: SSI was encountered more frequently in the diabetic group as compared with the nondiabetic group (6.1% vs 4.3%, P = .010). Also, the hospital length of stay was significantly longer in the diabetic group. In the diabetic group, laparoscopic appendectomy did not affect mortality, reoperation, SSI, and systemic infectious complication rates in patients with or without peritonitis (P > .05), but the hospital length of stay was significantly shorter when compared with the open procedure. CONCLUSIONS: Patients with diabetes and no significant comorbidities have a higher risk of developing SSIs and longer hospital stay than patients without diabetes. Laparoscopic appendectomy had no effect on SSIs in patients with diabetes. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is an endocrine disruptor that may have adverse effects on human health. We recently isolated protein- disulfide isomerase (PDI) as a BPA-binding protein from rat brain homogenates and found that BPA markedly inhibited PDI activity. To elucidate mechanisms of this inhibition, detailed structural, biophysical, and functional analyses of PDI were performed in the presence of BPA. BPA binding to PDI induced significant rearrangement of the N-terminal thioredoxin domain of PDI, resulting in more compact overall structure. This conformational change led to closure of the substrate- binding pocket in b' domain, preventing PDI from binding to unfolded proteins. The b' domain also plays an essential role in the interplay between PDI and ER oxidoreduclin 1α (Ero1α), a flavoenzyme responsible for reoxidation of PDI. We show that BPA inhibited Ero1α-catalyzed PDI oxidation presumably by inhibiting the interaction between the b' domain of PDI and Ero1α; the phenol groups of BPA probably compete with a highly conserved tryptophan residue, located in the protruding [ABSTRACT FROM AUTHOR]

The mammalian endoplasmic reticulum (ER) harbors disulfide bond-generating enzymes, including Ero1a and peroxiredoxin 4 (Prx4), and nearly 20 members of the protein disulfide isomerase family (PDIs), which together constitute a suitable environment for oxidative protein folding. Here, we clarified the Prx4 preferential recognition of two PDI family proteins, P5 and ERp46, and the mode of interaction between Prx4 and P5 thioredoxin domain. Detailed analyses of oxidative folding catalyzed by the reconstituted Prx4- PDIs pathways demonstrated that, while P5 and ERp46 are dedicated to rapid, but promiscuous, disulfide introduction, PDI is an efficient proofreader of non-native disulfides. Remarkably, the Prx4-dependent formation of native disulfide bonds was accelerated when PDI was combined with ERp46 or P5, suggesting that PDIs work synergistically to increase the rate and fidelity of oxidative protein folding. Thus, the mammalian ER seems to contain highly systematized oxidative networks for the efficient production of large quantities of secretory proteins. [ABSTRACT FROM AUTHOR]