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Abstract Intra-abdominal infections (IAIs) are an important cause of morbidity and mortality in hospital settings worldwide. The cornerstones of IAI management include rapid, accurate diagnostics; timely, adequate source control; appropriate, short-duration antimicrobial therapy administered according to the principles of pharmacokinetics/pharmacodynamics and antimicrobial stewardship; and hemodynamic and organ functional support with intravenous fluid and adjunctive vasopressor agents for critical illness (sepsis/organ dysfunction or septic shock after correction of hypovolemia). In patients with IAIs, a personalized approach is crucial to optimize outcomes and should be based on multiple aspects that require careful clinical assessment. The anatomic extent of infection, the presumed pathogens involved and risk factors for antimicrobial resistance, the origin and extent of the infection, the patient’s clinical condition, and the host’s immune status should be assessed continuously to optimize the management of patients with complicated IAIs.

Summary: Localization to the endoplasmic reticulum (ER) and subsequent disulfide bond formation are crucial processes governing the biogenesis of secretory pathway proteins in eukaryotes. Hence, comprehending the mechanisms underlying these processes is important. Here, we have engineered firefly luciferase (FLuc) as a tool to detect deficiencies in these processes within mammalian cells. To achieve this, we introduced multiple cysteine substitutions into FLuc and targeted it to the ER. The reporter exhibited FLuc activity in response to defects in protein localization or disulfide bond formation within the ER. Notably, this system exhibited outstanding sensitivity, reproducibility, and convenience in detecting abnormalities in these processes. We applied this system to observe a protein translocation defect induced by an inhibitor of HIV receptor biogenesis. Moreover, utilizing the system, we showed that modulating LMF1 levels dramatically impacted the ER’s redox environment, confirming that LMF1 plays some critical role in the redox control of the ER.

Background: Traumatic fibrinolytic dysfunction is often categorized into 3 phenotypes based on the result of thromboelastography (TEG) lysis at 30 minutes (LY30): fibrinolysis shutdown, physiologic fibrinolysis, and hyperfibrinolysis. However, the molecular pathophysiology of fibrinolytic dysfunction and the association with clinical outcomes have not been fully evaluated. Objectives: To assess whether posttraumatic fibrinolysis phenotypes identified by TEG correlate with levels of key fibrinolysis-related serum markers and with risk of mortality and hospital complications. Methods: This is a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. Patients were stratified according to the degree of fibrinolysis upon arrival using TEG LY30 values: low LY30,

Abstract ERGIC-53 transports certain subsets of newly synthesized secretory proteins and membrane proteins from the endoplasmic reticulum to the Golgi apparatus. Despite numerous structural and functional studies since its identification, the overall architecture and mechanism of action of ERGIC-53 remain unclear. Here we present cryo-EM structures of full-length ERGIC-53 in complex with its functional partner MCFD2. These structures reveal that ERGIC-53 exists as a homotetramer, not a homohexamer as previously suggested, and comprises a four-leaf clover-like head and a long stalk composed of three sets of four-helix coiled-coil followed by a transmembrane domain. 3D variability analysis visualizes the flexible motion of the long stalk and local plasticity of the head region. Notably, MCFD2 is shown to possess a Zn2+-binding site in its N-terminal lid, which appears to modulate cargo binding. Altogether, distinct mechanisms of cargo capture and release by ERGIC- 53 via the stalk bending and metal binding are proposed.

Abstract Background The early management of polytrauma patients with traumatic spinal cord injury (tSCI) is a major challenge. Sparse data is available to provide optimal care in this scenario and worldwide variability in clinical practice has been documented in recent studies. Methods A multidisciplinary consensus panel of physicians selected for their established clinical and scientific expertise in the acute management of tSCI polytrauma patients with different specializations was established. The World Society of Emergency Surgery (WSES) and the European Association of Neurosurgical Societies (EANS) endorsed the consensus, and a modified Delphi approach was adopted. Results A total of 17 statements were proposed and discussed. A consensus was reached generating 17 recommendations (16 strong and 1 weak). Conclusions This consensus provides practical recommendations to support a clinician’s decision making in the management of tSCI polytrauma patients.

Background: The lack of a widely-used tool for predicting early cricothyroidotomy in trauma patients prompted us to develop the Cricothyroidotomy After Trauma (CAT) score. We aimed to predict the need for cricothyroidotomy within one hour of trauma patient arrival. Methods: Derivation and validation datasets were obtained from the Trauma Quality Improvement Program (TQIP) database. Logistic modeling identified predictors, and weighted averages were used to create the CAT score. The score's performance was assessed using AUROC. Results: Among 1,373,823 derivation patients,

Introduction The analysis of surgical research using bibliometric measures has become increasingly prevalent. Absolute citation counts (CC) or indices are commonly used markers of research quality but may not adequately capture the most impactful research. A novel scoring system, the disruptive score (DS) has been found to identity academic work that either changes paradigms (disruptive (DIS) work) or entrenches ideas (developmental (DEV) work). We sought to analyze the most DIS and DEV versus most cited research in civilian trauma.Methods The top papers by DS and by CC from trauma and surgery journals were identified via a professional literature search. The identified publications were then linked to the National Institutes of Health iCite tool to quantify total CC and related metrics. The top 100 DIS and DEV publications by DS were analyzed based on the area of focus, citation, and perceived clinical impact, and compared with the top 100 papers by CC.Results 32 293 articles published between 1954 and 2014 were identified. The most common publication location of selected articles was published in Journal of Trauma (31%). Retrospective reviews (73%) were common in DIS (73%) and top CC (67%) papers, while DEV papers were frequently case reports (49%). Only 1 publication was identified in the top 100 DIS and top 100 CC lists. There was no significant correlation between CC and DS among the top 100 DIS papers (r=0.02; p=0.85), and only a weak correlation between CC and DS score (r=0.21; p

Abstract Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S’s) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 μg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations.

Abstract Zinc ions (Zn2+) are vital to most cells, with the intracellular concentrations of Zn2+ being tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. We herein present the 2.2-3.1 Å-resolution cryo-EM structures of a Golgi-localized human Zn2+/H+ antiporter ZnT7 (hZnT7) in Zn2+-bound and unbound forms. Cryo-EM analyses show that hZnT7 exists as a dimer via tight interactions in both the cytosolic and transmembrane (TM) domains of two protomers, each of which contains a single Zn2+-binding site in its TM domain. hZnT7 undergoes a TM-helix rearrangement to create a negatively charged cytosolic cavity for Zn2+ entry in the inward-facing conformation and widens the luminal cavity for Zn2+ release in the outward-facing conformation. An exceptionally long cytosolic histidine-rich loop characteristic of hZnT7 binds two Zn2+ ions, seemingly facilitating Zn2+ recruitment to the TM metal transport pathway. These structures permit mechanisms of hZnT7-mediated Zn2+ uptake into the Golgi to be proposed.

Abstract Laparotomy incisions provide easy and rapid access to the peritoneal cavity in case of emergency surgery. Incisional hernia (IH) is a late manifestation of the failure of abdominal wall closure and represents frequent complication of any abdominal incision: IHs can cause pain and discomfort to the patients but also clinical serious sequelae like bowel obstruction, incarceration, strangulation, and necessity of reoperation. Previous guidelines and indications in the literature consider elective settings and evidence about laparotomy closure in emergency settings is lacking. This paper aims to present the World Society of Emergency Surgery (WSES) project called ECLAPTE (Effective Closure of LAParoTomy in Emergency): the final manuscript includes guidelines on the closure of emergency laparotomy.

Abstract Supersulphides are inorganic and organic sulphides with sulphur catenation with diverse physiological functions. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here, we identify protective functions of supersulphides in viral airway infections (influenza and COVID-19), in aged lungs and in chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF). We develop a method for breath supersulphur-omics and demonstrate that levels of exhaled supersulphides increase in people with COVID-19 infection and in a hamster model of SARS-CoV-2 infection. Lung damage and subsequent lethality that result from oxidative stress and inflammation in mouse models of COPD, IPF, and ageing were mitigated by endogenous supersulphides production by CARS2/CPERS or exogenous administration of the supersulphide donor glutathione trisulphide. We revealed a protective role of supersulphides in airways with various viral or chronic insults and demonstrated the potential of targeting supersulphides in lung disease.

Abstract Intra-abdominal infections (IAI) are among the most common global healthcare challenges and they are usually precipitated by disruption to the gastrointestinal (GI) tract. Their successful management typically requires intensive resource utilization, and despite the best therapies, morbidity and mortality remain high. One of the main issues required to appropriately treat IAI that differs from the other etiologies of sepsis is the frequent requirement to provide physical source control. Fortunately, dramatic advances have been made in this aspect of treatment. Historically, source control was left to surgeons only. With new technologies non-surgical less invasive interventional procedures have been introduced. Alternatively, in addition to formal surgery open abdomen techniques have long been proposed as aiding source control in severe intra-abdominal sepsis. It is ironic that while a lack or even delay regarding source control clearly associates with death, it is a concept that remains poorly described. For example, no conclusive definition of source control technique or even adequacy has been universally accepted. Practically, source control involves a complex definition encompassing several factors including the causative event, source of infection bacteria, local bacterial flora, patient condition, and his/her eventual comorbidities. With greater understanding of the systemic pathobiology of sepsis and the profound implications of the human microbiome, adequate source control is no longer only a surgical issue but one that requires a multidisciplinary, multimodality approach. Thus, while any breach in the GI tract must be controlled, source control should also attempt to control the generation and propagation of the systemic biomediators and dysbiotic influences on the microbiome that perpetuate multi-system organ failure and death. Given these increased complexities, the present paper represents the current opinions and recommendations for future research of the World Society of Emergency Surgery, of the Global Alliance for Infections in Surgery of Surgical Infection Society Europe and Surgical Infection Society America regarding the concepts and operational adequacy of source control in intra-abdominal infections.

Introduction: There may be an association between violence and methamphetamine use. We hypothesized that trauma patients screening positive for methamphetamines are more likely to present after penetrating trauma and have increased mortality. Methods: The 2017–2019 TQIP was used to 1:2 match methamphetamine (meth+) patients to patients testing negative for all drugs (meth-). Patients with polysubstance/alcohol use were excluded. Bivariate and logistic regression analyses were performed. Results: The rate of methamphetamine use was 3.1 %. After matching, there was no difference in vitals, injury severity score, sex, and comorbidities between cohorts (all p > 0.05). Compared to meth-, the meth+ group was more commonly sustained penetrating trauma (19.8 % vs. 9.2 %, p

Abstract Many secretory enzymes acquire essential zinc ions (Zn2+) in the Golgi complex. ERp44, a chaperone operating in the early secretory pathway, also binds Zn2+ 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 Zn2+ into the Golgi lumen in exchange with protons. To identify their specific roles, we here perform quantitative Zn2+ imaging using super-resolution microscopy and Zn2+-probes targeted in specific Golgi subregions. Systematic ZnT-knockdowns reveal that ZnT4, ZnT5/ZnT6 and ZnT7 regulate labile Zn2+ 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 Zn2+ fluxes tune the localization, trafficking, and client-retrieval activity of ERp44. Altogether, this study provides deep mechanistic insights into how ZnTs control Zn2+ homeostasis and ERp44-mediated proteostasis along the early secretory pathway.

Abstract Acute mesenteric ischemia (AMI) is a group of diseases characterized by an interruption of the blood supply to varying portions of the intestine, leading to ischemia and secondary inflammatory changes. If untreated, this process may progress to life-threatening intestinal necrosis. The incidence is low, estimated at 0.09–0.2% of all acute surgical admissions, but increases with age. Although the entity is an uncommon cause of abdominal pain, diligence is required because if untreated, mortality remains in the range of 50%. Early diagnosis and timely surgical intervention are the cornerstones of modern treatment to reduce the high mortality associated with this entity. The advent of endovascular approaches in parallel with modern imaging techniques is evolving and provides new treatment options. Lastly, a focused multidisciplinary approach based on early diagnosis and individualized treatment is essential. Thus, we believe that updated guidelines from World Society of Emergency Surgery are warranted, in order to provide the most recent and practical recommendations for diagnosis and treatment of AMI.

Abstract Background In 2017, the World Society of Emergency Surgery published its guidelines for the management of adult and pediatric patients with splenic trauma. Several issues regarding the follow-up of patients with splenic injuries treated with NOM remained unsolved. Methods Using a modified Delphi method, we sought to explore ongoing areas of controversy in the NOM of splenic trauma and reach a consensus among a group of 48 international experts from five continents (Africa, Europe, Asia, Oceania, America) concerning optimal follow-up strategies in patients with splenic injuries treated with NOM. Results Consensus was reached on eleven clinical research questions and 28 recommendations with an agreement rate ≥ 80%. Mobilization after 24 h in low-grade splenic trauma patients (WSES Class I, AAST Grades I–II) was suggested, while in patients with high-grade splenic injuries (WSES Classes II–III, AAST Grades III–V), if no other contraindications to early mobilization exist, safe mobilization of the patient when three successive hemoglobins 8 h apart after the first are within 10% of each other was considered safe according to the panel. The panel suggests adult patients to be admitted to hospital for 1 day (for low-grade splenic injuries—WSES Class I, AAST Grades I–II) to 3 days (for high-grade splenic injuries—WSES Classes II–III, AAST Grades III–V), with those with high-grade injuries requiring admission to a monitored setting. In the absence of specific complications, the panel suggests DVT and VTE prophylaxis with LMWH to be started within 48–72 h from hospital admission. The panel suggests splenic artery embolization (SAE) as the first-line intervention in patients with hemodynamic stability and arterial blush on CT scan, irrespective of injury grade. Regarding patients with WSES Class II blunt splenic injuries (AAST Grade III) without contrast extravasation, a low threshold for SAE has been suggested in the presence of risk factors for NOM failure. The panel also suggested angiography and eventual SAE in all hemodynamically stable adult patients with WSES Class III injuries (AAST Grades IV–V), even in the absence of CT blush, especially when concomitant surgery that requires change of position is needed. Follow-up imaging with contrast-enhanced ultrasound/CT scan in 48–72 h post-admission of trauma in splenic injuries WSES Class II (AAST Grade III) or higher treated with NOM was considered the best strategy for timely detection of vascular complications. Conclusion This consensus document could help guide future prospective studies aiming at validating the suggested strategies through the implementation of prospective trauma databases and the subsequent production of internationally endorsed guidelines on the issue.

Summary: The endoplasmic reticulum (ER) maintains an oxidative redox environment that is advantageous for the oxidative folding of nascent polypeptides entering the ER. Reductive reactions within the ER are also crucial for maintaining ER homeostasis. However, the mechanism by which electrons are supplied for the reductase activity within the ER remains unknown. Here, we identify ER oxidoreductin-1α (Ero1α) as an electron donor for ERdj5, an ER-resident disulfide reductase. During oxidative folding, Ero1α catalyzes disulfide formation in nascent polypeptides through protein disulfide isomerase (PDI) and then transfers the electrons to molecular oxygen via flavin adenine dinucleotide (FAD), ultimately yielding hydrogen peroxide (H2O2). Besides this canonical electron pathway, we reveal that ERdj5 accepts electrons from specific cysteine pairs in Ero1α, demonstrating that the oxidative folding of nascent polypeptides provides electrons for reductive reactions in the ER. Moreover, this electron transfer pathway also contributes to maintaining ER homeostasis by reducing H2O2 production in the ER.

Abstract The aim of this paper was to review the recent literature to create recommendations for the day-to-day diagnosis and surgical management of small bowel and colon injuries. Where knowledge gaps were identified, expert consensus was pursued during the 8th International Congress of the World Society of Emergency Surgery Annual (September 2021, Edinburgh). This process also aimed to guide future research.

Abstract Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections. Together, the World Society of Emergency Surgery, the Global Alliance for Infections in Surgery, the Surgical Infection Society-Europe, The World Surgical Infection Society, and the American Association for the Surgery of Trauma have jointly completed an international multi-society document to promote global standards of care in SSTIs guiding clinicians by describing reasonable approaches to the management of SSTIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting evidence was shared by an international task force with different clinical backgrounds.

Abstract Background In severely injured patients, fibrinogen supplementation is recommended when fibrinogenemia is 1, hemoglobin level 5 mEq L−1. Data are expressed as count (%), median [IQR]. Results 1076 patients were included in the study and 266 (27%) had MFD-C, among them, 122/266 (46%) received fibrinogen. Patients with MFD-C who received fibrinogen were more severely injured (ISS: 27 [19–36] vs. 24 [17–29]) and had more impaired vital signs (base deficit: 5.4 [3.6–7.8] vs. 3.8 [2.0–6.0]). Linear regression analysis found a positive correlation between fibrinogen level and FIBTEM-A5 (r: 0.805). For a fibrinogen level 1, a hemoglobin level 5.0 mEq L−1 received fibrinogen. The relative risk [95% CI] for fibrinogen administration (SI > 1) were 1.39 [1.06–1.82] for MFD-C, and 2.17 [1.48–3.19] for MFD-A5. Results were not modified after adjustment on the ISS. Conclusions We have shown in this study an association between shock parameters and fibrinogen administration. Further studies are needed to determine how these parameters may be used to guide fibrinogen administration in trauma patients with MFD.

Abstract Anorectal emergencies comprise a wide variety of diseases that share common symptoms, i.e., anorectal pain or bleeding and might require immediate management. While most of the underlying conditions do not need inpatient management, some of them could be life-threatening and need prompt recognition and treatment. It is well known that an incorrect diagnosis is frequent for anorectal diseases and that a delayed diagnosis is related to an impaired outcome. This paper aims to improve the knowledge and the awareness on this specific topic and to provide a useful tool for every physician dealing with anorectal emergencies. The present guidelines have been developed according to the GRADE methodology. To create these guidelines, a panel of experts was designed and charged by the boards of the World Society of Emergency Surgery (WSES) and American Association for the Surgery of Trauma (AAST) to perform a systematic review of the available literature and to provide evidence-based statements with immediate practical application. All the statements were presented and discussed during the WSES-AAST-WJES Consensus Conference on Anorectal Emergencies, and for each statement, a consensus among the WSES-AAST panel of experts was reached. We structured our work into seven main topics to cover the entire management of patients with anorectal emergencies and to provide an up-to-date, easy-to-use tool that can help physicians and surgeons during the decision-making process.

Abstract Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in hospitals worldwide. The cornerstones of effective treatment of IAIs include early recognition, adequate source control, appropriate antimicrobial therapy, and prompt physiologic stabilization using a critical care environment, combined with an optimal surgical approach. Together, the World Society of Emergency Surgery (WSES), the Global Alliance for Infections in Surgery (GAIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), and the American Association for the Surgery of Trauma (AAST) have jointly completed an international multi-society document in order to facilitate clinical management of patients with IAIs worldwide building evidence-based clinical pathways for the most common IAIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting information was shared by an international task force from 46 countries with different clinical backgrounds. The aim of the document is to promote global standards of care in IAIs providing guidance to clinicians by describing reasonable approaches to the management of IAIs.

Background The effects of aortic occlusion (AO) on brain injury are not well defined. We examined the impact of AO by resuscitative endovascular balloon occlusion of the aorta (REBOA) and resuscitative thoracotomy (RT) on outcomes in the setting of traumatic brain injury (TBI).Methods Patients sustaining TBI who underwent RT or REBOA in zone 1 (thoracic aorta) from September 2013 to December 2018 were identified. The indication for REBOA or RT was hemodynamic collapse due to hemorrhage below the diaphragm. Primary outcomes included mortality and systemic complications.Results 282 patients underwent REBOA or RT. Of these, 76 had mild TBI (40 REBOA, 36 RT) and 206 sustained severe TBI (107 REBOA, 99 RT). Overall, the mean (±SD) age was 42±17 years, with an Injury Severity Score (ISS) of 40±17 and mean systolic blood pressure (SBP) at the time of REBOA or RT of 81±34 mm Hg. REBOA patients had a mean SBP at the time of AO of 78.39±29.45 mm Hg, whereas RT patients had a mean SBP of 83.18±37.87 mm Hg at the time of AO (p=0.24). 55% had ongoing cardiopulmonary resuscitation (CPR) at the time of AO, and the in-hospital mortality was 86%. Binomial logistic regression controlling for TBI severity, age, ISS, SBP at the time of AO, crystalloid infusion, and CPR during AO demonstrated that the odds of mortality are 3.1 times higher for RT compared with REBOA. No significant differences were found in systemic complications between RT and REBOA.Discussion Patients with TBI who receive REBOA may have improved survival, but no difference in systemic complications, compared with patients who receive RT for the same indication. Although some patients are receiving RT prior to arrest for extrathoracic hemorrhagic shock, these results suggest that REBOA should be considered as an alternative to RT when RT is chosen for the sole purpose of resuscitation in the setting of TBI.Level of evidence 4.

Abstract Acute colonic diverticulitis is one of the most common clinical conditions encountered by surgeons in the acute setting. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of acute left-sided colonic diverticulitis (ALCD) according to the most recent available literature. The update includes recent changes introduced in the management of ALCD. The new update has been further integrated with advances in acute right-sided colonic diverticulitis (ARCD) that is more common than ALCD in select regions of the world.

Abstract Liver injuries represent one of the most frequent life-threatening injuries in trauma patients. In determining the optimal management strategy, the anatomic injury, the hemodynamic status, and the associated injuries should be taken into consideration. Liver trauma approach may require non-operative or operative management with the intent to restore the homeostasis and the normal physiology. The management of liver trauma should be multidisciplinary including trauma surgeons, interventional radiologists, and emergency and ICU physicians. The aim of this paper is to present the World Society of Emergency Surgery (WSES) liver trauma management guidelines.

Background ‘Community consultation’ (CC) is a key step when conducting Exception From Informed Consent research. Social-media-based CC has been shown to reach more people than traditional methods, but it is unclear whether those reached are representative of the community as a whole.Methods This is a retrospective analysis of the CC performed in preparation for the PHOXSTAT trial. Social media advertisement campaigns were conducted in the catchment areas of the three participating trauma centers and evaluated by examining Facebook user statistics. We compared these data to georeferenced population data obtained from the U.S. Census Bureau. We examined variations in the proportion of each age group reached, by gender.Results Our social media advertisements reached a total of 332 081 individuals in Los Angeles, Birmingham, and Nashville. Although there were differences in the proportion of individuals reached within each age group and gender groups, compared with the population in each area, these were small (within 5%). In Birmingham, participants 55 to 64 years old, 25 to 34 years old, and females 18 to 24 years old were slightly over-represented (a larger proportion of individuals in this age group were reached by the social media campaign, compared with the population resident in this area). In contrast, in Nashville, female participants 45 to 64 years old, and males 25 to 64 years old were over-represented. In Los Angeles, females 45 to 64 years old, and males 25 to 64 years and over were over-represented.Discussion In conclusion, this study demonstrates that social media CC campaigns can be used to reach a sample of the community broadly representative of the population as a whole, in terms of age and gender. This finding is helpful to IRBs and investigators, as it lends further support to the use of social media to conduct CC. Further work is needed to analyze how representative community samples are in terms of other characteristics, such as race, ethnicity, and socioeconomic status.Level III evidence Economic & Value-based Evaluations.

Background: Endovascular repair has emerged as a viable repair option for axillo-subclavian arterial injuries in select patients; however, further study of contemporary outcomes is warranted. Methods: The American Association for the Surgery of Trauma (AAST) PROspective Observational Vascular Injury Treatment (PROOVIT) registry was used to identify patients with axillo-subclavian arterial injuries from 2013 to 2019. Demographics and outcomes were compared between patients undergoing endovascular repair versus open repair. Results: 167 patients were identified, with intervention required in 107 (64.1%). Among these, 24 patients underwent open damage control surgery (primary amputation = 3, ligation = 17, temporary vascular shunt = 4). The remaining 83 patients (91.6% male; mean age 26.0 ± 16) underwent either endovascular repair (36, 43.4%) or open repair (47, 56.6%). Patients managed with definitive endovascular or open repair had similar demographics and presentation, with the only exception being that endovascular repair was more commonly employed for traumatic pseudoaneurysms (p = 0.004). Endovascular repair was associated with lower 24-hour transfusion requirements (p = 0.012), but otherwise the two groups were similar with regards to in-hospital outcomes. Conclusion: Endovascular repair is now employed in > 40% of axillo-subclavian arterial injuries undergoing repair at initial operation and is associated with lower 24-hour transfusion requirements, but otherwise outcomes are comparable to open repair.

Summary: Arabidopsis FLOWERING LOCUS T (FT) is a pivotal component of florigen, a long-range mobile flowering signal. Here, we determined the 1.0 Å-resolution crystal structure of FT, a significantly higher-resolution crystal structure of FT than previously reported one (2.6 Å). The present crystallographic studies revealed 4 alternative configurations with the precise location of the surrounding water molecules. Using this structural data, computational docking simulation predicted the putative binding sites for phosphatidylcholine (PC), an endogenous ligand that interacts with FT to modulate flowering time. In vitro reconstitution of the lipid–protein interaction showed that mutations at two of the predicted sites significantly compromised the lipid binding ability of FT. In planta, one of the mutant FT proteins significantly affected FT function in flowering, emphasizing the involvement of PC binding in modulating FT function. Our structural, biochemical, and transgenic analyses reveal the molecular mechanism of PC binding in FT-mediated flowering time control. : Biological Sciences; Plant Biochemistry; Structural Biology; Plant Biology Subject Areas: Biological Sciences, Plant Biochemistry, Structural Biology, Plant Biology

Zinc ions (Zn2+) are imported by Golgi-resident transporters but the function of zinc in the early secretory pathway has remained unknown. Here the authors find that Zn2+ regulates protein quality control in the early secretory pathway by demonstrating that the pH-sensitive chaperone ERp44 binds Zn2+ and solving the Zn2+-bound ERp44 structure.

Summary: The mammalian endoplasmic reticulum (ER) harbors more than 20 members of the protein disulfide isomerase (PDI) family that act to maintain proteostasis. Herein, we developed an in vitro system for directly monitoring PDI- or ERp46-catalyzed disulfide bond formation in ribosome-associated nascent chains of human serum albumin. The results indicated that ERp46 more efficiently introduced disulfide bonds into nascent chains with a short segment exposed outside the ribosome exit site than PDI. Single-molecule analysis by high-speed atomic force microscopy further revealed that PDI binds nascent chains persistently, forming a stable face-to-face homodimer, whereas ERp46 binds for a shorter time in monomeric form, indicating their different mechanisms for substrate recognition and disulfide bond introduction. Thus, ERp46 serves as a more potent disulfide introducer especially during the early stages of translation, whereas PDI can catalyze disulfide formation when longer nascent chains emerge out from ribosome.

Rectal injuries are rare but potentially devastating injuries that are frequently associated with penetrating pelvic trauma or blunt pelvic fractures. Management principles for these injuries have gone through major paradigm shifts over time. Recently, large-scale civilian studies have been completed, providing valuable insight on best-practice strategies for contemporary trauma populations. The diagnosis of rectal injuries is accomplished with a combination of computed tomography (CT) scanning and rigid proctoscopy. Because the rectum is comprised of two distinct anatomic segments, the intra- and extraperitoneal rectum, management principles for rectal injuries are unique. Intraperitoneal rectal injuries are managed as colonic injuries, with small injuries primarily repaired and larger injuries resected. Extraperitoneal injuries are repaired primarily via a trans-anal approach, if feasible, and otherwise are managed with proximal diversion alone. Complications seen after rectal injuries include infection, strictures, and fistulae. The most provocative questions about rectal injuries that are currently unanswered relate to the possibility of nonoperative management for penetrating extraperitoneal rectal injuries and to the optimal timing of colostomy reversal after proximal diversion for extraperitoneal injuries.

Background Non-compressible truncal hemorrhage (NCTH) is the leading cause of preventable death after trauma. Resuscitative endovascular balloon occlusion of the aorta (REBOA) achieves temporary hemorrhage control, supporting cardiac and cerebral perfusion prior to definitive hemostasis. Aortic zone selection algorithms vary among institutions. We evaluated the efficacy of an algorithm for REBOA use.Methods A multicenter prospective, observational study conducted at six level 1 trauma centers over 12 months. Inclusion criteria were age >15 years with evidence of infradiaphragmatic NCTH needing emergent hemorrhage control within 60 min of ED arrival. An algorithm characterized by the results of focused assessment with sonography in trauma and pelvic X-ray was assessed post hoc for efficacy in a cohort of patients receiving REBOA.Results Of the 8166 patients screened, 78 patients had a REBOA placed. 21 patients were excluded, leaving 57 patients for analysis. The algorithm ensures REBOA deployment proximal to hemorrhage source to control bleeding in 98.2% of cases and accurately predicts the optimal REBOA zone in 78.9% of cases. If the algorithm was violated, bleeding was optimally controlled in only 43.8% (p=0.01). Three (75.0%) of the patients that received an inappropriate zone 1 REBOA died, two from multiple organ failure (MOF). All three patients that died with an inappropriate zone 3 REBOA died from exsanguination.Discussion This algorithm ensures proximal hemorrhage control and accurately predicts the primary source of hemorrhage. We propose a new algorithm that will be more inclusive. A zone 3 REBOA should not be performed when a zone 1 is indicated by the algorithm as 100% of these patients exsanguinated. MOF, perhaps from visceral ischemia in patients with an inappropriate zone 1 REBOA, may have been prevented with zone 3 placement or limited zone 1 occlusion time.Level of evidence Level III.

Genes encoding snake venom toxins have been studied extensively. However, genes involved in the modification and functioning of venom proteins are little known. Protobothrops is a genus of pit vipers, which are venomous and inhabit the Nansei (Southwest) islands of Japan, Taiwan China, Vietnam, Thailand, Myanmar, Nepal, Bhutan, and India. Our previous study decoded the genome of Protobothrops flavoviridis, a species endemic to the Nansei Islands, Japan, and revealed unique evolutionary processes of some venom genes. In this study, we analyzed genes that are highly expressed in venom glands to survey genes for candidate enzymes or chaperone proteins involved in toxin folding and modification. We found that, in addition to genes that encode venom proteins and ribosomal proteins, genes that encode protein disulfide isomerase (PDI) family members (orthologs of human P4HB and PDIA3), Selenoprotein M (SELENOM), and Calreticulin (CALR) are highly expressed in venom glands. Since these enzymes or chaperones are involved in protein modification and potentially possess protein folding functions, we propose that P4HB, SELENOM, CALR, and PDIA3 encode candidate enzymes or chaperones to confer toxic functions upon the venom transcriptome.

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 β-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine.

Background: The aim of this study was to evaluate patency following the deployment of a bare-metal stent (BMS) or covered stent (CS) across a traumatic occlusive peripheral arterial lesion and to estimate the feasibility of urgent stent placement for temporary endovascular shunting. Methods: Fifteen sheep (25–45 kg) underwent laparoscopic creation of a left external iliac artery (EIA) thrombosis by means of repeated clamping. Sixty minutes after achievement of thrombotic occlusion, animals were randomized into one of three groups: no-treatment (control group), a BMS group, or CS group. Animals were followed up for 30 days with no anticoagulants or anti-platelet drugs administered postoperatively. Doppler ultrasound, computed tomography angiography (CTA), and digital subtraction angiography (DSA) were used to evaluate EIA patency. Results: Stent implantation resulted in the restoration of in-line flow through the EIA in all cases. The peak systolic velocity (PSV) in the injured limb increased from 10 (0–16) to 31 (28–37) cm/s in the BMS group (p < 0.0001) and from 15 (7–18) to 24 (21–29) cm/s in the CS group (p = 0.043) immediately after stent deployment (both p = 0.001 compared with the control group). There was no difference in the PSV between the groups at post-injury day 3, and thereafter. Day-14 CTA and day-30 DSA demonstrated only one patent stent in each study group. Conclusions: Urgent stent (BMS or CS) implantation can restore arterial patency of a traumatic occlusion for a short period of time and serve as a temporary endovascular shunt. Distal embolization can complicate this procedure and worsen long-term patency.

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 pre-specified 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 Background Adhesive small bowel obstruction (ASBO) is a common surgical emergency, causing high morbidity and even some mortality. The adhesions causing such bowel obstructions are typically the footprints of previous abdominal surgical procedures. The present paper presents a revised version of the Bologna guidelines to evidence-based diagnosis and treatment of ASBO. The working group has added paragraphs on prevention of ASBO and special patient groups. Methods The guideline was written under the auspices of the World Society of Emergency Surgery by the ASBO working group. A systematic literature search was performed prior to the update of the guidelines to identify relevant new papers on epidemiology, diagnosis, and treatment of ASBO. Literature was critically appraised according to an evidence-based guideline development method. Final recommendations were approved by the workgroup, taking into account the level of evidence of the conclusion. Recommendations Adhesion formation might be reduced by minimally invasive surgical techniques and the use of adhesion barriers. Non-operative treatment is effective in most patients with ASBO. Contraindications for non-operative treatment include peritonitis, strangulation, and ischemia. When the adhesive etiology of obstruction is unsure, or when contraindications for non-operative management might be present, CT is the diagnostic technique of choice. The principles of non-operative treatment are nil per os, naso-gastric, or long-tube decompression, and intravenous supplementation with fluids and electrolytes. When operative treatment is required, a laparoscopic approach may be beneficial for selected cases of simple ASBO. Younger patients have a higher lifetime risk for recurrent ASBO and might therefore benefit from application of adhesion barriers as both primary and secondary prevention. Discussion This guideline presents recommendations that can be used by surgeons who treat patients with ASBO. Scientific evidence for some aspects of ASBO management is scarce, in particular aspects relating to special patient groups. Results of a randomized trial of laparoscopic versus open surgery for ASBO are awaited.

Abstract Damage control resuscitation may lead to postoperative intra-abdominal hypertension or abdominal compartment syndrome. These conditions may result in a vicious, self-perpetuating cycle leading to severe physiologic derangements and multiorgan failure unless interrupted by abdominal (surgical or other) decompression. Further, in some clinical situations, the abdomen cannot be closed due to the visceral edema, the inability to control the compelling source of infection or the necessity to re-explore (as a “planned second-look” laparotomy) or complete previously initiated damage control procedures or in cases of abdominal wall disruption. The open abdomen in trauma and non-trauma patients has been proposed to be effective in preventing or treating deranged physiology in patients with severe injuries or critical illness when no other perceived options exist. Its use, however, remains controversial as it is resource consuming and represents a non-anatomic situation with the potential for severe adverse effects. Its use, therefore, should only be considered in patients who would most benefit from it. Abdominal fascia-to-fascia closure should be done as soon as the patient can physiologically tolerate it. All precautions to minimize complications should be implemented.

Abstract Background The traditional sequence of trauma care: Airway, Breathing, Circulation (ABC) has been practiced for many years. It became the standard of care despite the lack of scientific evidence. We hypothesized that patients in hypovolemic shock would have comparable outcomes with initiation of bleeding treatment (transfusion) prior to intubation (CAB), compared to those patients treated with the traditional ABC sequence. Methods This study was sponsored by the American Association for the Surgery of Trauma multicenter trials committee. We performed a retrospective analysis of all patients that presented to trauma centers with presumptive hypovolemic shock indicated by pre-hospital or emergency department hypotension and need for intubation from January 1, 2014 to July 1, 2016. Data collected included demographics, timing of intubation, vital signs before and after intubation, timing of the blood transfusion initiation related to intubation, and outcomes. Results From 440 patients that met inclusion criteria, 245 (55.7%) received intravenous blood product resuscitation first (CAB), and 195 (44.3%) were intubated before any resuscitation was started (ABC). There was no difference in ISS, mechanism, or comorbidities. Those intubated prior to receiving transfusion had a lower GCS than those with transfusion initiation prior to intubation (ABC: 4, CAB:9, p = 0.005). Although mortality was high in both groups, there was no statistically significant difference (CAB 47% and ABC 50%). In multivariate analysis, initial SBP and initial GCS were the only independent predictors of death. Conclusion The current study highlights that many trauma centers are already initiating circulation first prior to intubation when treating hypovolemic shock (CAB), even in patients with a low GCS. This practice was not associated with an increased mortality. Further prospective investigation is warranted. Trial registration IRB approval number: HM20006627. Retrospective trial not registered.

P5 is one of protein disulfide isomerase family proteins (PDIs) involved in endoplasmic reticulum (ER) protein quality control that assists oxidative folding, inhibits protein aggregation, and regulates the unfolded protein response. P5 reportedly interacts with other PDIs via intermolecular disulfide bonds in cultured cells, but it remains unclear whether complex formation between P5 and other PDIs is involved in regulating enzymatic and chaperone functions. Herein, we established the far-western blot method to detect non-covalent interactions between P5 and other PDIs and found that PDI and ERp72 are partner proteins of P5. The enzymatic activity of P5-mediated oxidative folding is up-regulated by PDI, while the chaperone activity of P5 is stimulated by ERp72. These findings shed light on the mechanism by which the complex formations among PDIs drive to synergistically accelerate protein folding and prevents aggregation. This knowledge has implications for understanding misfolding-related pathology.

Cysteine hydropersulfides (CysSSH) are believed to have a cellular redox protective role. Here the authors show that these species can be produced from L-cysteine by cysteinyl-tRNA synthetases and that these enzymes are also involved in mitochondrial biogenesis and bioenergetics regulation.

Abstract Spleen injuries are among the most frequent trauma-related injuries. At present, they are classified according to the anatomy of the injury. The optimal treatment strategy, however, should keep into consideration the hemodynamic status, the anatomic derangement, and the associated injuries. The management of splenic trauma patients aims to restore the homeostasis and the normal physiopathology especially considering the modern tools for bleeding management. Thus, the management of splenic trauma should be ultimately multidisciplinary and based on the physiology of the patient, the anatomy of the injury, and the associated lesions. Lastly, as the management of adults and children must be different, children should always be treated in dedicated pediatric trauma centers. In fact, the vast majority of pediatric patients with blunt splenic trauma can be managed non-operatively. This paper presents the World Society of Emergency Surgery (WSES) classification of splenic trauma and the management guidelines.

Abstract Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in the emergency departments worldwide. The cornerstones of effective treatment of IAIs are early recognition, adequate source control, and appropriate antimicrobial therapy. Prompt resuscitation of patients with ongoing sepsis is of utmost important. In hospitals worldwide, non-acceptance of, or lack of access to, accessible evidence-based practices and guidelines result in overall poorer outcome of patients suffering IAIs. The aim of this paper is to promote global standards of care in IAIs and update the 2013 WSES guidelines for management of intra-abdominal infections.

Abstract Background Traumatic, non-iatrogenic esophageal injuries, despite their rarity, are associated with significant morbidity and mortality. The optimal management of these esophageal perforations remains largely debated. To date, only a few small case series are available with contrasting results. The purpose of this study was to examine a large contemporary experience with traumatic esophageal injury management and to analyze risk factors associated with mortality. Methods This National Trauma Data Bank (NTDB) database study included patients with non-iatrogenic esophageal injuries. Variables abstracted were demographics, comorbidities, mechanism of injury, Abbreviated Injury Scale (AIS), esophageal Organ Injury Scale (OIS), Injury Severity Score (ISS), level of injury, vital signs, and treatment. Multivariate analysis was used to identify independent predictors for mortality and overall complications. Results A total of 944 patients with non-iatrogenic esophageal injury were included in the final analysis. The cervical segment of the esophagus was injured in 331 (35%) patients. The unadjusted 24-h mortality (8.2 vs. 14%, p = 0.008), 30-day mortality (4.2 vs. 9.3%, p = 0.005), and overall mortality (7.9 vs. 13.5%, p = 0.009) were significantly lower in the group of patients with a cervical injury. The overall complication rate was also lower in the cervical group (19.8 vs. 27.1%, p = 0.024). Multilogistic regression analysis identified age >50, thoracic injury, high-grade esophageal injury (OIS IV–V), hypotension on admission, and GCS

Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a less-invasive technique for aortic occlusion (AO). Commonly performed in the emergency department (ED), the role of intraoperative placement is less defined. We hypothesized that operating room (OR) placement is associated with increased in-hospital mortality.Methods The American Association for the Surgery of Trauma AORTA registry was used to identify patients undergoing REBOA. Injury characteristics and outcomes data were compared between OR and ED groups. The primary outcome was in-hospital mortality; secondary outcomes included total AO time, transfusion requirements, and acute kidney injury.Results Location and timing of catheter insertion were available for 305 of 321 (95%) subjects. 58 patients underwent REBOA in the OR (19%). There were no differences with respect to sex, admission lactate, and Injury Severity Score. The OR group was younger (33 years vs. 41 years, p=0.01) and with more penetrating injuries (36% vs. 15%, p

Background: The introduction of low-profile devices designed for resuscitative endovascular balloon occlusion of the aorta (REBOA) after trauma has the potential to change practice, outcomes, and complication profiles. Methods: The AAST Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery (AORTA) registry was used to identify REBOA patients from 16 centers. Presentation, intervention, and outcome variables were compared via traditional 11–12 French access platforms and trauma-specific devices requiring only 7 French access. Results: From November 2013 to December 2017, 242 patients with complete data were identified, constituting 124 7 French and 118 11–12 French uses. Demographics of presentation were not diff erent between the two groups, except that patients using the 7 French had a higher mean Injury Severity Score (39.2 vs. 34.1, p = 0.028). The 7 French was associated with a lower cut-down requirement for access (22.6% vs. 37.3%, p = 0.049) and increased ultrasound guidance utilization (29.0% vs. 23.7%, p = 0.049). The 7 French afforded earlier aortic occlusion in the course of resuscitation (median 25.0 mins vs. 30 mins, p = 0.010) and a lower median requirement of packed red blood cells (10.0 vs. 15.5 units, p = 0.006) and fresh frozen plasma (7.5 vs. 14.0 units, p = 0.005). The 7 French patients were more likely to survive 24 h (58.1% vs. 42.4%, p = 0.015) and less likely to suff er in-hospital mortality (57.3% vs. 75.4%, p = 0.003). Finally, the 7 French device was associated with a four times lower rate of distal extremity embolism (20.0% vs. 5.6%, p = 0.014; OR 95% CI 4.25 [1.25–14.45]) compared to the 11–12 French. Conclusions: The introduction of trauma-specific 7 French REBOA devices appears to have infl uenced REBOA practices, with earlier use in severely injured hypotensive patients via less invasive means that are associated with lower transfusion requirements, fewer thrombotic complications, and improved survival. Additional study is required to determine optimal REBOA use.

ERp57, a member of the protein disulfide isomerase family, is a ubiquitous disulfide catalyst that functions in the oxidative folding of various clients in the mammalian endoplasmic reticulum (ER). In concert with ER lectin-like chaperones calnexin and calreticulin (CNX/CRT), ERp57 functions in virtually all folding stages from co-translation to post-translation, and thus plays a critical role in maintaining protein homeostasis, with direct implication for pathology. Here, we present mechanisms by which Ca2+ regulates the formation of the ERp57-calnexin complex. Biochemical and isothermal titration calorimetry analyses revealed that ERp57 strongly interacts with CNX via a non-covalent bond in the absence of Ca2+. The ERp57-CNX complex not only promoted the oxidative folding of human leukocyte antigen heavy chains, but also inhibited client aggregation. These results suggest that this complex performs both enzymatic and chaperoning functions under abnormal physiological conditions, such as Ca2+ depletion, to effectively guide proper oxidative protein folding. The findings shed light on the molecular mechanisms underpinning crosstalk between the chaperone network and Ca2+.