Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress

Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Demographic patterns and outcomes of patients in level I trauma centers in three international trauma systems

Introduction: Trauma systems were developed to improve the care for the injured. The designation and elements comprising these systems vary across countries. In this study, we have compared the demographic patterns and patient outcomes of Level I trauma centers in three international trauma systems. Methods: International multicenter prospective trauma registry-based study, performed in the University Medical Center Utrecht (UMCU), Utrecht, the Netherlands, John Hunter Hospital (JHH), Newcastle, Australia, and Harborview Medical Center (HMC), Seattle, the United States. Inclusion: patients =18 years, admitted in 2012, registered in the institutional trauma registry. Results: In UMCU, JHH, and HMC, respectively, 955, 1146, and 4049 patients met the inclusion criteria of which 300, 412, and 1375 patients with Injury Severity Score (ISS) > 15. Mean ISS was higher in JHH (13.5; p < 0.001) and HMC (13.4; p < 0.001) compared to UMCU (11.7). Unadjusted mortality: UMCU = 6.5 %, JHH = 3.6 %, and HMC = 4.8 %. Adjusted odds of death: JHH = 0.498 [95 % confidence interval (CI) 0.303-0.818] and HMC = 0.473 (95 % CI 0.325-0.690) compared to UMCU. HMC compared to JHH was 1.002 (95 % CI 0.664-1.514). Odds of death patients ISS > 15: JHH = 0.507 (95 % CI 0.300-0.857) and HMC = 0.451 (95 % CI 0.297-0.683) compared to UMCU. HMC = 0.931 (95 % CI 0.608-1.425) compared to JHH. TRISS analysis: UMCU: Ws = 0.787, Z = 1.31, M = 0.87; JHH, Ws = 3.583, Z = 6.7, M = 0.89; HMC, Ws = 3.902, Z = 14.6, M = 0.84. Conclusion: This study demonstrated substantial differences across centers in patient characteristics and mortality, mainly of neurological cause. Future research must investigate whether the outcome differences remain with nonfatal and long-term outcomes. Furthermore, we must focus on the development of a more valid method to compare systems

Venous thromboembolism (VTE) prophylaxis in severely injured patients: an international comparative assessment

PURPOSE: Venous thromboembolisms (VTE) are a major concern after acute survival from trauma. Variations in treatment protocols for trauma patients exist worldwide. This study analyzes the differences in the number of VTE events and the associated complications of thromboprophylaxis between two level I trauma populations utilizing varying treatment protocols. METHODS: International multicenter trauma registry-based study was performed at the University Medical Center Utrecht (UMCU) in The Netherlands (early commencement chemical prophylaxis), and Harborview Medical Center (HMC) in the United States (restrictive early chemical prophylaxis). All severely injured patients (ISS ≥ 16), aged ≥ 18 years, and admitted in 2013 were included. Primary outcomes were VTE [deep venous thrombosis (DVT) (no screening), pulmonary embolism (PE)], and hemorrhagic complications. RESULTS: In UMCU, 279 patients were included and in HMC, 974 patients. Overall, 75% of the admitted trauma patients in UMCU and 81% in HMC (p < 0.001) received thromboprophylaxis, of which 100% in and 75% at, respectively, UMCU and HMC consisted of chemical prophylaxis. From these patients, 72% at UMCU and 47% at HMC (p < 0.001) were treated within 48 h after arrival. At UMCU, 4 patients (1.4%) (PE = 3, DVT = 1) and HMC 37 patients (3.8%) (PE = 22, DVT = 16; p = 0.06) developed a VTE. At UMCU, a greater percent of patients with VTE had traumatic brain injuries (TBI). Most VTE occurred despite adequate prophylaxis being given (75% UMCU and 81% HMC). Hemorrhagic complications occurred in, respectively, 4 (1.4%) and 10 (1%) patients in UMCU and HMC (p = 0.570). After adjustment for age, ISS, HLOS, and injury type, no significant difference was demonstrated in UMCU compared to HMC for the development of VTE, OR 2.397, p = 0.102 and hemorrhagic complications, OR 0. 586, p = 0.383. CONCLUSIONS: A more early commencement protocol resulted in almost twice as much chemical prophylaxis being started within the first 48 h in comparison with a more delayed initiation of treatment. Interestingly, most episodes of VTE developed while receiving recommended prophylaxis. Early chemical thromboprophylaxis did not significantly increase the bleeding complications and it appears to be safe to start early

Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA)

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs

Management of intra-abdominal infections : recommendations by the WSES 2016 consensus conference

This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.Peer reviewe

Inter-rater reliability of the Abbreviated Injury Scale scores in patients with severe head injury shows good inter-rater agreement but variability between countries. An inter-country comparison study

Introduction: Substantial difference in mortality following severe traumatic brain injury (TBI) across international trauma centers has previously been demonstrated. This could be partly attributed to variability in the severity coding of the injuries. This study evaluated the inter-rater and intra-rater reliability of Abbreviated Injury Scale (AIS) scores of patients with severe TBI across three international level I trauma centers. Methods: A total 150 patients (50 per center) were randomly selected from each respective trauma registry: University Medical Center Utrecht (UMCU), the Netherlands; John Hunter Hospital (JHH), Australia; and Harborview Medical Center (HMC), the United States. Reliability between coders and trauma centers was measured with the intraclass correlation coefficient (ICC). Results: The reliability between the coders and the original trauma registry scores was 0.50, 0.50, and 0.41 in, respectively, UMCU, JHH, and HMC. The AIS coders at UMCU scored the most AIS codes of ≥ 4. Reliability within the trauma centers was substantial in UMCU (ICC = 0.62) and HMC (ICC = 0.78) and almost perfect in JHH (ICC = 0.85). Reliability between trauma centers was 0.70 between UMCU and JHH, 0.70 between JHH and HMC, and 0.59 between UMCU and HMC. Conclusion: The results of this study demonstrated a substantial and almost perfect reliability of the AIS coders within the same trauma center, but variability across trauma centers. This indicates a need to improve inter-rater reliability in AIS coders and quality assessments of trauma registry data, specifically for patients with head injuries. Future research should study the effect of differences in AIS scoring on outcome predictions

Preserve encephalus in surgery of trauma: online survey. (P.E.S.T.O)

Abstract Background Traumatic brain injury (TBI) is a global health problem. Extracranial hemorrhagic lesions needing emergency surgery adversely affect the outcome of TBI. We conducted an international survey regarding the acute phase management practices in TBI polytrauma patients. Methods A questionnaire was available on the World Society of Emergency Surgery website between December 2017 and February 2018. The main endpoints were the evaluation of (1) intracranial pressure (ICP) monitoring during extracranial emergency surgery (EES), (2) hemodynamic management without ICP monitoring during EES, (3) coagulation management, and (4) utilization of simultaneous multisystem surgery (SMS). Results The respondents were 122 representing 105 trauma centers worldwide. ICP monitoring was utilized in 10–30% of patients at risk of intracranial hypertension (IH) undergoing EES from about a third of the respondents [n = 35 (29%)]. The respondents reported that the safest values of systolic blood pressure during EES in patients at risk of IH were 90–100 mmHg [n = 35 (29%)] and 100–110 mmHg [n = 35 (29%)]. The safest values of mean arterial pressure during EES in patients at risk of IH were > 70 mmHg [n = 44 (36%)] and > 80 mmHg [n = 32 (26%)]. Regarding ICP placement, a large percentage of respondents considered a platelet (PLT) count > 50,000/mm3 [n = 57 (47%)] and a prothrombin time (PT)/activated partial thromboplastin time (aPTT)  100,000/mm3 [n = 67 (55%)] and a PT/aPTT < 1.5 times the normal control [n = 76 (62%)] to be the safest parameters. Almost half of the respondents [n = 53 (43%)], reported that they transfused red blood cells (RBCs)/plasma (P)/PLTs at a ratio of 1/1/1 in TBI polytrauma patients. SMS was performed in 5–19% of patients, requiring both an emergency neurosurgical operation and EES, by almost half of the respondents [n = 49 (40%)]. Conclusions A great variability in practices during the acute phase management of polytrauma patients with severe TBI was identified. These findings may be helpful for future investigations and educational purposes