Prevalence of Rotational Malalignment After Infrapatellar Versus Suprapatellar Intramedullary Nailing of Tibial Shaft Fractures.

Background: Up to 30% of patients with a tibial shaft fracture sustain iatrogenic rotational malalignment (RM) after infrapatellar (IP) nailing. Although IP nailing remains the management of choice for most patients, suprapatellar (SP) nailing has been gaining popularity. It is currently unknown whether SP nailing can provide superior outcomes with regard to tibial RM. The aim of this study was to compare the differences in the prevalence of RM following IP versus SP nailing. Methods: This retrospective study included 253 patients with a unilateral, closed tibial shaft fracture treated with either an IP or SP approach between January 2009 and April 2023 in a Level-I trauma center. All patients underwent a postoperative, protocolized, bilateral computed tomography (CT) scan for RM assessment. Results: RM was observed in 30% and 33% of patients treated with IP and SP nailing, respectively. These results indicate no significant difference (p = 0.639) in the prevalence of RM between approaches. Furthermore, there were no significant differences in the distribution (p = 0.553) and direction of RM (p = 0.771) between the 2 approaches. With the IP and SP approaches, nailing of left-sided tibial shaft fractures resulted in predominantly internal RM (85% and 73%, respectively), while nailing of right-sided tibial shaft fractures resulted in predominantly external RM (90% and 80%, respectively). The intraobserver reliability for the CT measurements was 0.95. Conclusions: The prevalence of RM was not influenced by the entry point of tibial nailing (i.e., IP versus SP). Hence, the choice of surgical approach should rely on factors other than the risk of RM. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Cast immobilization duration for distal radius fractures, a systematic review.

PURPOSE: The optimal duration of immobilization for the conservative treatment of non- or minimally displaced and displaced distal radius fractures remains under debate. This research aims to review studies of these treatments to add evidence regarding the optimal immobilization period. METHODS: A comprehensive database search was conducted. Studies investigating and comparing short (< 3 weeks) versus long (> 3 weeks) immobilizations for the conservative treatment of distal radius fractures were included. The studies were evaluated for radiological and functional outcomes, including pain, grip strength, and range of motion. Two reviewers independently reviewed all studies and performed the data extraction. RESULTS: The initial database search identified 11.981 studies, of which 16 (involving 1.118 patients) were ultimately included. Patient-reported outcome measurements, grip strength, range of motion, and radiological outcomes were often better after shorter immobilization treatments. Radiological outcomes were better with longer immobilization in two studies and shorter immobilization in one study. Fourteen studies concluded that early mobilization is preferred, while the remaining two studies observed better outcomes with longer immobilization. The data were unsuitable for meta-analysis due to their heterogeneous nature. CONCLUSION: Shorter immobilization for conservatively treated distal radius fractures often yield equal or better outcomes than longer immobilizations. The immobilization for non- or minimally displaced distal radius fractures could therefore be shortened to 3 weeks or less. Displaced and reduced distal radius fractures cannot be immobilized shorter than 4 weeks due to the risk of complications. Future research with homogeneous groups could elucidate the optimal duration of immobilization.

Sphingosine Prevents Rhinoviral Infections.

Rhinoviral infections cause approximately 50% of upper respiratory tract infections and novel treatment options are urgently required. We tested the effects of 10 µM to 20 µM sphingosine on the infection of cultured and freshly isolated human cells with minor and major group rhinovirus in vitro. We also performed in vivo studies on mice that were treated with an intranasal application of 10 µL of either a 10 µM or a 100 µM sphingosine prior and after infection with rhinovirus strains 1 and 2 and determined the infection of nasal epithelial cells in the presence or absence of sphingosine. Finally, we determined and characterized a direct binding of sphingosine to rhinovirus. Our data show that treating freshly isolated human nasal epithelial cells with sphingosine prevents infections with rhinovirus strains 2 (minor group) and 14 (major group). Nasal infection of mice with rhinovirus 1b and 2 is prevented by the intranasal application of sphingosine before or as long as 8 h after infection with rhinovirus. Nasal application of the same doses of sphingosine exerts no adverse effects on epithelial cells as determined by hemalaun and TUNEL stainings. The solvent, octylglucopyranoside, was without any effect in vitro and in vivo. Mechanistically, we demonstrate that the positively charged lipid sphingosine binds to negatively charged molecules in the virus, which seems to prevent the infection of epithelial cells. These findings indicate that exogenous sphingosine prevents infections with rhinoviruses, a finding that could be therapeutically exploited. In addition, we demonstrated that sphingosine has no obvious adverse effects on the nasal mucosa. Sphingosine prevents rhinoviral infections by a biophysical mode of action, suggesting that sphingosine could serve to prevent many viral infections of airways and epithelial cells in general. Future studies need to determine the molecular mechanisms of how sphingosine prevents rhinoviral infections and whether sphingosine also prevents infections with other viruses inducing respiratory tract infections. Furthermore, our studies do not provide detailed pharmacokinetics that are definitely required before the further development of sphingosine.

European military surgical teams in combat theater: A survey study on deployment preparation and experience.

INTRODUCTION: Adequate (predeployment) training of the nowadays highly specialized Western military surgical teams is vital to ensure a broad range of surgical skills to treat combat casualties. This survey study aimed to assess the self-perceived preparedness, training needs, deployment experience, and post-deployment impact of surgical teams deployed with the Danish, Dutch, or Finnish Armed Forces. Study findings may facilitate a customized predeployment training. METHODS: A questionnaire was distributed among Danish, Dutch, and Finnish military surgical teams deployed between January 2013 and December 2020 (N = 142). The primary endpoint of self-perceived preparedness ratings, and data on the training needs, deployment experiences, and post-deployment impacts were compared between professions and nations. RESULTS: The respondents comprised 35 surgeons, 25 anesthesiologists, and 39 supporting staff members, with a response rate of 69.7 % (99/142). Self-perceived deployment preparedness was rated with a median of 4.0 (IQR 4.0-4.0; scale: 1 [very unprepared]-5 [more than sufficient]). No differences were found among professions and nations. Skills that surgeons rated below average (median <6.0; scale: 1 [low]-10 [high]) included tropical disease management and maxillofacial, neurological, gynecological, ophthalmic, and nerve repair surgery. The deployment caseload was most often reported as <1 case per week (41/99, 41.4 %). The need for professional psychological help was rated at a median of 1.0 (IQR 1.0-1.0; scale: 1 [not at all]-5 [very much]). CONCLUSIONS: Military surgical teams report overall adequate preparedness for deployment. Challenges remain for establishing broadly skilled teams because of a low deployment caseload and ongoing primary specializations. Additional training and exposure were indicated for several specialism-specific skill areas. The need for specific training should be addressed through customized predeployment programs.

Are the non-weight bearing guidelines for the after treatment of calcaneal fractures still decisive? A Dutch survey among orthopaedic and trauma surgeons.

PURPOSE: The current rehabilitation for patients with surgically treated displaced intra-articular calcaneal fractures (DIACFs) consists of non-weightbearing for 8-12 weeks. The purpose of the present survey was to investigate the current pre-, peri- and post-operative practices among Dutch foot and ankle surgeons. Moreover, it aims to analyze whether surgeons comply to the Arbeitsgemeinschaft für Osteosynthesefragen (AO) guidelines and which decision criteria were used in the determination of the start of weightbearing. METHODS: A survey was distributed among Dutch trauma and orthopaedic surgeons to determine the most common practices in postoperative weightbearing in patients with DIACFs. RESULTS: 75 surgeons responded to the survey. 33% of the respondents adhered to the AO guidelines. 4% of the respondents strictly followed non-weightbearing guidelines, while 96% interpret the AO guidelines or their local protocol freely, in any frequency. When respondents tended to deviate from the AO guidelines or local protocol, a good patients' compliance to therapy was expected. 83% of the respondents started weightbearing on the fracture, based on reported patient complaints. 87% of the respondents did not see any relation between early weightbearing and the occurrence of complications, including loosening of osteosynthesis materials. CONCLUSION: This study demonstrates that there is limited consensus on the rehabilitation for DIACFs. Moreover, it shows that most surgeons are inclined to interpret the current (AO) guideline or their own local protocol freely. New guidelines, supported with well-founded literature, could help surgeons in a more appropriate daily practice in weightbearing for the rehabilitation of calcaneal fractures.

Sex Differences in Outcome of Trauma Patients Presented with Severe Traumatic Brain Injury: A Multicenter Cohort Study.

The objective of this study was to determine whether there is an association between sex and outcome in trauma patients presented with severe traumatic brain injury (TBI). A retrospective multicenter study was performed in trauma patients aged ≥ 16 years who presented with severe TBI (Head Abbreviated Injury Scale (AIS) ≥ 4) over a 4-year-period. Subgroup analyses were performed for ages 16-44 and ≥45 years. Also, patients with isolated severe TBI (other AIS ≤ 2) were assessed, likewise, with subgroup analysis for age. Sex differences in mortality, Glasgow Outcome Score (GOS), ICU admission/length of stay (LOS), hospital LOS, and mechanical ventilation (MV) were examined. A total of 1566 severe TBI patients were included (831 patients with isolated TBI). Crude analysis shows an association between female sex and lower ICU admission rates, shorter ICU/hospital LOS, and less frequent and shorter MV in severe TBI patients ≥ 45 years. After adjusting, female sex appears to be associated with shorter ICU/hospital LOS. Sex differences in mortality and GOS were not found. In conclusion, this study found sex differences in patient outcomes following severe TBI, potentially favoring (older) females, which appear to indicate shorter ICU/hospital LOS (adjusted analysis). Large prospective studies are warranted to help unravel sex differences in outcomes after severe TBI.

The past, present and future of the conservative treatment of distal radius fractures.

The distal radius fracture is a common fracture with a prevalence of 17% on the emergency departments. The conservative treatment of distal radius fractures usually consists of three to six weeks of plaster immobilization. Several studies show that one week of plaster immobilization is safe for non- or minimally displaced distal radius fractures that do not need reduction. A shorter period of immobilization may lead to a better functional outcome, faster reintegration and participation in daily activities. Due to upcoming innovations such as three-dimensional printed splints for distal radius fractures, a patient specific splint can be produced which may offer more comfort. Furthermore, these three-dimensional printed splints are expected to be more environmental friendly in comparison with traditional plaster casts.

Role of Tyrosine Nitrosylation in Stress-Induced Major Depressive Disorder: Mechanisms and Implications.

Major depressive disorder (MDD) has a lifetime prevalence of approximately 10% and is one of the most common diseases worldwide. Although many pathogenetic mechanisms of MDD have been proposed, molecular details and a unifying hypothesis of the pathogenesis of MDD remain to be defined. Here, we investigated whether tyrosine nitrosylation, which is caused by reaction of the C-atom 3 of the tyrosine phenol ring with peroxynitrate (ONOO-), plays a role in experimental MDD, because tyrosine nitrosylation may affect many cell functions altered in MDD. To this end, we induced stress through glucocorticoid application or chronic environmental unpredictable stress and determined tyrosine nitrosylation in the hippocampus through immuno-staining and ELISA. The role of catalases and peroxidases for tyrosine nitrosylation was measured using enzyme assays. We show that glucocorticoid- and chronic unpredictable environmental stress induced tyrosine nitrosylation in the hippocampus. Long-term treatment of stressed mice with the classical antidepressants amitriptyline or fluoxetine prevented tyrosine nitrosylation. Tyrosine nitrosylation was also prevented through i.v. application of anti-ceramide antibodies or recombinant ceramidase to neutralize or degrade, respectively, blood plasma ceramide that has been recently shown to induce experimental MDD. Finally, the application of phosphatidic acid, previously shown to be reduced in the hippocampus upon stress, also reverted stress-induced tyrosine nitrosylation. The inhibition of tyrosine nitrosylation by interfering with the formation of NO radicals at least partly restored normal behavior in stressed mice. These data suggest that tyrosine nitrosylation might contribute to the pathogenesis of MDD and targeting this process might contribute to the treatment of MDD.

Sex Dimorphism in Outcome of Trauma Patients Presenting with Severe Shock: A Multicenter Cohort Study.

Background: The objective of this study was to determine the association between sex and outcome among severely injured patients who were admitted in severe shock. Methods: A retrospective multicenter study was performed in trauma patients (Injury Severity Score (ISS) ≥ 16) aged ≥ 16 presenting with severe shock (Shock Index > 1.3) over a 4-year period. To determine if sex was associated with mortality, Intensive Care Unit (ICU) admission, mechanical ventilation, blood transfusion and in-hospital complications, multivariable logistic regressions were performed. Results: In total, 189 patients were admitted to the Emergency Department in severe shock. Multivariable logistic regression analysis showed that female sex was independently associated with a decreased likelihood of acute kidney injury (OR 0.184; 95% CI 0.041-0.823; p = 0.041) compared to the male sex. A significant association between female sex and mortality, ICU admission, mechanical ventilation, other complications and packed red blood cells transfusion after admission could not be confirmed. Conclusion: Female trauma patients in severe shock were significantly less likely to develop AKI during hospital stay. These results could suggest that female trauma patients may manifest a better-preserved physiologic response to severe shock when compared to their male counterparts. Prospective studies with a larger study population are warranted.

Quantifying the Differences between 3D Virtual Planning and Attained Postoperative Reduction on CT for Patients with Tibial Plateau Fractures; a Clinical Feasibility Study.

Background: Three-Dimensional Virtual Planning (3DVP) has been proven to be effective for limiting intra-articular screw penetration and improving the quality of reduction for numerous fractures. However, the value of 3DVP for patients with tibial plateau fractures has yet to be determined. Purposes: The research question of this study is: Can Computed Tomography Micromotion Analysis (CTMA) provide a reliable quantification of the difference between 3DVP and the postoperative reduction on CT for tibial plateau fractures? Methods: Nine consecutive adult patients who received surgical treatment for a tibial plateau fracture and received pre- and postoperative CT scans were included from a level I trauma center in the Netherlands. The preoperative CT scans of the patients were uploaded in a 3DVP software. In this software, fracture fragments were reduced and the reduction was saved as a 3D file (STL). The quality of the reduction from the 3DVP software was compared with the postoperative results using CT Micromotion Analysis (CTMA). In this analysis, the translation of the largest intra-articular fragment was calculated by aligning the postoperative CT with the 3DVP. Coordinates and measurement points were defined in the X, Y, and Z axes. The combined values of X and Y were used to define the intra-articular gap. The Z-axis was defined as the line from cranial to caudal and was used to define intra-articular step-off. Results: The intra-articular step-off was 2.4 mm (Range 0.5-4.6). Moreover, the mean translation of the X-axis and Y-axis, which was defined as the intra-articular gap, was 4.2 mm (Range 0.6-10.7). Conclusions: 3DVP provides excellent insight into the fracture and its fragments. Utilizing the largest intra-articular fragment, it is feasible to quantify the difference between 3DVP and a postoperative CT using CTMA. A prospective study to further analyze the use of 3DVP in terms of intra-articular reduction and surgical and patient-related outcomes has been started by our team.

Effectiveness of Postoperative Physiotherapy Compared to Postoperative Instructions by Treating Specialist Only in Patients With an Ankle Fracture: A Systematic Review.

Background: In current literature, the benefit of postoperative physiotherapy versus postoperative instructions by treating specialist only remains unclear. The aim of this review is to systematically assess existing literature regarding the functional outcome of postoperative physiotherapy compared to postoperative instructions by treating specialist only in the rehabilitation of patients with an ankle fracture. The secondary aim is to determine if there is a difference in ankle range of motion, strength, pain, complications, quality of life, and patient's satisfaction between these 2 rehabilitation methods. Methods: For this review, the PubMed/MEDLINE, PEDro, Embase, Cochrane, and CINAHL databases were searched for studies that compared postoperative rehabilitation groups. Results: The electronic data search detected 20 579 articles. After exclusion, 5 studies with a total of 552 patients were included. Overall, no significant benefit in functional outcome of postoperative physiotherapy was seen compared to the instructions-only group. One study even found a significant benefit in favor of the instructions-only group. An exemption for beneficial effect of the use of physiotherapy could be made for younger patients, as 2 studies described younger age as a factor for better outcomes (functional outcome and ankle range of motion) in the postoperative physiotherapy group. Patients' satisfaction, described by one study, was found to be significantly higher in the physiotherapy group (P = .047). All other secondary aims showed no significant difference. Conclusion: Because of the limited number of studies and the heterogeneity among studies, a valid conclusion about the general effect of physiotherapy cannot be formed. However, we identified limited evidence suggesting a possible benefit of physiotherapy in younger patients with an ankle fracture in functional outcome and ankle range of motion.

Accuracy of Prehospital Triage of Adult Patients With Traumatic Injuries Following Implementation of a Trauma Triage Intervention.

Importance: Adequate prehospital triage is pivotal to enable optimal care in inclusive trauma systems and reduce avoidable mortality, lifelong disabilities, and costs. A model has been developed to improve the prehospital allocation of patients with traumatic injuries and was incorporated in an application (app) to be implemented in prehospital practice. Objective: To evaluate the association between the implementation of a trauma triage (TT) intervention with an app and prehospital mistriage among adult trauma patients. Design, Setting, and Participants: This population-based, prospective quality improvement study was conducted in 3 of the 11 Dutch trauma regions (27.3%), with full coverage of the corresponding emergency medical services (EMS) regions participating in this study. Participants included adult patients (age ≥16 years) with traumatic injuries who were transported by ambulance between February 1, 2015, and October 31, 2019, from the scene of injury to any emergency department in the participating trauma regions. Data were analyzed between July 2020 and June 2021. Exposures: Implementation of the TT app and the awareness of need for adequate triage created by its implementation (ie, the TT intervention). Main Outcomes and Measures: The primary outcome was prehospital mistriage, evaluated in terms of undertriage and overtriage. Undertriage was defined as the proportion of patients with an Injury Severity Score (ISS) of 16 or greater who were initially transported to a lower-level trauma center (designated to treat patients who are mildly and moderately injured) and overtriage as the proportion of patients with an ISS of less than 16 who were initially transported to a higher-level trauma center (designated to treat patients who are severely injured). Results: A total of 80 738 patients were included (40 427 [50.1%] before and 40 311 [49.9%] after implementation of the intervention), with a median (IQR) age of 63.2 (40.0-79.7) years and 40 132 (49.7%) male patients. Undertriage decreased from 370 of 1163 patients (31.8%) to 267 of 995 patients (26.8%), while overtriage rates did not increase (8202 of 39 264 patients [20.9%] vs 8039 of 39 316 patients [20.4%]). The implementation of the intervention was associated with a statistically significantly reduced risk for undertriage (crude risk ratio [RR], 0.95; 95% CI, 0.92 to 0.99, P = .01; adjusted RR, 0.85; 95% CI, 0.76-0.95; P = .004), but the risk for overtriage was unchanged (crude RR, 1.00; 95% CI, 0.99-1.00; P = .13; adjusted RR, 1.01; 95% CI, 0.98-1.03; P = .49). Conclusions and Relevance: In this quality improvement study, implementation of the TT intervention was associated with improvements in rates of undertriage. Further research is needed to assess whether these findings are generalizable to other trauma systems.

The symmetry of the left and right tibial plateau: a comparison of 200 tibial plateaus.

PURPOSE: This study aims to investigate the symmetry of the left and right tibial plateau in young healthy individuals to determine whether left-right mirroring can be reliably used to optimize preoperative 3D virtual planning for patients with tibial plateau fractures. METHODS: One hundred healthy subjects, without previous knee surgery, severe knee trauma, or signs of osteoarthritis were included for a previous dynamic imaging study of the knee. The subjects underwent a CT scan, scanning the left and right knee with a slice thickness of 0.8 mm. 3D surface models of the femur, patella, and tibia were created using a convolutional neural network. The 3D models of the left and right tibias were exported to MATLAB © and the tibias were mirrored. The mirrored tibias were superimposed on the contralateral tibia using a coherent point drift surface matching algorithm. Correspondence points on both surfaces were established, the mean root squared distance was calculated and visualized in a boxplot and heatmaps. RESULTS: The overall mean difference between correspondence points on the left and right tibial plateau is 0.6276 ± 0.0343 mm. The greatest differences between correspondence points were seen around two specific surfaces on the outside of the tibial plateau; where the distal tibia was cut 15 mm below the tibial plateau and around the tibiofibular joint. CONCLUSIONS: The differences between the left and right tibial plateau are small and therefore, we can be confident that the mirrored contralateral, unfractured, tibial plateau can be used as a template for 3D virtual preoperative planning for young patients without previous damage to the knee.

Design recommendations for exoskeletons: Perspectives of individuals with spinal cord injury.

OBJECTIVE: This study investigated the expectations of individuals with spinal cord injury (SCI) regarding exoskeletons. DESIGN: The survey consisted out of questions regarding multiple aspects of exoskeleton technology. SETTING: An online survey was distributed via the monthly newsletter of the Dutch Patient Association for Spinal Cord Injury (SCI). PARTICIPANTS: Individuals with SCI who are members of the Dutch Patient Association for SCI. OUTCOME MEASURES: General impression of exoskeleton technology, expectations regarding capabilities and user-friendliness, training expectations and experiences, future perspectives and points of improvement. RESULTS: The survey was filled out by 95 individuals with SCI, exoskeletons were considered positive and desirable by 74.7%. About 11 percent (10.5%) thought one could ambulate faster, or just as fast, while wearing an exoskeleton as able-bodied people. Furthermore, 18.9% expected not to use a wheelchair or walking aids while ambulating with the exoskeleton. Twenty-five percent believed that exoskeletons could replace wheelchairs. Some main points of improvement included being able to wear the exoskeleton in a wheelchair and while driving a car, not needing crutches while ambulating, and being able to put the exoskeleton on by oneself. CONCLUSION: Individuals with SCI considered exoskeletons as a positive and desirable innovation. But based on the findings from the surveys, major points of improvement are necessary for exoskeletons to replace wheelchairs in the future. For future exoskeleton development, we recommend involvement of individuals with SCI to meet user expectations and improve in functionality, usability and quality of exoskeletons.

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo.

Ion channels are non-conventional, druggable oncological targets. The intermediate-conductance calcium-dependent potassium channel (KCa3.1) is highly expressed in the plasma membrane and in the inner mitochondrial membrane (mitoKCa3.1) of various cancer cell lines. The role mitoKCa3.1 plays in cancer cells is still undefined. Here we report the synthesis and characterization of two mitochondria-targeted novel derivatives of a high-affinity KCa3.1 antagonist, TRAM-34, which retain the ability to block channel activity. The effects of these drugs were tested in melanoma, pancreatic ductal adenocarcinoma and breast cancer lines, as well as in vivo in two orthotopic models. We show that the mitochondria-targeted TRAM-34 derivatives induce release of mitochondrial reactive oxygen species, rapid depolarization of the mitochondrial membrane, fragmentation of the mitochondrial network. They trigger cancer cell death with an EC50 in the µM range, depending on channel expression. In contrast, inhibition of the plasma membrane KCa3.1 by membrane-impermeant Maurotoxin is without effect, indicating a specific role of mitoKCa3.1 in determining cell fate. At sub-lethal concentrations, pharmacological targeting of mitoKCa3.1 significantly reduced cancer cell migration by enhancing production of mitochondrial reactive oxygen species and nuclear factor-κB (NF-κB) activation, and by downregulating expression of Bcl-2 Nineteen kD-Interacting Protein (BNIP-3) and of Rho GTPase CDC-42. This signaling cascade finally leads to cytoskeletal reorganization and impaired migration. Overexpression of BNIP-3 or pharmacological modulation of NF-κB and CDC-42 prevented the migration-reducing effect of mitoTRAM-34. In orthotopic models of melanoma and pancreatic ductal adenocarcinoma, the tumors at sacrifice were 60% smaller in treated versus untreated animals. Metastasis of melanoma cells to lymph nodes was also drastically reduced. No signs of toxicity were observed. In summary, our results identify mitochondrial KCa3.1 as an unexpected player in cancer cell migration and show that its pharmacological targeting is efficient against both tumor growth and metastatic spread in vivo.

Molecular targets of endothelial phosphatidic acid regulating major depressive disorder.

Major depressive disorder (MDD) is a severe disease of unknown pathogenesis with a lifetime prevalence of ~10%. Therapy requires prolonged treatment that often fails. We have previously demonstrated that ceramide levels in the blood plasma of patients and in mice with experimental MDD are increased. Neutralization of blood plasma ceramide prevented experimental MDD in mice. Mechanistically, we demonstrated that blood plasma ceramide accumulated in endothelial cells of the hippocampus, inhibited phospholipase D (PLD) and thereby decreased phosphatidic acid in the hippocampus. Here, we demonstrate that phosphatidic acid binds to and controls the activity of phosphotyrosine phosphatase (PTP1B) in the hippocampus and thus determines tyrosine phosphorylation of a variety of cellular proteins including TrkB. Injection of PLD, phosphatidic acid, or inhibition of PTP1B abrogated MDD and normalized cellular tyrosine phosphorylation, including phosphorylation of TrkB and neurogenesis in the hippocampus. Most importantly, these treatments also rapidly normalized behavior of mice with experimental MDD. Since phosphatidic acid binds to and inhibits PTP1B, the lack of phosphatidic acid results in increased activity of PTP1B and thereby in reduced tyrosine phosphorylation of TrkB and other cellular proteins. Thus, our data indicate a novel pathogenetic mechanism of and a rapidly acting targeted treatment for MDD.

Hospital Acquired Complications in South Australian major public hospitals.

The prevalence of Hospital Acquired Complications (HACs) within major hospitals and intensive care units (ICUs) is often used as an indication of care quality. We performed a retrospective cohort study of acute care separations from four adult public hospitals in the state of South Australia, Australia. Data were derived from the Integrated South Australian Activity Collection (ISAAC) database, subdivided into those admitted to ICU or non-ICU (Ward) in tertiary referral or (other major) metropolitan hospitals. During the five-year study period (1 July 2013 to 30 June 2018), there were 471,934 adult separations with 65,133 HAC events reported in 43,987 (9.32%) at a mean rate of 13.8 (95% confidence interval (CI) 13.7 to 13.9) HAC events per 100 separations and 18.5 (95% CI 18.4 to 18.7) per 1000 bed days. The Ward cohort accounted for the majority (430,583 (91.2%)) of separations, in-hospital deaths (6928 (66.4%)) and HAC events (29,826 (67.8%)). The smaller ICU cohort (41,351 (8.76%)) had a higher mortality rate (8.46% versus 1.61%; P < 0.001), longer length of stay (median 10.0 (interquartile range (IQR) 6.0-18.0) days versus 4.0 (IQR 3.0-8.0) days P < 0.001), and higher HAC prevalence (62.1 (95% CI 61.3 to 62.9) versus 9.16 (95% CI 9.07 to 9.25) per 100 separations P < 0.001). Both ICU and Ward HAC prevalence rates were higher in tertiary referral than major metropolitan hospitals (P < 0.001). In conclusion, higher HAC prevalence rates in the ICU and tertiary referral cohorts may be due to high-risk patient cohorts, variable provision of care, or both, and warrants urgent clinical investigation and further research.

Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma.

Major depressive disorder (MDD) is a very common, severe disease with a lifetime prevalence of ~ 10%. The pathogenesis of MDD is unknown and, unfortunately, therapy is often insufficient. We have previously reported that ceramide levels are increased in the blood plasma of patients with MDD and in mice with experimental MDD. Here, we demonstrate that ceramide-enriched exosomes in the blood plasma are increased in mice with stress-induced MDD. Genetic studies reveal that neutral sphingomyelinase 2 is required for the formation of ceramide-enriched exosomes in the blood plasma. Accordingly, induced deficiency of neutral sphingomyelinase 2 prevented mice from the development of stress-induced MDD. Intravenous injection of microparticles from mice with MDD or injection of ceramide-loaded exosomes induced MDD-like behavior in untreated mice, which was abrogated by ex vivo pre-incubation of purified exosomes with anti-ceramide antibodies or ceramidase. Mechanistically, injection of exosomes from mice with MDD or injection of ex vivo ceramide-loaded microparticles inhibited phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus, which has been previously shown to mediate MDD by plasma ceramide. In summary, our data indicate that ceramide-enriched exosomes are released by neutral sphingomyelinase 2 into the blood plasma upon stress and mediate stress-induced MDD. KEY MESSAGES: Stress induces ceramide-enriched exosomes in the blood plasma. Ceramide-enriched exosomes mediate major depressive disorder (MDD). Deficiency of neutral sphingomyelinase 2 protects from stress-induced MDD. Neutralization or digestion of ceramide in exosomes prevents stress-induced MDD. Ceramide-enriched exosomes inhibit endothelial phospholipase D in the hippocampus.

The prevalence of non-accidental trauma among children with polytrauma: A nationwide level-I trauma centre study.

OBJECTIVE: We aimed to investigate the prevalence and characteristics of non-accidental trauma (NAT) in children with polytrauma treated at level-I trauma centres (TC). SUMMARY OF BACKGROUND: Data 6-10% Of children who present at the emergency department with injuries, sustain polytrauma. Polytrauma may result from either accidental (AT) or NAT, i.e. inflicted or neglect. The prevalence of NAT among children with polytrauma is currently unclear. METHODS: This is a retrospective study that included children (0-18 years) with an Injury Severity Score >15, who presented at one of the 11 Level-I trauma centers (TC) in the Netherlands between January 1, 2010 and January 1, 2016. Outcomes were classified based on the conclusions of the Child Abuse and Neglect-team. Cases in which conclusions were unavailable and there was no clear accidental cause of injuries were reviewed by an expert panel. RESULTS: The study included 1623 children, 1452 (89%) were classified as AT, 171 (11%) as NAT; 39 (2,4%) inflicted and 132 (8,1%) neglect. Of pre-school aged children (<5 years) 41% sustained NAT (OR26.73, 95%CI 17.70-40.35), 35/342 (10%) inflicted and 104/342 (31%) neglect. Admission due to 'cardiopulmonary arrest' was the result of inflicted trauma (30% vs 0%,p < 0.001). NAT had a higher mortality rate (16% vs 10%, p = 0.006). Indicators of NAT were: (near-)drowning (OR10.74, 95%CI 5.94-19.41), burn (OR8.62, 95%CI 4.08-18.19) and fall from height (OR2.18, 95%CI 1.56-3.02). CONCLUSIONS: NAT was the cause of polytrauma in 11% of children in our nationwide level-I TC study; 41% of these polytrauma were the result of NAT experienced by preschool-aged children. Our data show the importance of awareness for NAT.