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ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

BackgroundPrehospital procedures (PHP) by emergency medical services (EMS) are performed regularly in penetrating trauma patients despite previous studies demonstrating no benefit. We sought to examine the influence of PHPs on outcomes in penetrating trauma patients in urban locations where transport to trauma center is not prolonged. We hypothesized that patients without PHPs would have better outcomes than those undergoing PHP.MethodsThis was an Eastern Association for the Surgery of Trauma-sponsored, multicenter, prospective, observational trial of adults (18+ years) with penetrating trauma to the torso and/or proximal extremity presenting at 25 urban trauma centers. The impact of PHPs and transport mechanism on in-hospital mortality were examined.ResultsOf 2,284 patients included, 1,386 (60.7%) underwent PHP. The patients were primarily Black (n = 1,527, 66.9%) males (n = 1,986, 87.5%) injured by gunshot wound (n = 1,510, 66.0%) with 34.1% (n = 726) having New Injury Severity Score of ≥16. A total of 1,427 patients (62.5%) were transported by Advanced Life Support EMS, 17.2% (n = 392) by private vehicle, 13.7% (n = 312) by police, and 6.7% (n = 153) by Basic Life Support EMS. Of the PHP patients, 69.1% received PHP on scene, 59.9% received PHP in route, and 29.0% received PHP both on scene and in route. Initial scene vitals differed between groups, but initial emergency department vitals did not. Receipt of ≥1 PHP increased mortality odds (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.01-1.83; p = 0.04). Logistic regression showed increased mortality with each PHP, whether on scene or during transport. Subset analysis of specific PHP revealed that intubation (OR, 10.76; 95% CI, 4.02-28.78; p < 0.001), C-spine immobilization (OR, 5.80; 95% CI, 1.85-18.26; p < 0.01), and pleural decompression (OR, 3.70; 95% CI, 1.33-10.28; p = 0.01) had the highest odds of mortality after adjusting for multiple variables.ConclusionPrehospital procedures in penetrating trauma patients impart no survival advantage and may be harmful in urban settings, even when performed during transport. Therefore, PHP should be forgone in lieu of immediate transport to improve patient outcomes.Level of evidencePrognostic, level III.

Abstract Background Focused ultrasound (FUS)-mediated blood–brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer’s disease (AD). Methods At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI. Results Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24–48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant. Conclusions FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics. Trial registration: ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018

Abstract A secondary function of the respiratory system of the mammals is, during inspiration, to heat the air to body temperature and to saturate it with water before it reaches the alveoli. Relying on a mathematical model, we propose a comprehensive analysis of this function, considering all the terrestrial mammals (spanning six orders of magnitude of the body mass, M) and focusing on the sole contribution of the lungs to this air conditioning. The results highlight significant differences between the small and the large mammals, as well as between rest and effort, regarding the spatial distribution of heat and water exchanges in the lungs, and also in terms of regime of mass transfer taking place in the lumen of the airways. Interestingly, the results show that the mammalian lungs appear to be designed just right to fully condition the air at maximal effort (and clearly over-designed at rest, except for the smallest mammals): all generations of the bronchial region of the lungs are mobilized for this purpose, with calculated values of the local evaporation rate of water from the bronchial mucosa that can be very close to the maximal ability of the serous cells to replenish this mucosa with water. For mammals with a mass above a certain threshold ( $$\simeq 5$$ ≃ 5 kg at rest and $$\simeq 50$$ ≃ 50 g at maximal effort), it appears that the maximal value of this evaporation rate scales as $$M^{-1/8}$$ M - 1 / 8 at rest and $$M^{-1/16}$$ M - 1 / 16 at maximal effort and that around 40% (at rest) or 50% (at maximal effort) of the water/heat extracted from the lungs during inspiration is returned to the bronchial mucosa during expiration, independently of the mass, due to a subtle coupling between different phenomena. This last result implies that, above these thresholds, the amounts of water and heat extracted from the lungs by the ventilation scale with the mass such as the ventilation rate does (i.e. as $$M^{3/4}$$ M 3 / 4 at rest and $$M^{7/8}$$ M 7 / 8 at maximal effort). Finally, it is worth to mention that these amounts appear to remain limited, but not negligible, when compared to relevant global quantities, even at maximal effort (4–6%).

IntroductionPatients who sustain orthopaedic trauma are at an increased risk of venous thromboembolism (VTE), including fatal pulmonary embolism (PE). Current guidelines recommend low-molecular-weight heparin (LMWH) for VTE prophylaxis in orthopaedic trauma patients. However, emerging literature in total joint arthroplasty patients suggests the potential clinical benefits of VTE prophylaxis with aspirin. The primary aim of this trial is to compare aspirin with LMWH as a thromboprophylaxis in fracture patients.Methods and analysisPREVENT CLOT is a multicentre, randomised, pragmatic trial that aims to enrol 12 200 adult patients admitted to 1 of 21 participating centres with an operative extremity fracture, or any pelvis or acetabular fracture. The primary outcome is all-cause mortality. We will evaluate non-inferiority by testing whether the intention-to-treat difference in the probability of dying within 90 days of randomisation between aspirin and LMWH is less than our non-inferiority margin of 0.75%. Secondary efficacy outcomes include cause-specific mortality, non-fatal PE and deep vein thrombosis. Safety outcomes include bleeding complications, wound complications and deep surgical site infections.Ethics and disseminationThe PREVENT CLOT trial has been approved by the ethics board at the coordinating centre (Johns Hopkins Bloomberg School of Public Health) and all participating sites. Recruitment began in April 2017 and will continue through 2021. As both study medications are currently in clinical use for VTE prophylaxis for orthopaedic trauma patients, the findings of this trial can be easily adopted into clinical practice. The results of this large, patient-centred pragmatic trial will help guide treatment choices to prevent VTE in fracture patients.Trial registration numberNCT02984384.

Social cognition (SC), the mental operations underlying social functioning, are impaired in schizophrenia. Their direct link to functional outcome and illness status have made them an important therapeutic target. However, no effective treatment for these deficits is currently applied as a standard of care. To address this need, we have developed SocialVille-an online, plasticity-based training program that targets SC deficits in schizophrenia. Here we report the outcomes of a double-blind, controlled, randomized, multi-site clinical trial of SocialVille. Outpatients with schizophrenia were randomized to complete 40 sessions of either SocialVille (N = 55 completers) or active control (computer games; N = 53 completers) from home. The a priori co-primary outcome measures were a social cognitive composite and a functional capacity outcome (UCSD Performance-based Skills Assessment [UPSA-2]). Secondary outcomes included a virtual functional capacity measure (VRFCAT), social functioning, quality of life, and motivation. Linear mixed models revealed a group × time interaction favoring the treatment group for the social cognitive composite (b = 2.81; P < .001) but not for the UPSA-2 measure. Analysis of secondary outcome measures showed significant group × time effects favoring the treatment group on SC and social functioning, on the virtual functional capacity measure and a motivation subscale, although these latter findings were nonsignificant with FDR correction. These results provide support for the efficacy of a remote, plasticity-based social cognitive training program in improving SC and social functioning in schizophrenia. Such treatments may serve as a cost-effective adjunct to existing psychosocial treatments. Trial Registration: NCT02246426.

Objective: This trial examined the effects of proximal/distal mediators and moderators of an Active Music Engagement (AME) intervention on young child/parent distress, quality of life, and family function outcomes. Methods: Child/parent dyads (n = 125) were randomized to AME or Audio-storybooks attention control condition. Each group received 3 sessions with a credentialed music therapist for 3 consecutive days with data collection at baseline, post-intervention (T2), and 30-days later (T3). Potential proximal mediators included within session child and parent engagement. Potential distal mediators included changes in perceived family normalcy, parent self-efficacy, and independent use of play materials. Potential moderators included parent/child distress with prior hospitalizations, parent traumatic stress screener (PCL-6), and child age. Outcomes included child emotional distress and quality of life; parent emotion, traumatic stress symptoms (IES-R), well-being; and family function. Mediation effects were estimated using ANCOVA, with indirect effects estimated using the percentile bootstrap approach. Moderation effects were tested by including appropriate interaction terms in models. Results: No significant mediation effects were observed. Child distress with prior hospitalizations moderated AME effects for IES-R intrusion subscale scores at T2 ( P = .01) and avoidance subscale scores at T3 ( P = .007). Traumatic stress screener scores (PCL-6) moderated intervention effects for IES-R hyperarousal subscale scores at T2 ( P = .01). There were no moderation effects for child age. Conclusions: AME is a promising intervention for mitigating traumatic stress symptoms and supporting well-being in parents of children with cancer, particularly for parents who screen high for traumatic stress and whose children are more highly distressed with hospitalization.

Objectives Fracture is a common injury after a traumatic event. The efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) to treat acute pain related to fractures is not well established.Methods Clinically relevant questions were determined regarding NSAID use in the setting of trauma-induced fractures with clearly defined patient populations, interventions, comparisons and appropriately selected outcomes (PICO). These questions centered around efficacy (pain control, reduction in opioid use) and safety (non-union, kidney injury). A systematic review including literature search and meta-analysis was performed, and the quality of evidence was graded per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The working group reached consensus on the final evidence-based recommendations.Results A total of 19 studies were identified for analysis. Not all outcomes identified as critically important were reported in all studies, and the outcome of pain control was too heterogenous to perform a meta-analysis. Nine studies reported on non-union (three randomized control trials), six of which reported no association with NSAIDs. The overall incidence of non-union in patients receiving NSAIDs compared with patients not receiving NSAIDs was 2.99% and 2.19% (p=0.04), respectively. Of studies reporting on pain control and reduction of opioids, the use of NSAIDs reduced pain and the need for opioids after traumatic fracture. One study reported on the outcome of acute kidney injury and found no association with NSAID use.Conclusions In patients with traumatic fractures, NSAIDs appear to reduce post-trauma pain, reduce the need for opioids and have a small effect on non-union. We conditionally recommend the use of NSAIDs in patients suffering from traumatic fractures as the benefit appears to outweigh the small potential risks.

As trauma surgeons, we focus on the immediate care and needs of the injured patient every day. Historically, trauma and injury research has focused on outcomes such as mortality, complications, and length of stay; and process metrics such as time to CT scan, resuscitation checklist frequencies, or venous thromboembolism prophylaxis rates. These outcomes are perceived by healthcare providers to be important, but patients likely have different perceptions of what outcomes are most important to measure and improve. True patient-centered outcomes research involves the healthcare providers, and the entire team of stakeholders including patients and the community. Understanding the process of stakeholder engagement and the barriers trauma researchers must overcome to effectively enter this field of research is important. This summary aims to inform the trauma research community on the basics of patient-centered outcomes research, priorities for funding from the Patient-Centered Outcomes Research Institute, resources for collaboration around patient-centered outcomes research, and a unique career development and training opportunity for early career trauma surgeons to develop a skill set in patient-centered outcomes research.

This paper describes the current funding, infrastructure growth and future state of trauma research. It also introduces a group of review articles generated from The Future of Trauma Research: Innovations in Research Methodology conference hosted by the American College of Surgeons Committee on Trauma in July 2019.

A breath of research has investigated how characteristics of visualizations and characteristics of texts influence learningand generalization. Given that students integrate information from visualizations and text, we investigate how the char-acteristics of the text depends on characteristics of the visualization. We focus on two characteristics of visualizations(perceptual richness, and whether they display variability), and one characteristic of the text (use of generic language). Wefound that the majority of visualization were detailed photographs and do not display variability. Most of the text usedgeneric language, but we found that some visualizations qualified these generic statements with more specific phrases.The use of generic was more common for visualizations that display variability and photographs. Our study highlightsthe importance of investigating what students are normally exposed to and suggest that future research on multi-medialearning should place close attention to the characteristics of the text that accompany the visualization.

Laura Deruyver,1 Clément Rigaut,2 Alejandro Gomez-Perez,3 Pierre Lambert,2 Benoit Haut,2 Jonathan Goole1 1Laboratoire de Pharmacie Galénique et Biopharmacie, Faculté de pharmacie, Université libre de Bruxelles, Brussels, Belgium; 2Transfers, Interfaces and Processes (TIPs), École Polytechnique de Bruxelles, Université libre de Bruxelles, Brussels, Belgium; 3NanoMegas SRPL, Brussels, 1050, BelgiumCorrespondence: Laura Deruyver, Boulevard du triomphe, CP207, accès 2, Campus Plaine, Bâtiment BC – 1B6 117, Brussels, 1050, Belgium, Tel +3226505221, Fax +3226505269, Email Laura.Deruyver@ulb.beIntroduction: This work aimed to develop chitosan-coated cubosomal nanoparticles intended for nose-to-brain delivery of paliperidone palmitate. They were compared with standard and cationic cubosomal nanoparticles. This comparison relies on numerous classical in vitro tests and powder deposition within a 3D-printed nasal cast.Methods: Cubosomal nanoparticles were prepared by a Bottom-up method followed by a spray drying process. We evaluated their particle size, polydispersity index, zeta-potential, encapsulation efficiency, drug loading, mucoaffinity properties and morphology. The RPMI 2650 cell line was used to assess the cytotoxicity and cellular permeation. An in vitro deposition test within a nasal cast completed these measurements.Results: The selected chitosan-coated cubosomal nanoparticles loaded with paliperidone palmitate had a size of 305.7 ± 22.54 nm, their polydispersity index was 0.166 ± 0.022 and their zeta potential was +42.4 ± 0.2 mV. This formulation had a drug loading of 70% and an encapsulation efficiency of 99.7 ± 0.1%. Its affinity with mucins was characterized by a ΔZP of 20.93 ± 0.31. Its apparent permeability coefficient thought the RPMI 2650 cell line was 3.00E-05 ± 0.24E-05 cm/s. After instillation in a 3D-printed nasal cast, the fraction of the injected powder deposited in the olfactory region reached 51.47 ± 9.30% in the right nostril and 41.20 ± 4.59% in the left nostril, respectively.Conclusion: The chitosan coated cubosomal formulation seems to be the most promising formulation for nose-to-brain delivery. Indeed, it has a high mucoaffinity and a significantly higher apparent permeability coefficient than the two other formulations. Finally, it reaches well the olfactory region.Graphical Abstract: Keywords: cubosomes, nasal cast, charged nanoparticles, RPMI 2650 cell line, nose-to-brain delivery, nasal powder formulation, chitosan