Introduction : La surveillance analgésique est essentielle pour préserver le confort des patients sédationnés non-communicants après un traumatisme craniocérébral (TCC). Bien que le réflexe de dilatation pupillaire (RDP) et les comportements puissent être utilisés pour évaluer l'analgésie, ils nécessitent l'application de stimulus nociceptifs. Récemment, le réflexe photomoteur (RPM) élicité via un flash lumineux non douloureux s’est montré utile pour prédire l’état analgésique des patients sans TCC. Nous avons examiné si le RPM peut prédire l’état analgésique et la réponse comportementale des patients TCC non-communicants. Méthode : Quinze patients TCC ventilés mécaniquement (11 hommes; 54±20 ans) ont été évalués avec un vidéo-pupillomètre et une échelle comportementale (BPS) dans les 72 heures suivant l’admission aux soins intensifs. À chaque évaluation, le diamètre pupillaire au repos et le RPM ont été enregistrés, suivis immédiatement du RDP et des comportements pendant un stimulus nociceptif calibré. Les concentrations sanguines d’analgésiques/sédatifs ont été mesurées. Résultats : 103 évaluations ont été réalisées. Lorsque les réflexes pupillaires ont été élicités, le diamètre pupillaire a varié de -19 % en moyenne pour le RPM et de +10 % en moyenne pour le RDP. Les variations du RPM et du RDP étaient plus prononcées chez les participants qui présentaient un score BPS > 3 (un signe reconnu de sous-analgésie) par rapport à ceux avec un score BPS = 3. Les analyses de régression multiple montrent un chevauchement significatif entre les fluctuations des réflexes pupillaires et la concentration sanguine de fentanyl, mais pas celle du propofol. Conclusion : Le RPM pourrait être utile pour évaluer les besoins analgésiques avant une procédure nociceptive chez les patients TCC sédationnés non-communicants. / Background: Analgesia monitoring is essential to preserve comfort in critically ill sedated patients with traumatic brain injury (TBI). While pupil dilation (PD) and pain behaviors can be used to assess analgesia, these indicators require application of noxious stimulations. Recently, the pupillary light reflex (PLR) has emerged as a non-noxious parameter that may be used to predict analgesia requirements in non-brain-injured patients. Here, we investigated whether PLR can be used for the purpose of analgesia monitoring in critically ill sedated TBI patients. Methods: Fifteen mechanically ventilated TBI patients (11 men; 54±20 years) under perfusions of analgesia and sedation were assessed at predefined time within 72 hours of intensive care unit admission. Data collection was performed using video-pupillometry and the Behavioral Pain Scale (BPS). At each assessment, pupil size and PLR at rest were recorded followed immediately by the documentation of PD and pain behaviors elicited by a calibrated noxious stimulation. Blood concentrations of analgesics/sedatives were monitored. Results: 103 assessments were completed. PLR resulted in an average decrease of -19% in pupil diameter and PD resulted in average increase of +10%. Variations in PLR and PD were more pronounced in participants who showed a BPS score > 3 (a recognized sign of sub analgesia) compared to those with no behavioral reaction. Multiple regression analyzes showed a significant overlap between fluctuations in pupillary reflexes and blood levels of fentanyl, not propofol. Conclusions: PLR may be useful to assess analgesia requirements before a nociceptive procedure in critically ill sedated patients with TBI.

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Fragestellung: Gegenstand dieser Untersuchung ist der diagnostische Nutzen der Neuro-Biomarker S100B-Protein und Neuronenspezifische Enolase (NSE) bei leichten Schädel-Hirn-Verletzungen im Kindesalter. Es wird untersucht, ob anhand der posttraumatischen S100B- und NSE-Serum-Konzentrationen Kinder mit einer Schädelprellung und einem leichten Schädel-Hirn-Trauma (SHT) differenziert werden können. Material und Methode: In einer prospektiven, klinischen Studie werden die posttraumatischen S100B- und NSE-Serum-Konzentrationen von Kindern im Alter zwischen 6 Monaten und 15 Jahren mit einer Schädelprellung oder einem leichten SHT untersucht. Kinder mit extrakraniellen Begleitverletzungen und Begleiterkrankungen sind ausgeschlossen. Die Blutentnahme erfolgt innerhalb von 6 Stunden nach dem Trauma. Es werden 2 diagnostische Gruppen definiert: Gruppe 1: asymptomatische Schädelprellungen (Glasgow-Coma-Scale [GCS] 15 Punkte), Gruppe 2: leichte SHT (GCS 13-15 Punkte) mit klinischen Zeichen einer Gehirnerschütterung (kurze Bewusstlosigkeit, Amnesie, Übelkeit, Erbrechen, Somnolenz, Kopfschmerzen, Schwindel, Sehstörungen, Kreislaufreaktion). Die S100B- und NSE- Konzentrationen werden zwischen beiden Diagnosegruppen verglichen. Die Korrelation zwischen S100B und NSE sowie zwischen den Markern und dem Alter der Kinder, dem Zeitraum zwischen Trauma und Blutentnahme, dem GCS-Wert und dem Vorhandensein von Kopfplatzwunden wird analysiert. Ergebnisse: 148 Kinder sind in die Studie eingeschlossen (53 Kinder mit einer Schädelprellung und 95 mit einem leichten SHT). Nach Adjustierung der gemessenen Marker-Konzentrationen auf Unterschiede im Alter und Zeitraum zwischen Trauma und Blutentnahme unterscheiden sich die S100B- und NSE-Konzentrationen nicht signifikant zwischen Kindern mit einer Schädelprellung und einem leichten SHT. Zwischen den S100B- und NSE-Konzentrationen besteht eine signifikant positive Korrelation. Beide Marker korrelieren signifikant negativ mit dem Alter und dem Entnahmezeitraum. Der GCS-Wert und das Vorhandensein von Kopfplatzwunden zeigen keinen Effekt auf die Marker-Konzentrationen. Schlussfolgerung: Die posttraumatischen S100B- und NSE-Serum-Konzentrationen zeigen keinen diagnostischen Nutzen bei der Differenzierung zwischen Kindern mit einer Schädelprellung und Kindern mit einem leichten SHT. S100B und NSE sind altersabhängige Marker.

The purpose of this systematic review is to provide insight into the impact traumatic brain injury (TBI) has on the executive function known as the working memory. TBI is a damage to the brain that occurs when the brain is critically injured to the degree that it impacts several brain regions and functions such as the hippocampus, its surrounding areas, the prefrontal cortex, and the performance of the working memory ability. TBI may occur from bleeding or infraction (stroke), lack of oxygen after cardiac arrest (anoxic brain injury), or diseases such as brain tumours or infections in the brain (encephalitis/meningitis). Working memory is the ability that maintains and manipulates information such as judgment and decision-making. TBI impacts several cognitive and executive functions such as the working memory. The implications that TBI has on working memory is that it relatively decreases the activation and connectivity capacity among the main areas of the working memory network which may result in difficulties of attention and concentration. This review summarises five studies about TBI and working memory that uses different working memory task while examiningwith brain imaging techniques. The studies conclude that TBI has a negative impact on working memory since the ability becomes weak.

Physicians encounter significant difficulty when faced with decisions related to withdrawal of life-sustaining therapy (WLST) in patients with devastating brain injury (DBI). The complexity of this decision-making process is multifactorial, including practitioner- and patient-specific variables, as well as surrogate decision-maker bias, inaccuracies in scoring systems, and inconsistencies in guidelines endorsed by professional societies; these issues all contribute to the significant uncertainty of these situations and variability in treatment paradigm. Solutions are complex; however, analyzing WLST with an urban bioethical lens — which emphasizes the principles of solidarity, agency, and social justice — can enhance physicians’ ability to navigate this uncertainty and ensure that potential solutions are patient-centered. / Urban Bioethics

Analytical method validation is the process of establishing that an analytical technique is applicable for a proposed objective. Early in the method development of a new analytical technique an understanding of the instrumental components and procedures is elaborated through scientifically based optimization. The optimization experiments are used to define the operational parameters that yield the maximum performance by the analytical technique for the target analyte before commencing validation studies. This dissertation details method development through experimental investigations instrumental components of LEMS (substrate, laser parameters, and electrospray source conditions). Each instrumental component has a number of induvial parameters which are optimized to yield the maximum laser electrospray mass spectrometry (LEMS) signal intensity for a given analytical problem. LEMS uses a nonresonant, femtosecond (fs) laser to ablate analytes from a surface. Those ablated analytes are then captured by a perpendicular electrospray, ionized, and desolvated to produce ions which travel into the inlet of the mass spectrometer for analysis. Each element of the LEMS experimental setup works in a complementary fashion to generate a mass spectral signal which have specific optimization steps that can dramatically impact the data that can be acquired. The results of the optimization for each instrumental component will then be applied to preliminary method development experiments for the analysis of pharmaceutical compounds from complex formulations biomarker discovery for mice afflicted with a traumatic brain injury.The effect of the laser pulse duration on the ablation mechanism and amount of laser induced conformational changes of aqueous myoglobin was investigated using 55 fs, 56 picosecond (ps), and 10 nanosecond (ns) pulses and laser pulse energies from 0.05 to 1.6 mJ. It was found that the optical properties of the substrates (stainless-steel and quartz) and laser intensity regimes accessible by each pulse duration determined the amount of myoglobin ablated and subsequent mass spectral signal intensity. Laser ablation of myoglobin from both substrates using all laser pulse energies was observed for the 55 fs pulse while the 10 ns pulse required minimum pulse energies of 0.4 and 1.2 mJ for ablation of myoglobin to occur from stainless-steel and quartz, respectively. As the pulse duration increases, thermal processes increase which dictated the relative amount of protein unfolding, number of phosphate adducts, and degree of solvent adduction. Many of the common laser electrospray ionization (ESI) hybrid techniques employ ns pulse durations. However, the amount of ablated myoglobin originating from a ns pulse was observed to be dependent on the amount of energy that was absorbed by the substrate or sample. Experiments to increase the signal intensity while implementing ns laser electrospray mass spectrometry (ns-LEMS) were performed by exploiting the optical properties of nanomaterials as a potential matrix for desorption and detection of myoglobin. To estimate the contribution of the surface plasmon resonance (SPR) to the desorption of myoglobin under the different pulse duration regimes, the addition of an aqueous gold nanostar (GNS) matrix was implemented. GNSs have a SPR maximum of ~750 nm which overlaps strongly with the 780 nm laser wavelength. Gold nanospheres, which have a SPR of ~530 nm, have an absorption overlap 25 times less than that of the nanostars with the 785 nm laser light and therefore were chosen as a control gold nanoparticle matrix. It was observed that protein mixed with solution phase GNSs improved the laser ablation and consequent mass spectral signal intensity of the protein in comparison to both the nanosphere addition and ablation from quartz without nanomaterial addition for the 55 fs, 56 ps, and 10 ns pulses. This dissertation also extends to an investigation of the electrospray source and the roles that the nebulizing gas pressure, electrospray solution flow rate, and needle protrusion from the emitter sheath effects the electrospray analyte signal and stability. Interactions between the electrospray droplets and nebulizing gas were elucidated using an ablation chamber in which laser ablated analytes were carried via the nebulizing gas flow through the nebulizer sheath to interact with the electrospray Taylor cone, jet, and subsequent droplets. The signal intensity and relative standard deviation (RSD) of an infused Victoria blue solution was used to assess conventional ESI optimization experiments while a mixture of Gly-Gly-His, lactose, adenosine, and vitamin B12 was laser ablated within the ablation chamber for the optimization of the remote ablation device. It was found that a needle protrusion flush with the nebulizing sheath wall, 9 psi nebulizing gas pressure, and 9 µL/min ESI flow rate yielded the highest signal intensity for low and high mass analytes when utilizing the ablation chamber. However, the conventional ESI signal and stability was maximized using a needle protrusion of 0.6 mm from the sheath, 18 psi nebulizing gas pressure, and 9 µL/ min ESI flow rate. The last two chapters describe collaborative efforts with GlaxoSmithKline (GSK) and Temple University’s Lewis Katz School of Medicine with the application of LEMS to real world problems. The first of these chapters explores the preliminary method development results for sampling protocols of LEMS in a pathway to measuring the active ingredient in a formulation when differences in concentration are a percent or less for GSK. The results from the method development and optimization experiments in the previous chapters were applied to the GSK pharmaceutical manufacturing paradigm to test product quality in-line and in real-time instead of testing in a lab at the end of the manufacturing process. The LEMS sampling protocols involved ablation of either powder, compressed form, or solution containing powder using laser ablation. The ablated material was then entrained in an electrospray aerosol and transferred into a mass spectrometer for quantitative measurement of the molecules making up the powder, pill, or solution. Measurement time was on the order of seconds so that thousands of samples can be potentially measured in an hour. Future prospective experiments include additional optimization of the solution phase and compressed form sampling methods and, ultimately, the method validation of LEMS for quantifying active ingredients in pharmaceutical formulations. The last chapter seeks to develop new methods to map all biomarkers in traumatic brain injury (TBI) through mass spectrometry imaging (MSI), serum analysis, and protein derivatization assays. In this work, the Ramirez laboratory employs the controlled cortical impact model of experimental TBI in mice, harvests the brain (post injury) and prepares sections for analytical analysis. TBI is a complex injury involving multiple physiological and biochemical alterations to tissue. The potentially thousands of relevant biomarkers spread over a volume of thousands of mm3 makes the spatially resolved chemical analysis of brain a big data problem to which principal component analysis is applied. / Chemistry

Bakgrund: Tidigare forskning har visat att parrelationer och sexualliv påverkats efter att den ena i förhållandet förvärvat en hjärnskada. Det kan finnas en diskrepans mellan parets olika syn på vad som är problematiskt i förhållandet. Ofta har hjärnskadan medfört att partnern fått ett ökat ansvar och därmed även en rollförändring.Syfte och metod: Syftet med studien är att belysa hur partners till personer som förvärvat en hjärnskada upplever parrelationen med särskilt fokus på det gemensamma sexuallivet. Studien bygger på åtta individuella intervjuer med partners till personer som i vuxen ålder förvärvat en hjärnskada. Resultat: De övergripande resultaten visar att den förvärvade hjärnskadan påverkat parets dagliga liv. De flesta uppgav att även sexuallivet påverkats, både det gemensamma och partnerns egen sexualitet. Detta har hanterats på olika sätt. En balansgång framträdde mellan att se till det bästa för relationen, och att se till individuella behov. Två olika inställningar till sexuallivet framkom. Å ena sidan ansågs sexuella aktiviteter vara något som skulle komma spontant, och å andra sidan att sexuallivet liksom andra aktiviteter behövde planeras. / Background: Earlier research has shown that relations and sexual life has been affected after one of the partners has acquired a brain injury. There might be a discrepancy between the partners as to what is problematic in the relationship. Often the brain injury has caused the partner to take greater responsibility, therefore also a change in roles. Purpose and method: The purpose of the study is to show how partners to people with brain injury experience their relationship, with focus on the sexual life. The study is based on eight individual’s interviews with partners to people who have acquired a brain injury in their adult life. Results: The overall results show that the brain injury has affected the couple’s daily life. Most said that their sexual life had also been affected, both the mutual and the partners own sexuality. There are different ways to cope with this. A balancing act was shown between a person’s individual needs and the needs of the partner. Two different points of view were expressed about the sexual life. On the one hand sexual activities were seen as something spontaneous, on the other hand, like so many other things, it needed planning.

<p>  </p> <p>Traumatic Brain Injuries (TBI) are a major cause of disability and death in the United States. One of the greatest consequences of the disease is the resulting long-term damage, especially in milder injury cases where the damage is initially subclinical and thus lacking acutely observable manifestations that over time can compound significantly. Among these chronic issues, Alzheimer’s Disease (AD) is one of the most serious. While multiple studies demonstrate an increased likelihood of developing neurodegenerative diseases in response to TBI, the underlying mechanisms remain undefined and no current treatment options are available. Multiple hypotheses have been postulated based on various animal and clinical models, which have contributed a great deal to our current knowledge base and implicated several targets of interest in this pathway (i.g. oxidative stress, inflammation, disruptions in proteostasis). While extremely valuable, these <em>in vivo</em> procedures and analyses are physiologically and ethically complex: there is currently no model capable of separating and visualizing TBI-induced sub-cellular damage in the moments (seconds) immediately following injury, and the subsequent associated long-term changes (AD). In addition, no mechanistic study has been performed to link mechanical-trauma independently with neurodegeneration initiation via protein aggregation. It is clear that additional investigative tools are needed to rectify these intricate issues, and while <em>in vitro </em>methodologies generally offer the type of resolution required, no such model replicates these phenomena. Therefore, we introduce the “TBI-on-a-chip” <em>in vitro </em>concussive model, with a series of concomitant targeted-experiments to address this urgent, currently unmet need. This dissertation work describes the development of our cellular trauma model, featuring a multi-disciplinary approach that provides investigatory opportunities into cellular mechanics, molecular biology, functional alterations (electrophysiology), and morphology, in both primary and secondary injury. Utilizing this model, we directly observe evidence of impact-induced electrical/functional and biochemical consequences, in addition to isolating oxidative stress as a key, contributing component. Taken together, these collective efforts suggest that oxidative stress may be a viable target for both acute and chronic potential therapeutic interventions.</p>