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BACKGROUND: Almost one-third of the U.S. military population is comprised of service members and veterans (SMVs) of color. Research suggests poorer functional and psychosocial outcomes among Black and Hispanic/Latine vs. White civilians following traumatic brain injury (TBI). OBJECTIVE: This study examined racial/ethnic differences in 5-year functional independence and life satisfaction trajectories among SMVs who had undergone acute rehabilitation at one of five Veterans Affairs (VA) TBI Model Systems (TBIMS) Polytrauma Rehabilitation Centers (PRCs). METHODS: Differences in demographic and injury-related factors were assessed during acute rehabilitation among White (n = 663), Black (n = 89), and Hispanic/Latine (n = 124) groups. Functional Independence Measure (FIM) Motor, FIM Cognitive, and Satisfaction with Life Scale (SWLS) scores were collected at 1, 2, and 5 years after injury. Racial/ethnic comparisons in these outcome trajectories were made using hierarchical linear modeling. RESULTS: Black SMVs were less likely than White and Hispanic/Latine SMVs to have been deployed to a combat zone; there were no other racial/ethnic differences in any demographic or injury-related variable assessed. In terms of outcomes, no racial/ethnic differences emerged in FIM Motor, FIM cognitive, or SWLS trajectories. CONCLUSION: The absence of observable racial/ethnic differences in 5-year outcome trajectories after TBI among SMVs from VA TBIMS PRCs contrasts sharply with previous research identifying disparities in these same outcomes and throughout the larger VA health care system. Individuals enrolled in VA PRCs are likely homogenized on key social determinants of health that would otherwise contribute to racial/ethnic disparities in outcome trajectories.

Hospital-acquired pressure injuries are problematic within organizations. The Centers for Medicare and Medicaid Services counts hospital-acquired pressure injuries as a patient safety event and encourages hospitals to reduce or eliminate them in part by reducing payments to the hospital. Individuals who are admitted to hospitals with acute heart failure are usually elderly with comorbidities that increase their risk of developing a pressure injury. Therefore, evidence-based protocols should be made, implemented, and analyzed by an interprofessional team to combat the development of pressure injuries to maintain the best quality of life for patients hospitalized with heart failure.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.TeaserWe present a global effort to devise harmonization procedures necessary to meaningfully leverage big data.

Children with cancer and those undergoing hematopoietic stem cell transplantation frequently require anesthesia for imaging as well as diagnostic and therapeutic procedures from diagnosis through follow-up. Due to their underlying disease and side effects of chemotherapy and radiation, they are at risk for complications during this time, yet no published guideline exists for preanesthesia preparation. A comprehensive literature review served as the basis for discussions among our multidisciplinary panel of oncologists, anesthesiologists, nurse practitioners, clinical pharmacists, pediatric psychologists, surgeons and child life specialists at the Children's Hospital of Philadelphia. Due to limited literature available, this panel created an expert consensus guideline addressing anesthesia preparation for this population.

Background Converging lines of evidence point to hippocampal dysfunction in schizophrenia. It is thought that hippocampal dysfunction spreads across hippocampal subfields and to cortical regions by way of long-range efferent projections. Importantly, abnormalities in the excitation/inhibition balance could impair the long-range modulation of neural networks. The goal of this project was twofold. First, we sought to identify replicable patterns of hippocampal dysconnectivity in patients with a psychosis spectrum disorder. Second, we aimed to investigate a putative link between glutamatergic metabolism and hippocampal connectivity alterations. Methods We evaluated resting-state hippocampal functional connectivity alterations in two cohorts of patients with a psychosis spectrum disorder. The first cohort consisted of 55 medication-naive patients with first-episode psychosis and 41 matched healthy control subjects, and the second cohort consisted of 42 unmedicated patients with schizophrenia and 41 matched control subjects. We also acquired measurements of glutamate + glutamine in the left hippocampus using magnetic resonance spectroscopy for 42 patients with first-episode psychosis and 37 healthy control subjects from our first cohort. Results We observed a pattern of hippocampal functional hypoconnectivity to regions of the default mode network and hyperconnectivity to the lateral occipital cortex in both cohorts. We also show that in healthy control subjects, greater hippocampal glutamate + glutamine levels predicted greater hippocampal functional connectivity to the anterior default mode network. Furthermore, this relationship was reversed in medication-naive subjects with first-episode psychosis. Conclusions These results suggest that an alteration in the relationship between glutamate and functional connectivity may disrupt the dynamic of major neural networks.

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Parkinson's disease is both a motor and non-motor disorder. Despite the non-motor being an intrinsic feature of PD, it has been poorly researched and understood in clinical practices; olfactory deficit is one of the first established non motor symptom and nearly all ∼90 % of sporadic PD cases are associated with olfactory dysfunction and there is inconsistency in various pharmacological approaches. Hence this study aimed to evaluate the impact of caffeine at the A2A receptors of the olfactory bulb of a rotenone rat model of Parkinson's disease.About 50 male Adult Wistar Rats were used for this study. The rats were randomly divided into five groups of 10 rats each as follows: Group A (vehicle; ethanol), Group B (rotenone 3 mg/kg, i.p), Group C (caffeine 30 mg/kg, i.p + rotenone 3 mg/kg, i.p), Group D (rotenone 3 mg/kg, i.p + caffeine 30 mg/kg, i.p), Group E (caffeine 30 mg/kg, i.p). The animals were subjected to neurobehavioral assay and sacrificed, and brains were excised, weighed, and processed histologically; appropriate sections were taken and processed. The photomicrographs, Morphometric and Statistical analysis was done using Omax led digital Microscope, Image J Software and Graph Pad Prism 7, respectively.The results showed a significant decrease in body weight (P 0.05), relative brain weight, mitral/tufted cells count, and high latency in food-seeking test in Rotenone treated groups. Histopathological presentations include degenerated concentric layers of Olfactory bulb, neuronal degeneration, distorted appearance, degenerated neuropile and vacuolation, all of which were abrogated/reversed following caffeine treatment.In conclusion, this study was able to establish the neuroprotective and therapeutic candidature of caffeine acting via the A2A receptor to ameliorate or reverse the various pathological insults caused by rotenone administration.

Traumatic brain injury (TBI) is an extremely complex condition due to heterogeneity in injury mechanism, underlying conditions, and secondary injury. Pre-clinical and clinical researchers face challenges with reproducibility that negatively impact translation and therapeutic development for improved TBI patient outcomes. To address this challenge, TBI Pre-clinical Working Groups expanded upon previous efforts and developed common data elements (CDEs) to describe the most frequently used experimental parameters. The working groups created 913 CDEs to describe study metadata, animal characteristics, animal history, injury models, and behavioral tests. Use cases applied a set of commonly used CDEs to address and evaluate the degree of missing data resulting from combining legacy data from different laboratories for two different outcome measures (Morris water maze [MWM]; RotorRod/Rotarod). Data were cleaned and harmonized to Form Structures containing the relevant CDEs and subjected to missing value analysis. For the MWM dataset (358 animals from five studies, 44 CDEs), 50% of the CDEs contained at least one missing value, while for the Rotarod dataset (97 animals from three studies, 48 CDEs), over 60% of CDEs contained at least one missing value. Overall, 35% of values were missing across the MWM dataset, and 33% of values were missing for the Rotarod dataset, demonstrating both the feasibility and the challenge of combining legacy datasets using CDEs. The CDEs and the associated forms created here are available to the broader pre-clinical research community to promote consistent and comprehensive data acquisition, as well as to facilitate data sharing and formation of data repositories. In addition to addressing the challenge of standardization in TBI pre-clinical studies, this effort is intended to bring attention to the discrepancies in assessment and outcome metrics among pre-clinical laboratories and ultimately accelerate translation to clinical research.

Despite being a major health concern, little is known about the pathophysiological changes that underly concussion. Nonetheless, emerging evidence suggests that selective damage to white matter axons, or diffuse axonal injury (DAI), disrupts brain network connectivity and function. While voltage-gated sodium channels (NaChs) and their anchoring proteins at the nodes of Ranvier (NOR) on axons are key elements of the brain's network signaling machinery, changes in their integrity have not been studied in context with DAI. Here, we utilized a clinically relevant swine model of concussion that induces evolving axonal pathology, demonstrated by accumulation of amyloid precursor protein (APP) across the white matter. Over a two-week follow-up post-concussion with this model, we found widespread loss of NaCh isoform 1.6 (Nav1.6), progressive increases in NOR length, the appearance of void and heminodes and loss of βIV-spectrin, ankyrin G, and neurofascin 186 or their collective diffusion into the paranode. Notably, these changes were in close proximity, yet distinct from APP-immunoreactive swollen axonal profiles, potentially representing a unique, newfound phenotype of axonal pathology in DAI. Since concussion in humans is non-fatal, the clinical relevance of these findings was determined through examination of post-mortem brain tissue from humans with higher levels of acute traumatic brain injury. Here, a similar loss of Nav1.6 and changes in NOR structures in brain white matter were observed as found in the swine model of concussion. Collectively, this widespread and progressive disruption of NaChs and NOR appears to be a form of sodium channelopathy, which may represent an important substrate underlying brain network dysfunction after concussion.

Objective To test the effectiveness of a 32-week, stepped-care intervention on disease remission rates in overweight and obese patients with medial tibiofemoral osteoarthritis (OA) compared to controls. Methods In this randomized controlled trial, eligible participants were ≥50 years of age with a body mass index of ≥28 kg/m2 and radiographic evidence of medial tibiofemoral OA. Participants were randomized to stepped-care (n = 87) or control group (n = 84). The stepped-care group received a 2-step intervention. The first step consisted of an 18-week diet and exercise program. The second step consisted of 4 treatment subgroups: 1) diet and exercise maintenance; 2) cognitive-behavioral therapy; 3) unloader knee brace; and 4) muscle strengthening exercises. Allocation into subgroups was based on disease remission state and clinical characteristics. The primary end point was the disease remission rate (yes/no) at 32 weeks, which was reached when participants achieved the Patient Acceptable Symptom State cutoff value for pain and for the patient global assessment of disease activity and/or functional impairment. Results Disease remission at 32 weeks was achieved by 18 of 68 (26%) in the control group and 32 of 82 (39%) in the stepped-care group (difference 12.6% [95% confidence interval -2.3, 27.4], P = 0.10). The stepped-care group showed an improvement in pain and function between baseline and 20 weeks. While functional improvement was maintained at 32 weeks, pain levels tended to get worse between weeks 20 and 32. Conclusion The proposed intervention did not promote a significant difference in the rate of disease remission in comparison to the control group for overweight or obese patients with medial tibiofemoral OA.

Conflict and tension in the couple relationship transfers to the parent-child relationship, amplifying the stress parents experience while parenting young children. Pinpointing moderating and individual-level factors that exist in this spillover process may identify both couple and individual areas where spillover might be mitigated. This study used a within-couple approach to test for gender differences in marital-to-parenting spillover and to examine the moderating roles of gender, parental identity, and the emotion regulation strategy cognitive reappraisal in the linkages between marital-parenting spillover. From a larger study of parenting experiences, 96 mother-father couples of young children (mean age = 3.22 years) reported on measures of marital satisfaction, cognitive reappraisal, parenting identity, and parenting stress. Using path model comparisons, we found more similarities than differences between mothers and fathers and, contrary to the hypothesis, that mothers experienced greater spillover between marital satisfaction and parental distress than fathers. Results differed between outcome measures, suggesting that parents experience more spillover from marital satisfaction to parenting in the context of parental distress than in dysfunctional interactions with their child. Importantly, we found that higher parental identity strengthened marital-to-parenting spillover for mothers in contrast to expectations based on theoretical assumptions, whereas cognitive reappraisal weakened marital-to-parenting spillover, supporting the broader emotion regulation literature. These results signify the importance of situating the marriage to parenting transfer in the context of affective experiences and intensified parenting expectations, wherein flexibility in role identity may help alleviate parenting stress.El conflicto y la tensión en la relación de pareja se traslada a la relación entre padres e hijos, lo cual intensifica el estrés que sufren los padres mientras crían a niños pequeños. La detección de los factores moderadores e individuales que existen en este proceso de desbordamiento puede identificar las áreas tanto a nivel de la pareja como individual donde el desbordamiento podría mitigarse. En este estudio se usó un enfoque dentro de la pareja para examinar las diferencias de género en el desbordamiento del matrimonio hacia la crianza de los niños y para analizar los roles moderadores del género, la identidad parental y la revaluación cognitiva de la estrategia de regulación emocional en las asociaciones entre el desbordamiento desde el matrimonio hacia la crianza. De un estudio más extenso de experiencias de crianza, 96 parejas de madres y padres de niños pequeños (edad promedio = 3.22 años) informaron medidas de satisfacción conyugal, revaluación cognitiva, identidad parental y estrés por la crianza. Utilizando comparaciones del modelo de pautas, encontramos más similitudes que diferencias entre las madres y los padres, y, contrariamente a la hipótesis, las madres experimentaron un mayor desbordamiento entre la satisfacción conyugal y el distrés parental que los padres. Los resultados variaron entre los criterios de valoración, lo cual indica que los padres experimentan más desbordamiento desde la satisfacción conyugal hacia la crianza en el contexto del distrés parental que en las interacciones disfuncionales con su hijo. Cabe destacar que descubrimos que una mayor identidad parental fortaleció el desbordamiento del matrimonio hacia la crianza en las madres en contraste con las expectativas basadas en supuestos teóricos, mientras que la revaluación cognitiva debilitó el desbordamiento desde el matrimonio hacia la crianza, lo cual respalda la bibliografía más amplia sobre regulación emocional. Estos resultados indican la importancia de ubicar el traslado desde el matrimonio a la crianza en el contexto de las experiencias afectivas y las expectativas de crianza intensificadas, donde la flexibilidad en la identidad de roles puede contribuir a aliviar el estrés por la crianza.伴侣关系中的冲突和紧张关系会转移到父母与子女的关系中, 增加父母在养育子女过程中的压力。找出在这一过程中存在的调节因素和个人层面的因素, 可以弄清楚伴侣和个人在哪些方面可以减轻溢出效应的影响。本研究采用伴侣内视角来考察婚姻对父母养育子女的外溢效应在性别方面的差异, 并探讨性别、家长身份认同、情绪调节策略认知再评价在婚姻-养育孩子的外溢关系之间的调节作用。从一项更大规模的关于养育孩子的经历的研究中, 96对幼儿的母亲-父亲夫妇 (平均年龄 = 3.22岁) 报告了婚姻满意度、认知再评价、家长身份和养育孩子压力的测量结果。利用路径模型比较, 我们发现母亲和父亲之间的相似性多于差异性, 而且与假设相反, 母亲比父亲在婚姻满意度和父母压力之间经历了更大的溢出效应。测量不同的结果发现得出的结果存在差异, 这表明当父母痛苦的时候, 与跟孩子的不正常互动的情况比较而言, 父母会经历更多的从婚姻满意度到养育孩子的溢出效应。重要的是, 我们发现, 与基于理论假设的期望相反, 较高的家长身份认同感加强了母亲方面的婚姻满意度到养育孩子的溢出效应, 而认知再评价则削弱了从婚姻到养育的溢出, 这些结果与更广泛的情绪调节文献一致。这些结果标志着将婚姻满意度的溢出影响到养育孩子的转移置于情感体验和强化的养育孩子的期望中的重要性, 其中角色认同的灵活性可能有助于缓解养育孩子的压力。.

BACKGROUND Neuroinflammation and cerebral edema development following severe traumatic brain injury (TBI) affect subsequent cognitive recovery. Independent of its anticoagulant effects, antithrombin III (AT-III) has been shown to block neurovascular inflammation after severe TBI, reduce cerebral endothelial-leukocyte interactions, and decrease blood-brain barrier permeability. We hypothesized that AT-III administration after TBI would improve post-TBI cognitive recovery, specifically enhancing learning, and memory. METHODS Fifteen CD1 male mice were randomized to undergo severe TBI (controlled cortical impact [CCI]: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy and received either intravenous AT-III (250 IU/kg) or vehicle (VEH/saline) 15 minutes and 24 hours post-TBI. Animals underwent Morris water maze testing from 6 to 14 days postinjury consisting of cued learning trials (platform visible), spatial learning trials (platform invisible, spatial cues present), and probe (memory) trials (platform removed, spatial cues present). Intergroup differences were assessed by the Kruskal-Wallis test (p < 0.05). RESULTS Morris water maze testing demonstrated that cumulative cued learning (overall mean time in seconds to reach the platform on days 6-8) was worst in CCI-VEH animals (26.1 ± 2.4 seconds) compared with CCI-AT-III counterparts (20.3 ± 2.1 seconds, p < 0.01). Cumulative noncued spatial learning was also worst in the CCI-VEH group (23.4 ± 1.8 seconds) but improved with AT-III (17.6 ± 1.5 seconds, p < 0.01). In probe trials, AT-III failed to significantly improve memory ability. Animals that underwent sham craniotomy demonstrated preserved learning and memory compared with all CCI counterparts (p < 0.05). CONCLUSION Antithrombin III improves neurocognitive recovery weeks after TBI. This improvement is particularly related to improvement in learning but not memory function. Pharmacologic support of enhanced learning may support new skill acquisition or relearning to improve outcomes after TBI. LEVEL OF EVIDENCE Therapeutic/care management, level II.

BACKGROUND: Acute traumatic coagulopathy often accompanies traumatic brain injury (TBI) and may impair cognitive recovery. Antithrombin III (AT-III) reduces the hypercoagulability of TBI. Antithrombin III and heparinoids such as enoxaparin (ENX) demonstrate potent anti-inflammatory activity, reducing organ injury and modulating leukocyte (LEU) activation, independent of their anticoagulant effect. It is unknown what impact AT-III exerts on cerebral LEU activation and blood-brain barrier (BBB) permeability after TBI. We hypothesized that AT-III reduces live microcirculatory LEU-endothelial cell (EC) interactions and leakage at the BBB following TBI. METHODS: CD1 mice (n = 71) underwent either severe TBI (controlled cortical impact (CCI), 6-m/s velocity, 1-mm depth, and 4-mm diameter) or sham craniotomy and then received either AT-III (250 IU/kg), ENX (1.5 mg/kg), or vehicle (saline) every 24 hours. Forty-eight hours post-TBI, cerebral intravital microscopy visualized in vivo penumbral microvascular LEU-EC interactions and microvascular leakage to assess BBB inflammation/permeability. Body weight loss and the Garcia neurological test (motor, sensory, reflex, balance) served as surrogates of clinical recovery. RESULTS: Both AT-III and ENX similarly reduced in vivo penumbral LEU rolling and adhesion (p < 0.05). Antithrombin III also reduced live BBB leakage (p < 0.05). Antithrombin III animals demonstrated the least 48-hour body weight loss (8.4 ± 1%) versus controlled cortical impact and vehicle (11.4 ± 0.5%, p < 0.01). Garcia neurological test scores were similar among groups. CONCLUSION: Antithrombin III reduces post-TBI penumbral LEU-EC interactions in the BBB leading to reduced neuromicrovascular permeability. Antithrombin III further reduced body weight loss compared with no therapy. Further study is needed to determine if these AT-III effects on neuroinflammation affect longer-term neurocognitive recovery after TBI.

To investigate satisfaction with a vacuum constriction device for middle-aged and older male Veterans with erectile dysfunction and their female partners.Patients (Over 96% of patients (The majority of male patients and their female partners receiving comprehensive training for vacuum constriction device use reported satisfaction with the device.Vacuum constriction devices can be highly effective in improving the sexual health and intimacy of Veterans of all ages experiencing erectile dysfunction.

Cognitive impairment is a common symptom following mild traumatic brain injury (mTBI or concussion) and can persist for years in some individuals. While the underlying mechanisms driving these impairments remain unknown, structural changes in the hippocampus post-mTBI have been reported in human patients, as well as electrophysiological changes in rodents following impact models of TBI. In addition, slice preparations from a closed-head, rotational acceleration injury (RAI) in swine showed reduced axonal function and hippocampal circuitry disruption. However, electrophysiological changes in neurons and their subtypes have not been examined. Using in vivo electrophysiology techniques, we examined the laminar oscillatory field potentials and single unit activity in the intact hippocampal network at 7 days post-RAI in anesthetized minipigs. Concussion altered the electrophysiological properties of pyramidal cells and interneurons differently in area CA1. Specifically, while firing rate and burst occurrence of CA1 interneurons were significantly decreased post-mTBI, these parameters were unchanged in putative CA1 pyramidal cells. However, pyramidal CA1 cells in TBI animals were significantly less entrained to hippocampal gamma (40 - 80 Hz) oscillations. In addition, stimulation of the Schaffer collaterals revealed hyperexcitability in the laminar CA1 response post-mTBI. Finally, computational simulations suggest that the reported changes in interneuronal firing rate and action potentials may be due to alterations in voltage-gated sodium channels. These data demonstrate that a single concussion can lead to significant neuronal and circuit level changes in the hippocampus, and that the loss of pyramidal gamma entrainment and changes in interneuronal firing may be important contributors to cognitive dysfunction following mTBI.

The R,R and S,S enantiomers of N,N'-bis(1-phenylpropyl)-2,6-pyridinedicarboxamide, L(Et), react with Ln3+ ions (Ln = La, Eu, Gd, and Tb) to give stable [Ln((R,R)- and (S,S)-L(Et))3]3+ in anhydrous acetonitrile solution, as evidenced by various spectroscopic measurements, including NMR and luminescence titrations. In addition to the characteristic Eu3+ and Tb3+ luminescence bands, the steady-state and time-resolved luminescence spectra of the aforementioned complexes show the residual ligand-centered emission of the 1ππ* to 3ππ* states, indicating an incomplete intersystem crossing (ISC) transfer from the 1ππ* to 3ππ* and ligand-to-Ln3+ energy transfer, respectively. The high circularly polarized luminescence (CPL) activity of [Eu(L(Et))3]3+ confirms that using a single enantiomer of L(Et) induces the preferential formation of one chiral [Eu(L(Et))3]3+ complex, consistent with the [EuL 3]3+ complexes formed with other ligands derived from a 2,6-pyridine dicarboxamide moiety. Furthermore, the CPL sign patterns of complexes with (R,R) or (S,S) enantiomer of L(Et) are consistent with the CPL sign pattern of related [LnL 3]3+ complexes with the (R,R) or (S,S) enantiomer of the respective ligands in this family.

In the period since Television & New Media’s inception, most of my scholarly endeavors have focused on sports media as a critical everyday site for discussion and realization of “community” in an era that often resists or, worse, actively undermines such a concept. As sports media have proliferated across this period (e.g., athlete/team/league Twitter and Instagram pages are now requisite “texts”), expectations for athletes to both stand in for entire populations’ political voice and to “shut up and dribble” have been amplified. This essay examines the LeBron (James) Family Foundation in conjunction with LeBron James’s public standing as a politicized, irrevocably geographic, and—per George Lipsitz and Ralina Joseph—always “racialized fact” to consider the increased expectation that sport/media icons are now obligated to remedy state failings through their charitable endeavors.

Traumatic brain injury (TBI) remains a prominent public health concern despite several decades of attempts to develop therapies for the associated neurological and cognitive deficits. Effective models of this condition are imperative for better defining its pathophysiology and testing therapeutics. Human brain organoids are stem cell–derived neural tissues that recapitulate many of the steps of normal neurodevelopment, resulting in the reproduction of a substantial degree of brain architecture. Organoids are highly relevant to clinical conditions because of their human nature and three-dimensional tissue structure, yet they are easier to manipulate and interrogate experimentally than animals. Thus, they have the potential to serve as a novel platform for studying TBI. In this article, we discuss available in vitro models of TBI, active areas of inquiry on brain organoids, and how these two concepts could be merged.

The dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation, and small-molecule ERK5 kinase inhibitors have been developed. However, selective ERK5 kinase inhibitors fail to recapitulate ERK5 genetic ablation phenotypes, suggesting kinase-independent functions for ERK5. Here we show that ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD). Using the ERK5 kinase inhibitor, Compound 26 (ERK5-IN-1), as a paradigm, we have developed kinase-active, drug-resistant mutants of ERK5. With these mutants, we show that induction of ERK5 transcriptional activity requires direct binding of the inhibitor to the kinase domain. This in turn promotes conformational changes in the kinase domain that result in nuclear translocation of ERK5 and stimulation of gene transcription. This shows that both the ERK5 kinase and TAD must be considered when assessing the role of ERK5 and the effectiveness of anti-ERK5 therapeutics., Selective ERK5 inhibitors target ERK5 kinase activity, but they do not phenocopy the effects of ERK5 genetic depletion. Here, the authors demonstrate that the direct interaction of these inhibitors to ERK5 kinase domain induces conformational changes that promote ERK5 nuclear translocation and transcriptional activities.

Splenic torsion is a rare potentially life-threatening condition characterized by rotation of the spleen around the gastrosplenic and phrenosplenic ligaments leading to occlusion of venous drainage and arterial supply. This retrospective study describes the CT characteristics for dogs with surgically confirmed splenic torsion from 2013 to 2018 using the submissions to a large multinational teleradiology database. Eight dogs had the splenic torsion confirmed with surgery. Seven of eight cases had histology confirming congestion, hemorrhage, and necrosis, and one had concurrent myelolipoma infiltration. The CT characteristics included an enlarged (8/8), rounded (7/8), folded C-shaped spleen (8/8) with a difference of median parenchymal attenuation between pre- and postcontrast of +1.15 HU (Hounsfield units). Other common features included a mainly homogeneous parenchyma on pre- and post-contrast images (6/8), lack of subjective and objective vascular and parenchymal contrast enhancement (6/8) and free peritoneal fluid (6/8). A "whirl sign" was seen in the majority of cases (7/8) alongside a strongly hyperattenuating center (95-416 HU) on the precontrast images (5/7), which has not been previously described in the veterinary literature. Gastric position was normal in all cases. More variable CT characteristics of the confirmed torsions were attributable to suspected partial torsion and myelolipomatous infiltration. Overall, primary splenic torsion confirmed with surgery showed consistent characteristics on CT.

Background Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. Moreover, microglial activation after TBI may play a role in hippocampal circuit and/or synaptic remodeling; however, the potential effects of chronic microglial changes are currently unknown. The objective of the current study was to assess neuropathological and neuroinflammatory changes in subregions of the dentate gyrus at acute to chronic time points following mild TBI using an established model of closed-head rotational acceleration induced TBI in pigs. Methods This study utilized archival tissue of pigs which were subjected to sham conditions or rapid head rotation in the coronal plane to generate mild TBI. A quantitative assessment of neuropathological changes in the hippocampus was performed via immunohistochemical labeling of whole coronal tissue sections at 3 days post-injury (DPI), 7 DPI, 30 DPI, and 1 year post-injury (YPI), with a focus on mossy cell atrophy and synaptic reorganization, in context with microglial alterations (e.g., density, proximity to mossy cells) in the dentate gyrus. Results There were no changes in mossy cell density between sham and injured animals, indicating no frank loss of mossy cells at the mild injury level evaluated. However, we found significant mossy cell hypertrophy at 7 DPI and 30 DPI in anterior (> 16% increase in mean cell area at each time; p = p = p = p = Conclusions The alterations of mossy cell size and synaptic inputs paired with changes in microglia density around the cells demonstrate the susceptibility of hilar mossy cells after even mild TBI. This subtle hilar mossy cell pathology may play a role in aberrant hippocampal function post-TBI, although additional studies are needed to characterize potential physiological and cognitive alterations.

BACKGROUND Bleeding is an important complication in children following tonsillectomy. Screening with coagulation tests prior to procedure is common to assess bleeding risk in the perioperative period, although ASH/ASPHO Choosing Wisely guidelines recommend against routine PT/PTT testing. Our aim was to compare von Willebrand factor antigen (VWF:Ag) and activity levels among patients with postoperative bleeding following tonsillectomy to evaluate for potential risk for bleeding. PROCEDURE Eligible subjects were aged 0-18 without significant personal or family history of major bleeding. Postoperative bleeding diaries were collected and symptoms measured using a postoperative bleeding score. Plasma VWF levels were drawn at time of anesthesia administration. RESULTS Postoperative bleeding occurred in 248 cases out of 1399 total subjects. Median VWF:Ag was 86 in patients with postoperative bleeding scores of 1-2, 86 for scores 3-4, 84 for scores 5-6, and 83 for scores >6, with no significant difference among groups (p = .98). Additionally, no difference was observed for subjects with multiple days of postoperative bleeding as compared to those with only 1 day of postoperative bleeding. Finally, no difference in VWF:Ag was observed for subjects whose first reported bleed occurred early in the postoperative course compared to those whose first reported bleed occurred later. VWF:Ag does not correlate with severity of bleeding, time of onset of first bleeding event, or recurrence of bleeding in healthy children with no personal or family history of bleeding who have postoperative bleeding following tonsillectomy. CONCLUSIONS This data does not support routine von Willebrand disease screening prior to tonsillectomy.