High-salt diet induces microbiome dysregulation, neuroinflammation and anxiety in the chronic period after mild repetitive closed head injury in adolescent mice.

The associations between human concussions and subsequent sequelae of chronic neuropsychiatric and cardiovascular diseases such as hypertension have been reported; however, little is known about the underlying biological processes. We hypothesized that dietary changes, including a high-salt diet, disrupt the bidirectional gut-brain axis, resulting in worsening neuroinflammation and emergence of cardiovascular and behavioural phenotypes in the chronic period after repetitive closed head injury in adolescent mice. Adolescent mice were subjected to three daily closed head injuries, recovered for 12 weeks and then maintained on a high-salt diet or a normal diet for an additional 12 weeks. Experimental endpoints were haemodynamics, behaviour, microglial gene expression (bulk RNA sequencing), brain inflammation (brain tissue quantitative PCR) and microbiome diversity (16S RNA sequencing). High-salt diet did not affect systemic blood pressure or heart rate in sham or injured mice. High-salt diet increased anxiety-like behaviour in injured mice compared to sham mice fed with high-salt diet and injured mice fed with normal diet. Increased anxiety in injured mice that received a high-salt diet was associated with microgliosis and a proinflammatory microglial transcriptomic signature, including upregulation in interferon-gamma, interferon-beta and oxidative stress-related pathways. Accordingly, we found upregulation of tumour necrosis factor-alpha and interferon-gamma mRNA in the brain tissue of high salt diet-fed injured mice. High-salt diet had a larger effect on the gut microbiome composition than repetitive closed head injury. Increases in gut microbes in the families Lachnospiraceae, Erysipelotrichaceae and Clostridiaceae were positively correlated with anxiety-like behaviours. In contrast, Muribaculaceae, Acholeplasmataceae and Lactobacillaceae were negatively correlated with anxiety in injured mice that received a high-salt diet, a time-dependent effect. The findings suggest that high-salt diet, administered after a recovery period, may affect neurologic outcomes following mild repetitive head injury, including the development of anxiety. This effect was linked to microbiome dysregulation and an exacerbation of microglial inflammation, which may be physiological targets to prevent behavioural sequelae in the chronic period after mild repetitive head injury. The data suggest an important contribution of diet in determining long-term outcomes after mild repetitive head injury.

Income Disparities in Survival and Receipt of Neoadjuvant Chemotherapy and Pelvic Lymph Node Dissection for Muscle-Invasive Bladder Cancer.

Background: Muscle-invasive bladder cancer (MIBC) is a potentially fatal disease, especially in the setting of locally advanced or node-positive disease. Adverse outcomes have also primarily been associated with low-income status, as has been reported in other cancers. While the adoption of neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) and pelvic lymph node dissection (PLND) has improved outcomes, these standard-of-care treatments may be underutilized in lower-income patients. We sought to investigate the economic disparities in NAC and PLND receipt and survival outcomes in MIBC. Methods: Utilizing the National Cancer Database, a retrospective cohort analysis of cT2-4N0-3M0 BCa patients with urothelial histology who underwent RC was conducted. The impact of income level on overall survival (OS) and the likelihood of receiving NAC and PLND was evaluated. Results: A total of 25,823 patients were included. This study found that lower-income patients were less likely to receive NAC and adequate PLND (≥15 LNs). Moreover, lower-income patients exhibited worse OS (Median OS 55.9 months vs. 68.2 months, p < 0.001). Our findings also demonstrated that higher income, treatment at academic facilities, and recent years of diagnosis were associated with an increased likelihood of receiving standard-of-care modalities and improved survival. Conclusions: Even after controlling for clinicodemographic variables, income independently influenced the receipt of standard MIBC treatments and survival. Our findings identify an opportunity to improve the quality of care for lower-income MIBC patients through concerted efforts to regionalize multi-modal urologic oncology care.

Delaying Surgery in Favorable-Risk Prostate Cancer Patients: An NCDB Analysis of Oncologic Outcomes.

INTRODUCTION: Concern for overtreatment in very low-, low-, and favorable intermediate-risk prostate cancer has promoted a more conservative approach through active surveillance (AS) with comparable survival outcomes. We analyzed the National Cancer Database (NCDB) to determine if delaying radical prostatectomy greater than 6 months is associated with an increase in the rate of adverse pathology or secondary treatment (adjuvant or salvage) at radical prostatectomy. METHODS: Utilizing the NCDB from 2004 to 2019, 40 to 75-year-old men with very low-, low-, and favorable-intermediate-risk prostate cancer, as defined by the National Comprehensive Cancer Network, were identified for this study. These individuals received radical prostatectomy either before or after 6 months following diagnosis. Clinical, demographic, and pathologic characteristics were obtained. Adverse pathologic outcomes were defined as pT3-4N0-1 and/or positive surgical margins. Multiple logistic regression models were used to predict delays in treatment, adverse pathologic outcomes, and receipt of secondary therapy. Survival analysis was performed using the Cox Proportional Hazards Model and the Kaplan-Meier Method. RESULTS: Of the 195,397 patients who met inclusion criteria, only 13,393 patients received surgery 6 months after diagnosis. The median time of delay was 7.5 months compared to 2.3 months in the immediate treatment group. Overall, delaying surgery had no statistically significant impact on adverse pathologic outcomes, regardless of risk category. However, when accounting for the interaction between race and delayed treatment, non-Hispanic black patients who received a delay in treatment were more likely to experience adverse features (OR 1.12, 95%CI 1.00-1.26, P = .041). Conversely, patients who had delayed surgery were less likely to receive additional therapy (either adjuvant or salvage) (OR 0.60, 95%CI 0.52-0.68, P < .001). Survival analysis showed that both groups fared well, with a 5-year survival of 97% for both groups. The treatment group was not predictive of survival. CONCLUSION: Overall, delaying surgery more than 6 months following diagnosis did not have a significant impact on adverse pathologic features or overall survival. However, when specifically looking at non-Hispanic black patients with a treatment delay, these patients were at increased risk for adverse features, suggesting that the negative impact of treatment delay depends on the patient's race. As race is a social construct, this finding likely points to the complex socioeconomic factors that contribute to overall health outcomes rather than any inherent disease characteristics. Lastly, delayed treatment patients were actually less likely to require secondary therapy, regardless of race, possibly reflecting high clinician acumen in selecting patients appropriate for treatment delay. The results suggest that patients who ultimately "fail" AS and require subsequent surgery have overall comparable survival outcomes. However, pathologic outcomes are dependent on the patient's underlying race, with non-Hispanic black patients experiencing an increased risk of adverse outcomes if treatment is delayed.

Efficacy of cytoreductive radical cystectomy in metastatic urothelial bladder cancer based on site and number of metastases.

BACKGROUND: Recent studies have highlighted the overall survival (OS) benefit of cytoreductive radical cystectomy (CRC) in metastatic bladder cancer (mBCa). Cytoreductive surgery has been established in other urologic cancers. However, the efficacy of CRC and optimal criteria for patient selection in mBCa is unclear. This study investigated the oncologic efficacy of CRC, particularly emphasizing the location and number of metastasis sites as a predictor of survival and treatment response. METHODS: A retrospective analysis of cT2-4N0-3M1 mBCa patients treated with multiagent chemotherapy between 2004 and 2019 was conducted using the National Cancer Database. Patients were classified by additional treatment with CRC or conservative local treatment (CLT), consisting of transurethral resection of bladder tumor, radiation, or no local treatment and propensity score (PS) matched. Kaplan-Meier analysis and multivariate Cox Proportional Hazards model assessed the effect of CRC or CLT on OS within the matched cohort and in four subgroups (1) patients with only distant lymph node (LN) metastasis vs. any organ metastasis, (2) patients with single metastasis vs. multiple metastases. Sensitivity analysis estimated the influence of unmeasured confounders on CRC OS benefit. RESULTS: Propensity matching yielded 247 and 251 patients treated with CRC and CLT, respectively. Median OS in patients who received CRC was greater than that of patients treated with CLT (20.4 months vs. 12.0 months, P < 0.001). CRC was associated with reduced mortality risk in patients with only distant LN metastases (HR = 0.545, P = 0.039), any organ metastasis (HR = 0.421, P < 0.001), and single visceral metastasis (HR = 0.483, P = 0.002). However, CRC did not significantly improve OS in patients with multiple metastases (HR = 0.501, P = 0.064). CONCLUSION: These findings demonstrate an OS benefit of CRC with multiagent chemotherapy and pinpoint multiple visceral metastases as a potential contraindication for CRC. Although limited by the influence of unmeasured confounders, these findings may inform future prospective investigations into CRC.

Non-Invasive Vagal Nerve Stimulation Pre-Treatment Reduces Neurological Dysfunction After Closed Head Injury in Mice.

Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1ß) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1ß activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI.

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Evaluating Transcranial Photobiomodulation as Treatment for Concussion.

INTRODUCTION: Literature indicating that transcranial photobiomodulation (tPBM) may enable the brain to recover normal function after concussion, resulting in symptoms reduction, and improved cognitive function after concussion is limited by small sample sizes and lack of controls. METHODS: We conducted a randomized, double-blind, placebo-controlled trial examining the effect of 6 wk of tPBM in patients 11 yr or older who received care for persistent postconcussion symptoms between September 2012 and December 2015. Our primary outcome measure was the mean difference in Postconcussion Symptom Scale total score and the raw Immediate Postconcussion Assessment and Cognitive Testing composite scores between study entry and treatment completion. Participants received two, 10-min sessions either with tPBM units or via two placebo units, three times per week. We screened for potential confounding variables using univariable analyses. We entered covariables that differed between the two groups on univariable screening into a regression analysis. We considered adjusted odds ratio that did not cross one statistically significant. RESULTS: Forty-eight participants completed the study. Most were female (63%), and a majority sustained their injury during sports or exercise (71%). Despite randomization, those that received tPBM therapy reported a greater number of previous concussions. After adjusting for the effect of previous concussions and multiple comparisons, there were no significant differences between tPBM and placebo groups at 3 or 6 wk of treatment. CONCLUSIONS: Despite showing promise in previous investigations, our study did not show benefit to tPBM over placebo therapy in patients experiencing persistent postconcussion symptoms. Further investigation is needed to determine if varying the dose or timing alters the efficacy of tPBM after concussion.

Rare adrenal cavernous hemangioma: a case report highlighting diagnostic challenges.

Introduction: Adrenal cavernous hemangiomas are rare benign vascular tumors that pose significant diagnostic challenges. Despite their benign nature, features overlapping with malignancies often complicate management decisions. Case presentation: A 64-year-old male presented with a 4.4 cm necrotic left adrenal mass discovered incidentally on imaging. His medical history included papillary thyroid carcinoma, with subsequent thyroidectomy and radioactive iodine ablation. Evaluations for hiccups revealed multiple lung nodules, hypertrophic cardiomyopathy, and anemia. Given the patient's previous cancer history, elevated aldosterone/renin ratio, and mass size, our multidisciplinary tumor board decided to proceed with a left adrenalectomy. Post-surgical pathology confirmed a diagnosis of adrenal cavernous hemangioma. Conclusion: The occurrence of ambiguous adrenal mass with other pathologies, such as our patient's papillary thyroid carcinoma, complicates the diagnostic and therapeutic landscape. As demonstrated in our case, opting for surgery remains a viable solution for adrenal cavernous hemangiomas, especially for masses greater than 4 cm. Interdisciplinary collaboration, exemplified by our tumor board's decision-making process, is crucial for optimal management. This case underscores the need for a multifaceted approach when confronting adrenal masses with such diagnostic ambiguity.

Current laser therapy options for endoscopic treatment of upper tract urothelial carcinoma.

Endoscopic management via retrograde ureteroscopic laser ablation of upper tract urothelial carcinoma (UTUC) has become the preferred treatment modality for low-risk tumors. The most popular ablative lasers over the past 15-20 years have been the holmium:yttrium-aluminum-garnet (Ho:YAG) and neodymium (Nd:YAG) lasers, but recently the thulium (Th:YAG) laser has emerged as a potential alternative. This review compares the mechanism of action, physiological properties and effects, and oncologic outcomes of Ho:YAG/Nd:YAG lasers versus the Th:YAG laser for UTUC treatment. Potential advantages of the Th:YAG laser over existing technologies are outlined, followed by a discussion of emerging laser technologies in UTUC management.

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.

Unveiling the genomic landscape of possible metastatic malignant transformation of teratoma secondary to cisplatin-chemotherapy: a Tempus gene analysis-based case report literature review.

In this case report, we describe a patient who developed metastatic liver cancer of unknown primary origin one year following the surgical removal of a retroperitoneal adenocarcinoma. The retroperitoneal adenocarcinoma is considered a malignant transformation of teratoma (MTT), given the patient's distant history of testicular tumor excised 25 years prior and treated with chemotherapy. Despite no primary tumor being identified, the leading primary hypothesis is that the liver metastasis stemmed from the resected retroperitoneal adenocarcinoma from one year prior. We theorize that the patient's cisplatin-based chemotherapy 25 years ago may have triggered the MTT, as documented in the existing literature. Using TEMPUS gene testing on both the retroperitoneal adenocarcinoma and the recently discovered liver metastasis, we identified several genes with variants of unknown significance (VUS) that could potentially be linked to cisplatin chemotherapy resistance. While we cannot conclude that this patient definitively underwent MTT, it remains the most plausible explanation. Future research should investigate both the validity of the genes we have uncovered with respect to cisplatin resistance, as well as other genes associated with cisplatin resistance to further understand the pathogenesis of cisplatin resistance for better prediction of treatment response. As the world of medicine shifts towards individualized therapies and precision medicine, reporting and analyzing genetic mutations derived from tumors remains imperative. Our case report aims to contribute to the growing database of defined mutations and underscores the immense potential of genetic analysis in directing personalized treatment options.

Evaluating the baseline hemoglobin, albumin, lymphocyte, and platelet (HALP) score in the United States adult population and comorbidities: an analysis of the NHANES.

Introduction: As a composite immunonutritional biomarker, the Hemoglobin, Albumin, Lymphocyte, Platelet (HALP) score has shown promise in assessing a patient's overall health status by integrating several routinely collected laboratory indicators. This biomarker has been examined in many different populations of patients and disease states (i.e., cancer), but an integrated, universal rubric using standardized thresholds has not thus far been developed. Pre-existing large population-based databases represent an ideal source to examine the distribution of HALP and the influence of diverse health statuses on this score. Methods: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) between 2017-2020, evaluating 8,245 participants across numerous demographic, socioeconomic, and health-related variables. Univariate and multivariate linear regression analyses assessed the associations between HALP scores and these factors. Results: Our findings revealed significant associations between HALP scores and various demographic, socioeconomic, and health conditions. The median HALP score among the representative population was 49.0, with varying median scores across different groups and normal reference ranges for males and females. Multivariate regression analysis showed that anemia treatment, age over 65 years, weak/failing kidneys, and cancer were independent risk factors associated with lower HALP scores. Male participants demonstrated higher HALP scores than female participants, and age was inversely related to HALP. Moreover, HALP scores were negatively associated with the number of comorbidities. Conclusion/discussion: This study set out to explore the HALP score from a population-based perspective, uncovering notable associations that offer vital insights into the score's clinical relevance and future applications. By determining a median HALP score of 49.0 and normal reference ranges within our diverse, representative sample, we establish a robust foundation for researchers to refine optimal HALP applications and thresholds. Considering the growing focus on personalized medicine, HALP holds promise as a prognostic tool, enabling clinicians to comprehend their patients' immunonutritional status better and deliver customized care.

B cell treatment promotes a neuroprotective microenvironment after traumatic brain injury through reciprocal immunomodulation with infiltrating peripheral myeloid cells.

Traumatic brain injury (TBI) remains a major cause of death and severe disability worldwide. We found previously that treatment with exogenous naïve B cells was associated with structural and functional neuroprotection after TBI. Here, we used a mouse model of unilateral controlled cortical contusion TBI to investigate cellular mechanisms of immunomodulation associated with intraparenchymal delivery of mature naïve B lymphocytes at the time of injury. Exogenous B cells showed a complex time-dependent response in the injury microenvironment, including significantly increased expression of IL-10, IL-35, and TGFß, but also IL-2, IL-6, and TNFα. After 10 days in situ, B cell subsets expressing IL-10 or TGFß dominated. Immune infiltration into the injury predominantly comprised myeloid cells, and B cell treatment did not alter overall numbers of infiltrating cells. In the presence of B cells, significantly more infiltrating myeloid cells produced IL-10, TGFß, and IL-35, and fewer produced TNFα, interferon-γ and IL-6 as compared to controls, up to 2 months post-TBI. B cell treatment significantly increased the proportion of CD206+ infiltrating monocytes/macrophages and reduced the relative proportion of activated microglia starting at 4 days and up to 2 months post-injury. Ablation of peripheral monocytes with clodronate liposomes showed that infiltrating peripheral monocytes/macrophages are required for inducing the regulatory phenotype in exogenous B cells. Reciprocally, B cells specifically reduced the expression of inflammatory cytokines in infiltrating Ly6C+ monocytes/macrophages. These data support the hypothesis that peripheral myeloid cells, particularly infiltrating monocyte/macrophages, are key mediators of the neuroprotective immunomodulatory effects observed after B cell treatment.

Hemoglobin, Albumin, Lymphocyte, and Platelet Count is a Significant Biomarker Surrogate for Nutritional Status to Predict Overall Survival in Patients Post-radical Cystectomy.

INTRODUCTION: Nutritional status is an independent predictor of overall survival after radical cystectomy. Various biomarkers of nutritional status are proposed to predict postoperative outcome, including albumin, anemia, thrombocytopenia, and sarcopenia. Recently, a score comprising hemoglobin, albumin, lymphocyte, and platelet counts was postulated as an encompassing biomarker to predict overall survival post-radical cystectomy in a single-institution study. However, cutoffs for hemoglobin, albumin, lymphocyte, and platelet count are not well defined. In this study, we analyzed hemoglobin, albumin, lymphocyte, and platelet count thresholds predicting overall survival and examined the platelet-to-lymphocyte as an additional prognostic biomarker. METHODS: Fifty radical cystectomy patients were retrospectively evaluated from 2010-2021. American Society of Anesthesiologists classification, pathological data, and survival were extracted from our institutional registry. Univariable and multivariable Cox regression analysis was fit to the data to predict overall survival. RESULTS: Median follow-up was 22 (12-54) months. Hemoglobin, albumin, lymphocyte, and platelet count (continuous) was a significant predictor of overall survival on multivariable Cox regression analysis (HR 0.95, 95% CI: 0.90-0.99, P = .03), adjusting for Charlson Comorbidity Index, lymphadenopathy (pN >N0), muscle-invasive disease, and neoadjuvant chemotherapy. Optimal hemoglobin, albumin, lymphocyte, and platelet count cutoff was 25.0. Patients with hemoglobin, albumin, lymphocyte, and platelet count <25.0 had inferior overall survival (median, 33 months) vs with those with hemoglobin, albumin, lymphocyte, and platelet count ≥25.0 (median, not reached) (P = .03). CONCLUSIONS: Low hemoglobin, albumin, lymphocyte, and platelet count <25.0 was an independent predictor of inferior overall survival.

What is hemoglobin, albumin, lymphocyte, platelet (HALP) score? A comprehensive literature review of HALP's prognostic ability in different cancer types.

Since its inception, the Hemoglobin, Albumin, Lymphocyte, Platelet Score (HALP) has gained attention as a new prognostic biomarker to predict several clinical outcomes in a multitude of cancers. In our review, we searched PubMed for articles between the first paper on HALP in 2015 through September 2022, yielding 32 studies in total that evaluated HALP's association with various cancers, including Gastric, Colorectal, Bladder, Prostate, Kidney, Esophageal, Pharyngeal, Lung, Breast, and Cervical cancers, among others. This review highlights the collective association HALP has with demographic factors such as age and sex in addition to TNM staging, grade, and tumor size. Furthermore, this review summarizes HALP's prognostic ability to predict overall survival, progression-free survival, recurrence-free survival, among other outcomes. In some studies, HALP has also been able to predict response to immunotherapy and chemotherapy. This review article also aims to serve as a comprehensive and encyclopedic report on the literature that has evaluated HALP as a biomarker in various cancers, highlighting the heterogeneity surrounding HALP's utilization. Because HALP requires only a complete blood count and albumin - already routinely collected for cancer patients - HALP shows potential as a cost-effective biomarker to aid clinicians in improving outcomes for immuno-nutritionally deficient patients.

Role of Race and Insurance Status in Prostate Cancer Diagnosis-to-Treatment Interval.

INTRODUCTION: Numerous studies have shown that both race and insurance status may affect prostate cancer (PCa) workup and treatment. Preliminary investigations have shown that these factors may be associated with treatment delays, which may indicate inequitable care and increase risk of tumor progression. This investigation aimed to assess whether race and insurance impacted the interval between multiparametric MRI (mpMRI)-to-biopsy, and biopsy-to-prostatectomy. MATERIALS AND METHODS: A single-institution analysis of 261 patients with recorded race and insurance data was performed using an Institutional Review Board-compliant database with information spanning from 2016 to 2022. Race was self-reported during intake, and insurance status was retrieved from the electronic medical record. Insurance was sub-divided into private, Medicare, and Medicaid. Diagnostic or treatment latency was defined as time between mpMRI-to-biopsy, or biopsy-to-surgery. RESULTS: Stratified by race, there was no difference in either latency period when comparing African American (AA) and white patients. Stratified by insurance status, there was no difference in time from mpMRI-to-biopsy (P = .50), but there was a significantly longer interval from biopsy-to-prostatectomy for patients with Medicaid insurance (P = .02). Patients with Medicaid waited on average 168 days to receive surgery, in contrast to 92 days for private and 87 for Medicare. Notably, 82% of Medicaid patients were AA. CONCLUSION: Insurance status, which is inherently linked to race and social determinants of health, portended a significantly increased interval between biopsy and surgery. Physicians should be aware of the relationship between insurance status and treatment delay, as well as its potential downstream consequences.

Comparative Effectiveness of Diversion of Cerebrospinal Fluid for Children With Severe Traumatic Brain Injury.

Importance: Diversion of cerebrospinal fluid (CSF) has been used for decades as a treatment for children with severe traumatic brain injury (TBI) and is recommended by evidenced-based guidelines. However, these recommendations are based on limited studies. Objective: To determine whether CSF diversion is associated with improved Glasgow Outcome Score-Extended for Pediatrics (GOS-EP) and decreased intracranial pressure (ICP) in children with severe TBI. Design, Setting, and Participants: This observational comparative effectiveness study was performed at 51 clinical centers that routinely care for children with severe TBI in 8 countries (US, United Kingdom, Spain, the Netherlands, Australia, New Zealand, South Africa, and India) from February 2014 to September 2017, with follow-up at 6 months after injury (final follow-up, October 22, 2021). Children with severe TBI were included if they had Glasgow Coma Scale (GCS) scores of 8 or lower, had intracranial pressure (ICP) monitor placed on-site, and were aged younger than 18 years. Children were excluded if they were pregnant or an ICP monitor was not placed at the study site. Consecutive children were screened and enrolled, data regarding treatments were collected, and at discharge, consent was obtained for outcomes testing. Propensity matching for pretreatment characteristics was performed to develop matched pairs for primary analysis. Data analyses were completed on April 18, 2022. Exposures: Clinical care followed local standards, including the use of CSF diversion (or not), with patients stratified at the time of ICP monitor placement (CSF group vs no CSF group). Main Outcomes and Measures: The primary outcome was GOS-EP at 6 months, while ICP was considered as a secondary outcome. CSF vs no CSF was treated as an intention-to-treat analysis, and a sensitivity analysis was performed for children who received delayed CSF diversion. Results: A total of 1000 children with TBI were enrolled, including 314 who received CSF diversion (mean [SD] age, 7.18 [5.45] years; 208 [66.2%] boys) and 686 who did not (mean [SD] age, 7.79 [5.33] years; 437 [63.7%] boys). The propensity-matched analysis included 98 pairs. In propensity score-matched analyses, there was no difference between groups in GOS-EP (median [IQR] difference, 0 [-3 to 1]; P = .08), but there was a decrease in overall ICP in the CSF group (mean [SD] difference, 3.97 [0.12] mm Hg; P < .001). Conclusions and Relevance: In this comparative effectiveness study, CSF diversion was not associated with improved outcome at 6 months after TBI, but a decrease in ICP was observed. Given the higher quality of evidence generated by this study, current evidence-based guidelines related to CSF diversion should be reconsidered.

Localization of Multi-Lamellar Vesicle Nanoparticles to Injured Brain Tissue in a Controlled Cortical Impact Injury Model of Traumatic Brain Injury in Rodents.

Severe traumatic brain injury (TBI), such as that suffered by patients with cerebral contusion, is a major cause of death and disability in young persons. Effective therapeutics to treat or mitigate the effects of severe TBI are lacking, in part because drug delivery to the injured brain remains a challenge. Promising therapeutics targeting secondary injury mechanisms may have poor pharmacokinetics/pharmacodynamics, unwanted side effects, or high hydrophobicity. To address these challenges, we have developed a multi-lamellar vesicle nanoparticle (MLV-NP) formulation with a narrow size distribution (243 nm in diameter, 0.09 polydispersity index) and the capability of encapsulating hydrophobic small molecule drugs for delivery to the injured brain. To demonstrate the utility of these particles, we produced dual-fluorescent labeled nanoparticles containing the organic dyes, coumarin 153 and rhodamine B, that were delivered intravenously to Sprague-Dawley rats and C57Bl6/J mice at 1, 1 and 4, 24, or 48 h after controlled cortical impact injury. Distribution of particles was measured at 5, 25, 48, or 49 h post-injury by fluorescence microscopy of coronal brain sections. In all cases of MLV administration, a 1.2- to 1.9-fold enhancement of ipsilateral fluorescence signal was observed compared to the contralateral cortex. Enhanced fluorescence was also observed in the injured hippocampal tissue in these animals. MLV-NPs administered at 1 h were observed intracellularly in the injured hemisphere at 48 h, suggesting the possibility of concentrated drug delivery to injured cells. These results suggest that MLV-NP delivery of therapeutic agents may be a viable strategy for treating cerebral contusion TBI.

Cortical Spreading Depolarization, Blood Flow, and Cognitive Outcomes in a Closed Head Injury Mouse Model of Traumatic Brain Injury.

BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in many forms of acute brain injury, including traumatic brain injury (TBI). Animal models could be helpful in developing new therapies or biomarkers to improve outcomes in survivors of TBI. Recently, investigators have observed CSDs in murine models of mild closed head injury (CHI). We designed the currently study to determine additional experimental conditions under which CSDs can be observed, from mild to relatively more severe TBI. METHODS: Adult male C57Bl/6J mice (8-14 weeks old) were anesthetized with isoflurane and subjected to CHI with an 81-g weight drop from 152 or 183 cm. CSDs were detected with minimally invasive visible light optical intrinsic signal imaging. Cerebral blood flow index (CBFi) was measured in the 152-cm drop height cohort using diffuse correlation spectroscopy at baseline before and 4 min after CHI. Cognitive outcomes were assessed at 152- and 183-cm drop heights for the Morris water maze hidden platform, probe, and visible platform tests. RESULTS: CSDs occurred in 43% (n = 12 of 28) of 152-cm and 58% (n = 15 of 26) of 183-cm drop height CHI mice (p = 0.28). A lower baseline preinjury CBFi was associated with development of CSDs in CHI mice (1.50 ± 0.07 × 10-7 CHI without CSD [CSD-] vs. 1.17 ± 0.04 × 10-7 CHI with CSD [CSD+], p = 0.0001). Furthermore, in CHI mice that developed CSDs, the ratio of post-CHI to pre-CHI CBFi was lower in the hemisphere ipsilateral to a CSD compared with non-CSD hemispheres (0.19 ± 0.07 less in the CSD hemisphere, p = 0.028). At a 152-cm drop height, there were no detectable differences between sham injured (n = 10), CHI CSD+ (n = 12), and CHI CSD- (n = 16) mice on Morris water maze testing at 4 weeks. At a 183-cm drop height, CHI CSD+ mice had worse performance on the hidden platform test at 1-2 weeks versus sham mice (n = 15 CHI CSD+, n = 9 sham, p = 0.045), but there was no appreciable differences compared with CHI CSD- mice (n = 11 CHI CSD-). CONCLUSIONS: The data suggest that a lower baseline cerebral blood flow prior to injury may contribute to the occurrence of a CSD. Furthermore, a CSD at the time of injury can be associated with worse cognitive outcome under the appropriate experimental conditions in a mouse CHI model of TBI.

Inactivation of RIP3 kinase sensitizes to 15LOX/PEBP1-mediated ferroptotic death.

Ferroptosis and necroptosis are two pro-inflammatory cell death programs contributing to major pathologies and their inhibition has gained attention to treat a wide range of disease states. Necroptosis relies on activation of RIP1 and RIP3 kinases. Ferroptosis is triggered by oxidation of polyunsaturated phosphatidylethanolamines (PUFA-PE) by complexes of 15-Lipoxygenase (15LOX) with phosphatidylethanolamine-binding protein 1 (PEBP1). The latter, also known as RAF kinase inhibitory protein, displays promiscuity towards multiple proteins. In this study we show that RIP3 K51A kinase inactive mice have increased ferroptotic burden and worse outcome after irradiation and brain trauma rescued by anti-ferroptotic compounds Liproxstatin-1 and Ferrostatin 16-86. Given structural homology between RAF and RIP3, we hypothesized that PEBP1 acts as a necroptosis-to-ferroptosis switch interacting with either RIP3 or 15LOX. Using genetic, biochemical, redox lipidomics and computational approaches, we uncovered that PEBP1 complexes with RIP3 and inhibits necroptosis. Elevated expression combined with higher affinity enables 15LOX to pilfer PEBP1 from RIP3, thereby promoting PUFA-PE oxidation and ferroptosis which sensitizes Rip3K51A/K51A kinase-deficient mice to total body irradiation and brain trauma. This newly unearthed PEBP1/15LOX-driven mechanism, along with previously established switch between necroptosis and apoptosis, can serve multiple and diverse cell death regulatory functions across various human disease states.