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Spread of Mycobacterium tuberculosis (MTB) to the larynx is exceedingly rare and can be obscured by more common conditions such as laryngeal cancer or oropharyngeal candidiasis, complicating an accurate diagnosis. Risk factors for chronic laryngeal disease, such as smoking and toxin exposure, place TB infection comparatively lower for consideration on a physician's differential. However, identifying these lesions is crucial from a medical and public health perspective to prevent community spread. We report the case of a 60-year-old male who presented with dysphonia, pharyngitis, aphasia, and significant unintentional weight loss. X-rays demonstrated focal opacities in the upper lung lobes. Laryngoscope biopsy revealed caseating granulomas and a positive culture for MTB. Laryngeal TB presents as a suspicious throat mass with nonspecific symptoms and should be thoroughly investigated by clinicians., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Rohan Dipesh Agarwal et al.)

Introduction: Upper tract urothelial carcinoma (UTUC) is a rare malignancy with poor prognosis. Radical nephroureterectomy (RNU) remains the standard treatment for high-risk UTUC. Considering the decline in renal function with RNU and results from prospective trials, NAC has emerged as a favored perioperative treatment for chemo-eligible patients with UTUC. However, strong evidence of the efficacy of NAC and predictors for its use are scarce. We aimed to assess trends in NAC utilization and pathologic outcomes and survival with NAC use., Methods: The National Cancer Database was queried for patients with high-grade cTanyNanyM0 UTUC treated with RNU from 2004 to 2019. Outcomes included overall survival (OS), pathologic response (pR) and pathologic complete response (pCR), defined as ≤pT1pN0/X and pT0pN0/X, respectively., Results: Of 6,645 patients treated with RNU, 209 received RNU NAC. Greater distance from treatment facility decreased the likelihood of receiving NAC. Higher cT stages (OR 1.72, P = .028), cN+ status (OR 7.40, P < .001) and treatment at an academic facility (OR 2.02, P < .001) predicted NAC treatment. NAC was associated with 34.0% pR and 5.3% pCR. In multivariable analysis, patients with pR and pCR had improved OS (HR = 0.176, P < .014)., Conclusion: We report significant response rates with NAC and improved OS in patients who experienced pR or pCR. Over a 15-year study period, NAC was underutilized, especially in nonacademic settings and among patients living farther from care facilities, underscoring the need for improved regionalization and multidisciplinary approaches in UTUC management., Competing Interests: Disclosures None of the authors have any relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The genetic landscape of urologic cancers has evolved with the identification of actionable mutations that impact diagnosis, prognosis, and therapeutic strategies. This narrative review consolidates existing literature on genetic mutations across key urologic cancers, including bladder, renal, prostate, upper tract urothelial, testicular, and penile. The review highlights mutations in DNA damage repair genes, such as BRCA1/2 and PTEN, as well as pathway alterations like FGFR and PD-L1 overexpression. These mutations influence tumor behavior and therapeutic outcomes, emphasizing the need for precision oncology approaches. Molecular profiling, through tools like next-generation sequencing, has revolutionized patient care by enabling targeted treatment strategies, especially in cancers with distinct molecular subtypes such as luminal or basal bladder cancer and clear cell renal carcinoma. Emerging therapies, including FGFR inhibitors and immune checkpoint blockade, offer new treatment avenues, although resistance mechanisms remain a challenge. We also emphasize the importance of biomarker identification for personalized management, especially in metastatic settings where treatment intensification is often required. Future research is needed to further elucidate our understanding of the genetics affecting urologic cancers, which will help develop novel, individualized therapies to enhance oncologic outcomes.

Surgical site infections (SSIs) represent a major source of postoperative complications adversely impacting morbidity and mortality indices in surgical care. The discovery of antibiotics in the mid-20th century, and their ensuing use for preoperative antimicrobial bowel preparation and prophylaxis, drastically reduced the occurrence of SSIs providing a major tool to surgeons of various specialties, including urology. Because, the appropriate use of these antimicrobials is critical for their continued safety and efficacy, an understanding of the recommendations guiding their application is essential for all surgeons. Here, we comprehensively review these recommendations with a focus on open and laparoscopic urologic surgeries., Competing Interests: Disclosure The authors have none to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Rinsing only with water or washing with soap and water are common methods of skin decontamination for skin contaminated during a chemical hazard release. The null hypothesis was that a 15-minute water irrigation (decontamination method 1) would not be superior to decontamination using a microfiber towel, followed by a wet wipe (Signature Select Softly Flushable Tissue Better Living Brands LLC, Pleasanton, CA), followed by using another microfiber towel (decontamination method 2)., Methods: A simulated contaminant (Magic Fluorescent Glow Paint for Face and Body, iLC Shenzhen Fulimei Technology Co. LTD, Shenzhen, the People's Republic of China) was applied to the dorsal skin of each subject's forearms. Then, photographs of these subject's skin were taken before and after decontamination of the simulated contaminant by using either decontamination method 1 or 2. Each of the subjects underwent both decontamination methods in separate trials, with each subject using one forearm for decontamination method 1 and their other forearm for decontamination method 2. Discrete points of contamination were quantified on the photographs that were taken with the skin illuminated by ambient visible light or ultraviolet light (395nm, Roceei ultraviolet flashlight, China)., Results: Under visible light, no residual contamination was seen by inspecting photographs taken after decontaminating with either method. Under ultraviolet light, less visible contamination was seen by inspecting photographs taken after decontaminating with method 1 than after decontaminating with method 2., Conclusion: In this study, skin decontamination with water irrigation was superior to skin decontamination without water irrigation.

Introduction: Bladder cancer (BCa) with variant histology (VH) is notably aggressive and not as well studied as pure urothelial carcinoma (UC). The characteristics of variant BCa in the setting of metastatic disease may contribute to treatment response/resistance and subsequent disease progression. In this study, we sought to assess VH's impact on metastasis sites at presentation in metastatic BCa., Methods: The National Cancer Database was queried from 2004 to 2019 to analyze cT1-4 cN0-3 cM1 patients with UC and VH BCa. The primary endpoint was the presence of metastasis to different organs. Binomial multivariable logistic regression was performed to determine the impact of VH on metastatic sites while controlling for multiple variables., Results: Total 6005 eligible patients diagnosed with either UC or VH were included. Patients with small cell histology, the second most common VH, were more likely to have liver metastasis (OR: 4.335) while less likely to have lung metastases (OR: 0.521). Squamous cell carcinoma decreased the odds of bone metastasis (OR: 0.449). Adenocarcinoma increased the odds of lung metastases (OR: 1.690). Micropapillary VH is less likely to metastasize to the lungs (OR: 0.182) but more likely to spread to nonregional lymph nodes (OR: 2.623). Sarcomatoid subtype did not exhibit a statistically significant variation in the odds ratio for any of the metastatic sites., Conclusion: This study comprehensively analyzes the limited research regarding metastatic BCa and VH. Our analysis underscores each subtype exhibiting heterogeneous metastatic tropism. Importantly, these findings illustrate the role of routine somatic gene expression profiling to guide adequate staging and treatment intensification and to offer a foundation for future studies of VH BCa care., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prostate cancer is the most common non-cutaneous malignancy in men, with the majority of newly diagnosed patients eligible for active surveillance. Despite definitive treatment, a considerable percentage of men will experience biochemical recurrence and even regional and distant metastatic recurrence after radiation therapy or radical prostatectomy. Salvage prostatectomy, while oncologically effective, poses significant morbidity with poor functional outcomes. Salvage cryotherapy has emerged as a promising alternative for localized recurrence, demonstrating safety and efficacy. This review examines the oncologic and functional outcomes of whole-gland and focal salvage cryotherapy, including disease-free survival, cancer-specific survival, and overall survival. The crucial role of multiparametric prostate MRI and evolving role of next-generation PSMA-targeted PET imaging are also examined. The comparison of outcomes of cryotherapy to other salvage ablation modalities, such as high-intensity focused ultrasound (HIFU), is also explored.

Background: Partial cystectomy (PC) offers potential benefits for select patients with muscle-invasive bladder cancer (MIBC). However, the oncologic efficacy of PC may be compromised due to the underutilization of standard-of-care modalities, such as neoadjuvant chemotherapy (NAC) and pelvic lymph node dissection (PLND). We aimed to assess factors influencing the incorporation of NAC and PLND with PC and evaluate their impact on overall survival (OS)., Methods: We identified 2,832 patients with cT2-4N0M0 bladder cancer (BCa) who underwent PC between 2004 and 2019 using the National Cancer Database (NCDB). The primary endpoint was OS. Kaplan-Meier analysis compared OS in treatment modalities in PC patients. Multivariate Cox Proportional Hazards (CPH) model assessed the impact of age, sex, race, insurance, income, Charlson-Deyo Index (CDI), clinical T-stage, facility type, histology, surgical margins, NAC, PLND adequacy [≥10 lymph node (LN) yield], and adjuvant radiation treatment on OS. Multivariate logistic regressions were performed to examine predictors of NAC and PLND receipt in PC patients., Results: Two hundred and thirty-one patients received multi-agent NAC with PC. NAC treatment with PLND was associated with significantly improved OS (P<0.001). Median OS was 43.9 months in patients treated with PC alone, while median OS was not reached in PC patients treated with NAC & PLND. Furthermore, patients who received NAC without any PLND had a median OS of 50.6 months, while those treated with PLND without NAC had a median OS of 76.5 months. This persisted in the adjusted CPH model, where private insurance, NAC, and PLND significantly improved OS, especially when PLND yielded ≥10 LN. Conversely, age >80 years old, CDI >2, cT3-4, positive margins, and adjuvant radiation all increased adjusted mortality risk. After controlling for clinicopathologic variables, females were less likely to receive PLND [odds ratio (OR) 0.719, P=0.005], while NAC was more likely administered to PC patients diagnosed from 2016-2019 (OR 5.295, P<0.001). PC patients who received NAC were more likely to have PLND performed as part of their treatment regimen (OR 2.189, P<0.001). Additionally, patients treated at academic centers were more likely to have NAC administered and PLND performed (OR 1.745, P=0.003; OR 2.465, P<0.001, respectively)., Conclusions: Despite guideline recommendations, the utilization of NAC and PLND with PC remains insufficient. Our analysis underscores the significant OS benefit of these recommended treatments as part of MIBC care. Importantly, we highlight a gradual increase in NAC and PLND receipt in recent years, centered largely at academic facilities. Notably, gender disparities exist in PLND receipt, emphasizing the need for further investigation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-165/coif). The authors have no conflicts of interest to declare., (2024 Translational Andrology and Urology. All rights reserved.)

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., Competing Interests: Disclosure The authors have no financial conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 by the American College of Sports Medicine.)

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-1β) 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-1β 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., (© Andreia Morais et al., 2024; Published by Mary Ann Liebert, Inc.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Antar, Farag, Youssef, Xu, Drouaud, Panitch, Tariq, Alzeer and Whalen.)

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., (© 2023. The Author(s).)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 TGFβ, but also IL-2, IL-6, and TNFα. After 10 days in situ, B cell subsets expressing IL-10 or TGFβ 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, TGFβ, 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., (© 2023. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Antar, Farag, Xu, Drouaud, Gordon and Whalen.)

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.

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., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

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.

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.

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., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

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., Competing Interests: No competing financial interests exist., (© Ricky Whitener et al., 2022; Published by Mary Ann Liebert, Inc.)

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 Rip3 K51A/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., (Copyright © 2022. Published by Elsevier B.V.)

Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1β processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 ( IL-1R1 ) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1β and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1β) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration. SIGNIFICANCE STATEMENT Repetitive mild closed head injury in adolescent male mice leads to impaired proteostasis, tau phosphorylation, and inflammasome activation in neurons later in adulthood through mechanisms involving IL-1 receptor 1. The data are the first to link repetitive mild traumatic brain injury in adolescence to neurodegeneration and suggest molecular targets and pathways to prevent neurologic sequelae in the chronic period after injuries., (Copyright © 2022 the authors.)

Introduction: Despite concerns of atypical recurrence following robotic-assisted radical cystectomy (RARC), utilization of the modality is increasing. The presumed mechanisms of peritoneal immunomodulation and pneumoperitoneum-induced tumor cell intravasation are especially relevant for higher stage, locally advanced disease, where intrinsic metastatic potential of tumor cells may be greater. This study aims to compare the oncologic outcomes and survival after RARC compared to open radical cystectomy (ORC) among patients with stage pT3-4 or node-positive muscle-invasive bladder cancer., Patients and Methods: Retrospective cohort analysis of pT3-4N0-3 and pT(any)N1-3 patients who underwent RARC or ORC was performed using the National Cancer Database (2010-2016) to investigate perioperative and oncologic outcomes., Results: 9,062 ORC cases and 2,544 RARC cases met inclusion criteria. The robotic approach was significantly associated with superior unadjusted survival compared to open as well as lower proportions of unadjusted 30- and 90-day mortality, lower positive margin status, and shorter surgical inpatient stay (all respective P<.05). However, after adjusting for confounding covariates, multivariable analysis revealed no difference in mortality hazard or odds of any of the above secondary outcomes with the exception of shorter inpatient stay and higher lymph node yield. Patients treated with RARC were more likely to have neoadjuvant chemotherapy., Conclusions: RARC is no less safe than ORC for patients with locally advanced bladder cancer on the basis of overall, 30- and 90-day survival. Unadjusted mortality and surgical outcomes demonstrate advantages to RARC, which are attenuated after multivariate analysis. Perioperative benefits may favor the robotic approach, consistent with previous randomized control studies., (Copyright © 2021. Published by Elsevier Inc.)

Cerebrovascular reactivity (CVR) deficits in adolescents with concussion may persist after resolution of neurological symptoms. Whether or not CVR deficits predict long term neurological function is unknown. We used adolescent mice closed head injury (CHI) models (54 g, 107 cm or 117 cm drop height), followed by blood oxygenation level dependent (BOLD)-functional MRI with CO 2 challenge to assess CVR and brain connectivity. At one week, 3HD 107 cm mice showed delayed BOLD responses (p = 0.0074), normal striatal connectivity , and an impaired respiratory rate response to CO 2 challenge (p = 0.0061 in ΔRmax). The 107 cm group developed rotarod deficits at 6 months (p = 0.02) and altered post-CO 2 brain connectivity (3-fold increase in striatum to motor cortex correlation coefficient) by one year, but resolved their CVR and respiratory rate impairments, and did not develop cognitive or circadian activity deficits. In contrast, the 117 cm group had persistent CVR (delay time: p = 0.016; washout time: p = 0.039) and circadian activity deficits (free-running period: 23.7 hr in sham vs 23.9 hr in 3HD; amplitude: 0.15 in sham vs 0.2 in 3HD; peak activity: 18 in sham vs 21 in 3HD) at one year. Persistent CVR deficits after concussion may portend long-term neurological dysfunction. Further studies are warranted to determine the utility of CVR to predict chronic neurological outcome after mild traumatic brain injury.

Exogenously applied mature naïve B220 + /CD19 + /IgM + /IgD + B cells are strongly protective in the context of tissue injury. However, the mechanisms by which B cells detect tissue injury and aid repair remain elusive. Here, we show in distinct models of skin and brain injury that MyD88-dependent toll-like receptor (TLR) signaling through TLR2/6 and TLR4 is essential for the protective benefit of B cells in vivo, while B cell-specific deletion of MyD88 abrogated this effect. The B cell response to injury was multi-modal with simultaneous production of both regulatory cytokines, such as IL-10, IL-35, and transforming growth factor beta (TGFβ), and inflammatory cytokines, such as tumor necrosis factor alpha (TNFα), IL-6, and interferon gamma. Cytometry analysis showed that this response was time and environment-dependent in vivo, with 20%-30% of applied B cells adopting an immune modulatory phenotype with high co-expression of anti- and pro-inflammatory cytokines after 18-48 h at the injury site. B cell treatment reduced the expression of TNFα and increased IL-10 and TGFβ in infiltrating immune cells and fibroblasts at the injury site. Proteomic analysis further showed that B cells have a complex time-dependent homeostatic effect on the injured microenvironment, reducing the expression of inflammation-associated proteins, and increasing proteins associated with proliferation, tissue remodeling, and protection from oxidative stress. These findings chart and validate a first mechanistic understanding of the effects of B cells as an immunomodulatory cell therapy in the context of tissue injury., (© 2021 Federation of American Societies for Experimental Biology.)

Traumatic brain injury (TBI) is a leading cause of death and disability with no specific effective therapy, in part because disease driving mechanisms remain to be elucidated. Receptor interacting protein kinases (RIPKs) are serine/threonine kinases that assemble multi-molecular complexes that induce apoptosis, necroptosis, inflammasome and nuclear factor kappa B activation. Prior studies using pharmacological inhibitors implicated necroptosis in the pathogenesis of TBI and stroke, but these studies cannot be used to conclusively demonstrate a role for necroptosis because of the possibility of off target effects. Using a model of cerebral contusion and RIPK3 and mixed lineage kinase like knockout (MLKL -/- ) mice, we found evidence for activation of RIPK3 and MLKL and assembly of a RIPK1-RIPK3-MLKL necrosome complex in pericontusional brain tissue. Phosphorylated forms of RIPK3 and MLKL were detected in endothelium, CD11b + immune cells, and neurons, and RIPK3 was upregulated and activated in three-dimensional human endothelial cell cultures subjected to CCI. RIPK3 -/- and MLKL -/- mice had reduced blood-brain barrier damage at 24 h (p < 0.05), but no differences in neuronal death (6 h, p = ns in CA1, CA3 and DG), brain edema (24 h, p = ns), or lesion size (4 weeks, p = ns) after CCI. RIPK3 -/- , but not MLKL -/- mice, were protected against postinjury motor and cognitive deficits at 1-4 weeks (RIPK3 -/- vs WT: p < 0.05 for group in wire grip, Morris water maze hidden platform trials, p < 0.05 for novel object recognition test, p < 0.01 for rotarod test). RIPK3 -/- mice had reduced infiltrating leukocytes (p < 0.05 vs WT in CD11b + cells, microglia and macrophages), HMGB1 release and interleukin-1 beta activation at 24-48 h (p < 0.01) after CCI. Our data indicate that RIPK3 contributes to functional outcome after cerebral contusion by mechanisms involving inflammation but independent of necroptosis., (© 2021. The Author(s).)

The corpus callosum is the largest white matter tract and critical for interhemispheric connectivity. Unfortunately, neurocognitive deficits after experimental white matter lesions are subtle and variable, limiting their translational utility. We examined resting state functional connectivity (RSFC) as a surrogate after a focal lesion in the lateral corpus callosum induced by stereotaxic injection of L-NIO in mice. RSFC was performed via optical intrinsic signal imaging through intact skull before and on days 1 and 14 after injection, using interhemispheric homotopic and seed-based temporal correlation maps. We measured the lesion volumes at 1 month in the same cohort. L-NIO induced focal lesions in the corpus callosum. Interhemispheric homotopic connectivity decreased by up to 50% 24 h after L-NIO, partially sparing the visual cortex. All seeds showed loss of connectivity to the contralateral hemisphere. Moreover, ipsilesional motor and visual cortices lost connectivity within the same hemisphere. Sham-operated mice did not show any lesion or connectivity changes. RSFC imaging reliably detects acute disruption of long interhemispheric and intrahemispheric connectivity after a corpus callosum lesion in mice. This noninvasive method can be a functional surrogate to complement neurocognitive testing in both therapeutic and recovery studies after white matter injury., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Microvascular failure is one of the key pathogenic factors in the dynamic pathological evolution after traumatic brain injury (TBI). Our laboratory and others previously reported that Annexin A2 functions in blood-brain barrier (BBB) development and cerebral angiogenesis, and recombinant human Annexin A2 (rA2) protected against hypoxia plus IL-1β-induced cerebral trans-endothelial permeability in vitro , and cerebral angiogenesis impairment of AXNA2 knock-out mice in vivo . We thereby hypothesized that ANXA2 might be a cerebrovascular therapy candidate that targets early BBB integrity disruption, and subacute/delayed cerebrovascular remodeling after TBI, ultimately improve neurological outcomes. In a controlled cortex impact (CCI) mice model, we found rA2 treatment (1 mg/kg) significantly reduced early BBB disruption at 24 h after TBI; and rA2 daily treatment for 7 days augmented TBI-induced mRNA levels of pro-angiogenic and endothelial-derived trophic factors in cerebral microvessels. In cultured human brain microvascular endothelial cells (HBMEC), through MAPKs array, we identified that rA2 significantly activated Akt, ERK, and CREB, and the activated CREB might be responsible for the rA2-induced VEGF and BDNF expression. Moreover, rA2 administration significantly increased cerebral angiogenesis examined at 14 days and vessel density at 28 days after TBI in mice. Consistently, our results validated that rA2 significantly induced angiogenesis in vitro , evidenced by tube formation and scratched migration assays in HBMEC. Lastly, we demonstrated that rA2 improved long-term sensorimotor and cognitive function, and reduced brain tissue loss at 28 days after TBI. Our findings suggest that rA2 might be a novel vascular targeting approach for treating TBI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cheng, Wang, Jiang, Li, Liao, Li, Yu, Whalen, Lok, Dumont, Liu and Wang.)

Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell death and inflammation, and mediates programmed necrosis (necroptosis) via mixed-lineage kinase like (MLKL) protein. Prior studies in experimental intracerebral hemorrhage (ICH) implicated RIPK1 in the pathogenesis of neuronal death and cognitive outcome, but the relevant cell types involved and potential role of necroptosis remain unexplored. In mice subjected to autologous blood ICH, early RIPK1 activation was observed in neurons, endothelium and pericytes, but not in astrocytes. MLKL activation was detected in astrocytes and neurons but not endothelium or pericytes. Compared with WT controls, RIPK1 kinase-dead ( RIPK1 D138N/D138N ) mice had reduced brain edema (24 h) and blood-brain barrier (BBB) permeability (24 h, 30 d), and improved postinjury rotarod performance. Mice deficient in MLKL ( Mlkl -/- ) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT. The data support a central role for RIPK1 in the pathogenesis of ICH, including cell death, edema, BBB permeability, and motor deficits. These effects may be mediated in part through the activation of MLKL-dependent necroptosis in neurons. The data support development of RIPK1 kinase inhibitors as therapeutic agents for human ICH.

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI-which is commonly used to assess RSFC in humans-have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

Traumatic brain injury (TBI) survivors suffer long term from mental illness, neurodegeneration, and neuroinflammation. Studies of 3D tissue models have provided new insights into the pathobiology of many brain diseases. Here, a 3D in vitro contusion model is developed consisting of mouse cortical neurons grown on a silk scaffold embedded in collagen and used outcomes from an in vivo model for benchmarking. Molecular, cellular, and network events are characterized in response to controlled cortical impact (CCI). In this model, CCI induces degradation of neural network structure and function and release of glutamate, which are associated with the expression of programmed necrosis marker phosphorylated Mixed Lineage Kinase Domain Like Pseudokinase (pMLKL). Neurodegeneration is observed first in the directly impacted area and it subsequently spreads over time in 3D space. CCI reduces phosphorylated protein kinase B (pAKT) and Glycogen synthase kinase 3 beta (GSK3β) in neurons in vitro and in vivo, but discordant responses are observed in phosphprylated ribosomal S6 kinase (pS6) and phosphorylated Tau (pTau) expression. In summary, the 3D brain-like culture system mimicked many aspects of in vivo responses to CCI, providing evidence that the model can be used to study the molecular, cellular, and functional sequelae of TBI, opening up new possibilities for discovery of therapeutics., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2) , and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2 , and TNF-α , and revealed an ultra-early IL-1β response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.

Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood-brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

Repetitive mild traumatic brain injury during adolescence can induce neurological dysfunction through undefined mechanisms. Interleukin-1 (IL-1) contributes to experimental adult diffuse and contusion TBI models, and IL-1 antagonists have entered clinical trials for severe TBI in adults; however, no such data exist for adolescent TBI. We developed an adolescent mouse repetitive closed head injury (rCHI) model to test the role of IL-1 family members in post-injury neurological outcome. Compared to one CHI, three daily injuries (3HD) produced acute and chronic learning deficits and emergence of hyperactivity, without detectable gliosis, neurodegeneration, brain atrophy, and white matter loss at one year. Mature IL-1β and IL-18 were induced in brain endothelium in 3HD but not 1HD, three hit weekly, or sham animals. IL-1β processing was induced cell-autonomously in three-dimensional human endothelial cell cultures subjected to in vitro concussive trauma. Mice deficient in IL-1 receptor-1 or caspase-1 had improved post-injury Morris water maze performance. Repetitive mild CHI in adolescent mice may induce behavioral deficits in the absence of significant histopathology. The endothelium is a potential source of IL-1β and IL-18 in rCHI, and IL-1 family members may be therapeutic targets to reduce or prevent neurological dysfunction after repetitive mild TBI in adolescents.