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Dysregulation of calcium signaling has been causally implicated in brain aging and Alzheimer's disease. Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease. To elucidate the cellular mechanisms underlying these disturbances, we studied calcium signaling in fibroblasts isolated from mutant PS1 knockin mice. Mutant PS1 knockin cells exhibited a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation. These cells also showed significant impairments in capacitative calcium entry (CCE, also known as store-operated calcium entry), an important cellular signaling pathway wherein depletion of intracellular calcium stores triggers influx of extracellular calcium into the cytosol. Notably, deficits in CCE were evident after agonist stimulation, but not if intracellular calcium stores were completely depleted with thapsigargin. Treatment with ionomycin and thapsigargin revealed that calcium levels within the ER were significantly increased in mutant PS1 knockin cells. Collectively, our findings suggest that the overfilling of calcium stores represents the fundamental cellular defect underlying the alterations in calcium signaling conferred by presenilin mutations.

Background and Objectives: Educational environments are the most effective factors for physical growth, mental development, and learning of students. The purpose of this study was to investigate the environmental health status of schools in Saleh Abad district -- Mehran city- using national indicators in 2017. Materials and Methods: This descriptive cross-sectional study was conducted in 2017. Sampling was done by census method and collection tool was a checklist for assessing the health status of the school environment.The information was gathered by interviewing and direct observation. Excel software was used to describe the statistics and drawing the figures. Results: The overall health status of individual, building, safety, and equipment in the schools were 46.4%, 61.1%, 39.6%, and 79.3%, respectively, in accordance with the environmental health regulation. Conclusion: The status of the doors, windows, and the floor of the schools courtyard was not in accordance with the regulations, which requires more attention from authorities and actions to improve the situation. [ABSTRACT FROM AUTHOR]

Introduction: Disorders of consciousness (DoC) represent a range of clinical states, affect hundreds of thousands of people in the United States, and have relatively poor outcomes. With few effective pharmacotherapies, neuromodulation has been investigated as an alternative for treating DoC. To summarize the available evidence, a systematic review of studies using various forms of neuromodulation to treat DoC was conducted., Materials and Methods: Adhering to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic literature review, the PubMed, Scopus, and Web of Science databases were queried to identify articles published between 1990 and 2023 in which neuromodulation was used, usually in conjunction with pharmacologic intervention, to treat or reverse DoC in humans and animals. Records were excluded if DoC (eg, unresponsive wakefulness syndrome, minimally conscious state, etc) were not the primary clinical target., Results: A total of 69 studies (58 human, 11 animal) met the inclusion criteria for the systematic review, resulting in over 1000 patients and 150 animals studied in total. Most human studies investigated deep brain stimulation (n = 15), usually of the central thalamus, and transcranial magnetic stimulation (n = 18). Transcranial direct-current stimulation (n = 15) and spinal cord stimulation (n = 6) of the dorsal column also were represented. A few studies investigated low-intensity focused ultrasound (n = 2) and median nerve stimulation (n = 2). Animal studies included primate and murine models, with nine studies involving deep brain stimulation, one using ultrasound, and one using transcranial magnetic stimulation., Discussion: While clinical outcomes were mixed and possibly confounded by natural recovery or pharmacologic interventions, deep brain stimulation appeared to facilitate greater improvements in DoC than other modalities. However, repetitive transcranial magnetic stimulation also demonstrated clinical potential with much lower invasiveness., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Precision and timeliness in breast cancer detection are paramount for improving patient outcomes. Traditional diagnostic methods have predominantly relied on unimodal approaches, but recent advancements in medical data analytics have enabled the integration of diverse data sources beyond conventional imaging techniques. This review critically examines the transformative potential of integrating histopathology images with genomic data, clinical records, and patient histories to enhance diagnostic accuracy and comprehensiveness in multi-modal diagnostic techniques. It explores early, intermediate, and late fusion methods, as well as advanced deep multimodal fusion techniques, including encoder-decoder architectures, attention-based mechanisms, and graph neural networks. An overview of recent advancements in multimodal tasks such as Visual Question Answering (VQA), report generation, semantic segmentation, and cross-modal retrieval is provided, highlighting the utilization of generative AI and visual language models. Additionally, the review delves into the role of Explainable Artificial Intelligence (XAI) in elucidating the decision-making processes of sophisticated diagnostic algorithms, emphasizing the critical need for transparency and interpretability. By showcasing the importance of explainability, we demonstrate how XAI methods, including Grad-CAM, SHAP, LIME, trainable attention, and image captioning, enhance diagnostic precision, strengthen clinician confidence, and foster patient engagement. The review also discusses the latest XAI developments, such as X-VARs, LeGrad, LangXAI, LVLM-Interpret, and ex-ILP, to demonstrate their potential utility in multimodal breast cancer detection, while identifying key research gaps and proposing future directions for advancing the field., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Abdullakutty, Akbari, Al-Maadeed, Bouridane, Talaat and Hamoudi.)

By integrating IoT technology, smart door locks can provide greater convenience, security, and remote access. This paper presents a novel framework for smart doors that combines face detection and recognition techniques based on mmWave radar and camera sensors. The proposed framework aims to improve the accuracy and some security aspects arising from some limitations of the camera, such as overlapping and lighting conditions. By integrating mmWave radar and camera-based face detection and recognition algorithms, the system can accurately detect and identify people approaching the door, providing seamless and secure access. This framework includes four key components: person detection based on mmWave radar, camera preparation and integration, person identification, and door lock control. The experiments show that the framework can be useful for a smart home.

Background Point-of-care (POC) MRI is a bedside imaging technology with fewer than five units in clinical use in the United States and a paucity of scientific studies on clinical applications. Purpose To evaluate the clinical and operational impacts of deploying POC MRI in emergency department (ED) and intensive care unit (ICU) patient settings for bedside neuroimaging, including the turnaround time. Materials and Methods In this preliminary retrospective study, all patients in the ED and ICU at a single academic medical center who underwent noncontrast brain MRI from January 2021 to June 2021 were investigated to determine the number of patients who underwent bedside POC MRI. Turnaround time, examination limitations, relevant findings, and potential CT and fixed MRI findings were recorded for patients who underwent POC MRI. Descriptive statistics were used to describe clinical variables. The Mann-Whitney U test was used to compare the turnaround time between POC MRI and fixed MRI examinations. Results Of 638 noncontrast brain MRI examinations, 36 POC MRI examinations were performed in 35 patients (median age, 66 years [IQR, 57-77 years]; 21 women), with one patient undergoing two POC MRI examinations. Of the 36 POC MRI examinations, 13 (36%) occurred in the ED and 23 (64%) in the ICU. There were 12 of 36 (33%) POC MRI examinations interpreted as negative, 14 of 36 (39%) with clinically significant imaging findings, and 10 of 36 (28%) deemed nondiagnostic for reasons such as patient motion. Of 23 diagnostic POC MRI examinations with comparison CT available, three (13%) demonstrated acute infarctions not apparent on CT scans. Of seven diagnostic POC MRI examinations with subsequent fixed MRI examinations, two (29%) demonstrated missed versus interval subcentimeter infarctions, while the remaining demonstrated no change. The median turnaround time of POC MRI was 3.4 hours in the ED and 5.3 hours in the ICU. Conclusion Point-of-care (POC) MRI was performed rapidly in the emergency department and intensive care unit. A few POC MRI examinations demonstrated acute infarctions not apparent at standard-of-care CT examinations. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Anzai and Moy in this issue.

Zn 2+ is an important contributor to ischemic brain injury, and recent studies support the hypothesis that mitochondria are key sites of its injurious effects. In murine hippocampal slices (both sexes) subjected to oxygen glucose deprivation (OGD), we found that Zn 2+ accumulation and its entry into mitochondria precedes and contributes to the induction of acute neuronal death. In addition, if the ischemic episode is short (and sublethal), there is ongoing Zn 2+ accumulation in CA1 mitochondria after OGD that may contribute to their delayed dysfunction. Using this slice model of sublethal OGD, we have examined Zn 2+ contributions to the progression of changes evoked by OGD and occurring over 4-5 h. We detected progressive mitochondrial depolarization occurring from ∼2 h after ischemia, a large increase in spontaneous synaptic activity between 2 and 3 h, and mitochondrial swelling and fragmentation at 4 h. Blockade of the primary route for Zn 2+ entry, the mitochondrial Ca 2+ uniporter (with ruthenium red [RR]) or Zn 2+ chelation shortly after OGD withdrawal substantially attenuated the mitochondrial depolarization and the changes in synaptic activity. RR also largely reversed the mitochondrial swelling. Finally, using an in vivo rat (male) asphyxial cardiac arrest model of transient global ischemia, we found that ∼8 min asphyxia induces considerable injury of CA1 neurons 4 h later that is associated with strong Zn 2+ accumulation within many damaged mitochondria. These effects were substantially attenuated by infusion of RR on reperfusion. Our findings highlight mitochondrial Zn 2+ accumulation after ischemia as a possible target for neuroprotective therapy. SIGNIFICANCE STATEMENT Brain ischemia is a leading cause of mortality and long-term disability that still lacks effective treatment. After transient ischemia, delayed death of neurons occurs in vulnerable brain regions. There is a critical need to understand mechanisms of this delayed neurodegeneration which can be targeted for neuroprotection. We found progressive and long-lasting mitochondrial Zn 2+ accumulation to occur in highly vulnerable CA1 neurons after ischemia. Here we demonstrate that this Zn 2+ accumulation contributes strongly to deleterious events occurring after ischemia, including mitochondrial dysfunction, swelling, and structural changes. We suggest that this mitochondrial Zn 2+ entry may constitute a promising target for development of therapeutic interventions to be delivered after termination of an episode of transient global ischemia., (Copyright © 2022 the authors.)

Background: Spreading depolarizations (SDs) are self-propagating waves of neuronal and glial depolarizations often seen in neurological conditions in both humans and animal models. Because SD is thought to worsen neurological injury, the role of SD in a variety of cerebral insults has garnered significant investigation. Anoxic SD is a type of SD that occurs because of anoxia or asphyxia. Although asphyxia leading to a severe drop in blood pressure may affect cerebral hemodynamics and is widely known to cause anoxic SD, the effect of anoxic SD on peripheral blood pressure in the extremities has not been investigated. This relationship is especially important to understand for conditions such as circulatory shock and cardiac arrest that directly affect both peripheral and cerebral perfusion in addition to producing anoxic SD in the brain., Methods: In this study, we used a rat model of asphyxial cardiac arrest to investigate the role of anoxic SD on cerebral hemodynamics and metabolism, peripheral blood pressure, and the relationship between these variables in 8- to 12-week-old male rats. We incorporated a multimodal monitoring platform measuring cortical direct current simultaneously with optical imaging., Results: We found that during anoxic SD, there is decoupling of peripheral blood pressure from cerebral blood flow and metabolism. We also observed that anoxic SD may modify cerebrovascular resistance. Furthermore, shorter time difference between anoxic SDs measured at different locations in the same rat was associated with better neurological outcome on the basis of the recovery of electrocorticography activity (bursting) immediately post resuscitation and the neurological deficit scale score 24 h post resuscitation., Conclusions: To our knowledge, this is the first study to quantify the relationship between peripheral blood pressure, cerebral hemodynamics and metabolism, and neurological outcome in anoxic SD. These results indicate that the characteristics of SD may not be limited to cerebral hemodynamics and metabolism but rather may also encompass changes in peripheral blood flow, possibly through a brain-heart connection, providing new insights into the role of anoxic SD in global ischemia and recovery., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Automatic dating tools for historical documents can greatly assist paleographers and save them time and effort. This paper describes a novel method for estimating the date of historical Arabic documents that employs hierarchical fusions of multiple features. A set of traditional features and features extracted by a residual network (ResNet) are fused in a hierarchical approach using joint sparse representation. To address noise during the fusion process, a new approach based on subsets of multiple features is being considered. Following that, supervised and unsupervised classifiers are used for classification. We show that using hierarchical fusion based on subsets of multiple features in the KERTAS dataset can produce promising results and significantly improve the results.

Background: There is little information regarding the safety of intravenous tissue plasminogen activator (IV-tPA) in patients with stroke and COVID-19., Methods: This multicenter study included consecutive stroke patients with and without COVID-19 treated with IV-tPA between February 18, 2019, to December 31, 2020, at 9 centers participating in the CASCADE initiative. Clinical outcomes included modified Rankin Scale (mRS) at hospital discharge, in-hospital mortality, the rate of hemorrhagic transformation. Using Bayesian multiple regression and after adjusting for variables with significant value in univariable analysis, we reported the posterior adjusted odds ratio (OR, with 95% Credible Intervals [CrI]) of the main outcomes., Results: A total of 545 stroke patients, including 101 patients with COVID-19 were evaluated. Patients with COVID-19 had a more severe stroke at admission. In the study cohort, 85 (15.9%) patients had a hemorrhagic transformation, and 72 (13.1%) died in the hospital. After adjustment for confounding variables, discharge mRS score ≥2 (OR: 0.73, 95% CrI: 0.16, 3.05), in-hospital mortality (OR: 2.06, 95% CrI: 0.76, 5.53), and hemorrhagic transformation (OR: 1.514, 95% CrI: 0.66, 3.31) were similar in COVID-19 and non COVID-19 patients. High-sensitivity C reactive protein level was a predictor of hemorrhagic transformation in all cases (OR:1.01, 95%CI: 1.0026, 1.018), including those with COVID-19 (OR:1.024, 95%CI:1.002, 1.054)., Conclusion: IV-tPA treatment in patients with acute ischemic stroke and COVID-19 was not associated with an increased risk of disability, mortality, and hemorrhagic transformation compared to those without COVID-19. IV-tPA should continue to be considered as the standard of care in patients with hyper acute stroke and COVID-19., Competing Interests: Declaration of Competing Interest Authors reports no disclosures., (Copyright © 2021. Published by Elsevier Inc.)

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

Significance: Quantitative measures of blood flow and metabolism are essential for improved assessment of brain health and response to ischemic injury. Aim: We demonstrate a multimodal technique for measuring the cerebral metabolic rate of oxygen ( CMRO 2 ) in the rodent brain on an absolute scale ( μ M   O 2 / min ). Approach: We use laser speckle imaging at 809 nm and spatial frequency domain imaging at 655, 730, and 850 nm to obtain spatiotemporal maps of cerebral blood flow, tissue absorption ( μ a ), and tissue scattering ( μ s ' ). Knowledge of these three values enables calculation of a characteristic blood flow speed, which in turn is input to a mathematical model with a "zero-flow" boundary condition to calculate absolute CMRO 2 . We apply this method to a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation. With this model, the zero-flow condition occurs during entry into CA. Results: The CMRO 2 values calculated with our method are in good agreement with those measured with magnetic resonance and positron emission tomography by other groups. Conclusions: Our technique provides a quantitative metric of absolute cerebral metabolism that can potentially be used for comparison between animals and longitudinal monitoring of a single animal over multiple days. Though this report focuses on metabolism in a model of ischemia and reperfusion, this technique can potentially be applied to far broader types of acute brain injury and whole-body pathological occurrences., (© 2021 The Authors.)

While interest toward caloric restriction (CR) in various models of brain injury has increased in recent decades, studies have predominantly focused on the benefits of chronic or intermittent CR. The effects of ultra-short, including overnight, CR on acute ischemic brain injury are not well studied. Here, we show that overnight caloric restriction (75% over 14 h) prior to asphyxial cardiac arrest and resuscitation (CA) improves survival and neurological recovery as measured by, behavioral testing on neurological deficit scores, faster recovery of quantitative electroencephalography (EEG) burst suppression ratio, and complete prevention of neurodegeneration in multiple regions of the brain. We also show that overnight CR normalizes stress-induced hyperglycemia, while significantly decreasing insulin and glucagon production and increasing corticosterone and ketone body production. The benefits seen with ultra-short CR appear independent of Sirtuin 1 (SIRT-1) and brain-derived neurotrophic factor (BDNF) expression, which have been strongly linked to neuroprotective benefits seen in chronic CR. Mechanisms underlying neuroprotective effects remain to be defined, and may reveal targets for providing protection pre-CA or therapeutic interventions post-CA. These findings are also of high importance to basic sciences research as we demonstrate that minor, often-overlooked alterations to pre-experimental dietary procedures can significantly affect results, and by extension, research homogeneity and reproducibility, especially in acute ischemic brain injury models., 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 Azadian, Tian, Bazrafkan, Maki, Rafi, Chetty, Desai, Otarola, Aguirre, Zaher, Khan, Suri, Wang, Lopour, Steward and Akbari.)

Background: The emergence of the COVID-19 pandemic has significantly impacted global healthcare systems and this may affect stroke care and outcomes. This study examines the changes in stroke epidemiology and care during the COVID-19 pandemic in Zanjan Province, Iran., Methods: This study is part of the CASCADE international initiative. From February 18, 2019, to July 18, 2020, we followed ischemic and hemorrhagic stroke hospitalization rates and outcomes in Valiasr Hospital, Zanjan, Iran. We used a Bayesian hierarchical model and an interrupted time series analysis (ITS) to identify changes in stroke hospitalization rate, baseline stroke severity [measured by the National Institutes of Health Stroke Scale (NIHSS)], disability [measured by the modified Rankin Scale (mRS)], presentation time (last seen normal to hospital presentation), thrombolytic therapy rate, median door-to-needle time, length of hospital stay, and in-hospital mortality. We compared in-hospital mortality between study periods using Cox-regression model., Results: During the study period, 1,026 stroke patients were hospitalized. Stroke hospitalization rates per 100,000 population decreased from 68.09 before the pandemic to 44.50 during the pandemic, with a significant decline in both Bayesian [Beta: -1.034; Standard Error (SE): 0.22, 95% CrI: -1.48, -0.59] and ITS analysis (estimate: -1.03, SE = 0.24, p < 0.0001). Furthermore, we observed lower admission rates for patients with mild (NIHSS < 5) ischemic stroke (p < 0.0001). Although, the presentation time and door-to-needle time did not change during the pandemic, a lower proportion of patients received thrombolysis (-10.1%; p = 0.004). We did not see significant changes in admission rate to the stroke unit and in-hospital mortality rate; however, disability at discharge increased (p < 0.0001)., Conclusion: In Zanjan, Iran, the COVID-19 pandemic has significantly impacted stroke outcomes and altered the delivery of stroke care. Observed lower admission rates for milder stroke may possibly be due to fear of exposure related to COVID-19. The decrease in patients treated with thrombolysis and the increased disability at discharge may indicate changes in the delivery of stroke care and increased pressure on existing stroke acute and subacute services. The results of this research will contribute to a similar analysis of the larger CASCADE dataset in order to confirm findings at a global scale and improve measures to ensure the best quality of care for stroke patients during the COVID-19 pandemic., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Methamphetamine use is an emerging risk factor for intracerebral hemorrhage (ICH). The aim of this study was to investigate the use of urine drug screen (UDS) for identifying methamphetamine-associated ICH., Methods: This is a retrospective, single-center study of consecutive patients hospitalized with spontaneous ICH from January 2013 to December 2017. Patients were divided into groups based on presence of UDS. The characteristics of patients with and without UDS were compared. Factors associated with getting UDS were explored using multivariable analyses., Results: Five hundred ninety-six patients with ICH were included. UDS was performed in 357 (60%), and positive for methamphetamine in 44 (12.3%). In contrast, only 19 of the 357 patients (5.3%) had a documented history of methamphetamine use. Multivariable analysis demonstrated that patients screened with UDS were more likely to be younger than 45 (OR, 2.24; 95% CI, 0.26-0.78; p = 0.004), male (OR, 1.65; 95% CI, 0.44-0.84; p = 0.003), smokers (OR, 1.74; 95% CI, 1.09-2.77; p <  0.001), with history of methamphetamine use (OR, 10.48; 95% CI, 2.48-44.34; p <  0.001), without diabetes (OR 1.47; 95% CI, 0.471-0.975; p = 0.036), not on anticoagulant (OR, 2.20; 95% CI, 0.26-0.78; p = 0.004), with National Institutes of Health Stroke Scale (NIHSS) > 4 (OR, 1.92; 95%CI, 1.34-2.75; p <  0.001), or require external ventricular drain (EVD) (OR, 1.63; 95%CI, 1.07-2.47; p = 0.021. There was no significant difference in race (p = 0.319). Reported history of methamphetamine use was the strongest predictor of obtaining a UDS (OR,10.48). Five percent of patients without UDS admitted history of use., Conclusion: UDS identified 12.3% of ICH patients with methamphetamine use as compared to 5.3% per documented history of drug use. There was no racial bias in ordering UDS. However, it was more often ordered in younger, male, smokers, with history of methamphetamine use, without diabetes or anticoagulant use.

Background/objective: Intravenous nicardipine infusion is effective for rapid blood pressure control. However, its use requires hemodynamic monitoring in the intensive care unit (ICU) and is associated with high hospital cost. This study aimed to examine the effect of early versus late initiation of oral antihypertensives on ICU length of stay (LOS) and cost of hospitalization in patients with hypertensive intracerebral hemorrhage (ICH)., Methods: This is a single-center retrospective study of patients with hypertensive ICH treated with nicardipine infusion from January 1, 2013, to December 31, 2017. Patients were dichotomized into study and control groups, based on receiving oral antihypertensives within 24 h versus after 24 h of emergency department arrival. Baseline characteristics, duration of nicardipine infusion, LOS in the ICU and hospital, functional outcome at discharge, and hospital cost were compared between the two groups using univariate and multivariate analysis., Results: A total of 90 patients in the study group and 76 in the control group were identified. There was no significant difference in demographics, past medical history, and initial SBP between the two groups. After adjusting for confounding factors with multivariate regression models, early initiation of oral antihypertensives was associated with significant reductions in duration of nicardipine infusion (55.5 ± 60.1 vs 121.6 ± 141.3 h, p <0.005), nicardipine cost ($14,207 vs $29,299, p < 0.01), ICU LOS (2 vs 5 days, p < 0.005), and cost of hospitalization ($24,564 vs $47,366, p < 0.01). There was no significant difference in adversary renal events, favorable outcomes, and mortality between the two groups., Conclusions: Early initiation of oral antihypertensives is safe and may have a significant financial impact on patients with hypertensive ICH.

Cardiac arrest (CA) afflicts ~ 550,000 people each year in the USA. A small fraction of CA sufferers survive with a majority of these survivors emerging in a comatose state. Many CA survivors suffer devastating global brain injury with some remaining indefinitely in a comatose state. The pathogenesis of global brain injury secondary to CA is complex. Mechanisms of CA-induced brain injury include ischemia, hypoxia, cytotoxicity, inflammation, and ultimately, irreversible neuronal damage. Due to this complexity, it is critical for clinicians to have access as early as possible to quantitative metrics for diagnosing injury severity, accurately predicting outcome, and informing patient care. Current recommendations involve using multiple modalities including clinical exam, electrophysiology, brain imaging, and molecular biomarkers. This multi-faceted approach is designed to improve prognostication to avoid "self-fulfilling" prophecy and early withdrawal of life-sustaining treatments. Incorporation of emerging dynamic monitoring tools such as diffuse optical technologies may provide improved diagnosis and early prognostication to better inform treatment. Currently, targeted temperature management (TTM) is the leading treatment, with the number of patients needed to treat being ~ 6 in order to improve outcome for one patient. Future avenues of treatment, which may potentially be combined with TTM, include pharmacotherapy, perfusion/oxygenation targets, and pre/postconditioning. In this review, we provide a bench to bedside approach to delineate the pathophysiology, prognostication methods, current targeted therapies, and future directions of research surrounding hypoxic-ischemic brain injury (HIBI) secondary to CA.

Spreading depolarizations (SDs) are profound disruptions of cellular homeostasis that slowly propagate through gray matter and present an extraordinary metabolic challenge to brain tissue. Recent work has shown that SDs occur commonly in human patients in the neurointensive care setting and have established a compelling case for their importance in the pathophysiology of acute brain injury. The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in September of 2018 included a discussion session focused on the question of "Which SDs are deleterious to brain tissue?" iCSD is attended by investigators studying various animal species including invertebrates, in vivo and in vitro preparations, diseases of acute brain injury and migraine, computational modeling, and clinical brain injury, among other topics. The discussion included general agreement on many key issues, but also revealed divergent views on some topics that are relevant to the design of clinical interventions targeting SDs. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was then formally collated, reviewed and incorporated into the final document. It is hoped that this report will stimulate collection of data that are needed to develop a more nuanced understanding of SD in different pathophysiological states, as the field continues to move toward effective clinical interventions.

Background Impaired neurological function affects 85% to 90% of cardiac arrest (CA) survivors. Pulsatile blood flow may play an important role in neurological recovery after CA. Cerebral blood flow (CBF) pulsatility immediately, during, and after CA and resuscitation has not been investigated. We characterized the effects of asphyxial CA on short-term (<2 hours after CA) CBF and femoral arterial blood pressure (ABP) pulsatility and studied their relationship to cerebrovascular resistance (CVR) and short-term neuroelectrical recovery. Methods and Results Male rats underwent asphyxial CA followed by cardiopulmonary resuscitation. A multimodal platform combining laser speckle imaging, ABP, and electroencephalography to monitor CBF, peripheral blood pressure, and brain electrophysiology, respectively, was used. CBF and ABP pulsatility and CVR were assessed during baseline, CA, and multiple time points after resuscitation. Neuroelectrical recovery, a surrogate for neurological outcome, was assessed using quantitative electroencephalography 90 minutes after resuscitation. We found that CBF pulsatility differs significantly from baseline at all experimental time points with sustained deficits during the 2 hours of postresuscitation monitoring, whereas ABP pulsatility was relatively unaffected. Alterations in CBF pulsatility were inversely correlated with changes in CVR, but ABP pulsatility had no association to CVR. Interestingly, despite small changes in ABP pulsatility, higher ABP pulsatility was associated with worse neuroelectrical recovery, whereas CBF pulsatility had no association. Conclusions Our results reveal, for the first time, that CBF pulsatility and CVR are significantly altered in the short-term postresuscitation period after CA. Nevertheless, higher ABP pulsatility appears to be inversely associated with neuroelectrical recovery, possibly caused by impaired cerebral autoregulation and/or more severe global cerebral ischemia.

Mitochondrial Zn2+ accumulation, particularly in CA1 neurons, occurs after ischemia and likely contributes to mitochondrial dysfunction and subsequent neurodegeneration. However, the relationship between mitochondrial Zn2+ accumulation and their disruption has not been examined at the ultrastructural level in vivo. We employed a cardiac arrest model of transient global ischemia (TGI), combined with Timm's sulfide silver labeling, which inserts electron dense metallic silver granules at sites of labile Zn2+ accumulation, and used transmission electron microscopy (TEM) to examine subcellular loci of the Zn2+ accumulation. In line with prior studies, TGI-induced damage to CA1 was far greater than to CA3 pyramidal neurons, and was substantially progressive in the hours after reperfusion (being significantly greater after 4- than 1-hour recovery). Intriguingly, TEM examination of Timm's-stained sections revealed substantial Zn2+ accumulation in many postischemic CA1 mitochondria, which was strongly correlated with their swelling and disruption. Furthermore, paralleling the evolution of neuronal injury, both the number of mitochondria containing Zn2+ and the degree of their disruption were far greater at 4- than 1-hour recovery. These data provide the first direct characterization of Zn2+ accumulation in CA1 mitochondria after in vivo TGI, and support the idea that targeting these events could yield therapeutic benefits., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Quantifying rapidly varying perturbations in cerebral tissue absorption and scattering can potentially help to characterize changes in brain function caused by ischemic trauma. We have developed a platform for rapid intrinsic signal brain optical imaging using macroscopically structured light. The device performs fast, multispectral, spatial frequency domain imaging (SFDI), detecting backscattered light from three-phase binary square-wave projected patterns, which have a much higher refresh rate than sinusoidal patterns used in conventional SFDI. Although not as fast as "single-snapshot" spatial frequency methods that do not require three-phase projection, square-wave patterns allow accurate image demodulation in applications such as small animal imaging where the limited field of view does not allow single-phase demodulation. By using 655, 730, and 850 nm light-emitting diodes, two spatial frequencies ([Formula: see text] and [Formula: see text]), three spatial phases (120 deg, 240 deg, and 360 deg), and an overall camera acquisition rate of 167 Hz, we map changes in tissue absorption and reduced scattering parameters ([Formula: see text] and [Formula: see text]) and oxy- and deoxyhemoglobin concentration at [Formula: see text]. We apply this method to a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) to quantify hemodynamics and scattering on temporal scales ([Formula: see text]) ranging from tens of milliseconds to minutes. We observe rapid concurrent spatiotemporal changes in tissue oxygenation and scattering during CA and following CPR, even when the cerebral electrical signal is absent. We conclude that square-wave SFDI provides an effective technical strategy for assessing cortical optical and physiological properties by balancing competing performance demands for fast signal acquisition, small fields of view, and quantitative information content.

Cardiac arrest (CA) affects >550,000 people annually in the United States whereas 80-90% of survivors suffer from a comatose state. Arousal from coma is critical for recovery, but mechanisms of arousal are undefined. Orexin-A, a hypothalamic excitatory neuropeptide, has been linked to arousal deficits in various brain injuries. We investigated the orexinergic system's role in recovery from CA-related neurological impairments, including arousal deficits. Using an asphyxial CA and resuscitation model in rats, we examine neurological recovery post-resuscitation in conjunction with changes in orexin-A levels in cerebrospinal fluid (CSF) and orexin-expressing neurons. We also conduct pharmacological inhibition of orexin post-resuscitation. We show that recovery from neurological deficits begins between 4 and 24 h post-resuscitation, with additional recovery by 72 h post-resuscitation. Orexin-A levels in the CSF are lowest during periods of poorest arousal post-resuscitation (4 h) and recover to control levels by 24 h. Immunostaining revealed that the number of orexin-A immunoreactive neurons declined at 4 h post-resuscitation, but increased to near normal levels by 24 h. There were no significant changes in the number of neurons expressing melanin-concentrating hormone, another neuropeptide localized in similar hypothalamus regions. Last, administration of the dual orexin receptor antagonist, suvorexant, during the initial 24 h post-resuscitation, led to sustained neurological deficits. The orexin pathway is critical during early phases of neurological recovery post-CA. Blocking this early action leads to persistent neurological deficits. This is of considerable clinical interest given that suvorexant recently received U.S. Food and Drug Administration approval for insomnia treatment.

Background: Hypertension (HTN) is the most common cause of spontaneous intracerebral hemorrhage (ICH). The aim of this study is to investigate the role of resistant HTN in patients with ICH., Methods and Results: We conducted a retrospective study of all consecutive ICH admissions at our medical center from November 2013 to October 2015. The clinical features of patients with resistant HTN (requiring four or more antihypertensive agents to keep systolic blood pressure <140 mm Hg) were compared with those with responsive HTN (requiring three or fewer agents). Of the 152 patients with hypertensive ICH, 48 (31.6%) had resistant HTN. Resistant HTN was independently associated with higher body mass index and proteinuria. Compared to the responsive group, patients with resistant HTN had higher initial blood pressures and greater requirement for ventilator support, hematoma evacuation, hypertonic saline therapy, and nicardipine infusion. Resistant HTN increases length of stay (LOS) in the intensive care unit (ICU) (4.2 vs 2.1 days; p  = 0.007) and in the hospital (11.5 vs 7.0 days; p  = 0.003). Multivariate regression analysis showed that the rate of systolic blood pressure >140 mm Hg and duration of nicardipine infusion were independently associated with LOS in the ICU. There was no significant difference in hematoma expansion and functional outcome at hospital discharge between the two groups., Conclusion: Resistant HTN in patients with ICH is associated with more medical interventions and longer LOS without effecting outcome at hospital discharge.

Recent electrophysiological studies have suggested surges in electrical correlates of consciousness (i.e., elevated gamma power and connectivity) after cardiac arrest (CA). This study examines electrocorticogram (ECoG) activity and coherence of the dying brain during asphyxial CA. Male Wistar rats (n = 16) were induced with isoflurane anesthesia, which was washed out before asphyxial CA. Mean phase coherence and ECoG power were compared during different stages of the asphyxial period to assess potential neural correlates of consciousness. After asphyxia, the ECoG progressed through four distinct stages (asphyxial stages 1-4 [AS1-4]), including a transient period of near-electrocerebral silence lasting several seconds (AS3). Electrocerebral silence (AS4) occurred within 1 min of the start of asphyxia, and pulseless electrical activity followed the start of AS4 by 1-2 min. AS3 was linked to a significant increase in frontal coherence between the left and right motor cortices (p < 0.05), with no corresponding increase in ECoG power. AS3 was also associated with a significant posterior shift of ECoG power, favoring the visual cortices (p < 0.05). Although the ECoG during AS3 appears visually flat or silent when viewed with standard clinical settings, our study suggests that this period of transient near-electrocerebral silence contains distinctive neural activity. Specifically, the burst in frontal coherence and posterior shift of ECoG power that we find during this period immediately preceding CA may be a neural correlate of conscious processing.

In the present study, we have developed a multi-modal instrument that combines laser speckle imaging, arterial blood pressure, and electroencephalography (EEG) to quantitatively assess cerebral blood flow (CBF), mean arterial pressure (MAP), and brain electrophysiology before, during, and after asphyxial cardiac arrest (CA) and resuscitation. Using the acquired data, we quantified the time and magnitude of the CBF hyperemic peak and stabilized hypoperfusion after resuscitation. Furthermore, we assessed the correlation between CBF and MAP before and after stabilized hypoperfusion. Finally, we examined when brain electrical activity resumes after resuscitation from CA with relation to CBF and MAP, and developed an empirical predictive model to predict when brain electrical activity resumes after resuscitation from CA. Our results show that: 1) more severe CA results in longer time to stabilized cerebral hypoperfusion; 2) CBF and MAP are coupled before stabilized hypoperfusion and uncoupled after stabilized hypoperfusion; 3) EEG activity (bursting) resumes after the CBF hyperemic phase and before stabilized hypoperfusion; 4) CBF predicts when EEG activity resumes for 5-min asphyxial CA, but is a poor predictor for 7-min asphyxial CA. Together, these novel findings highlight the importance of using multi-modal approaches to investigate CA recovery to better understand physiological processes and ultimately improve neurological outcome.

Body image activists have proposed adding disclaimer labels to digitally altered media as a way to promote positive body image. Another approach advocated by activists is to alter advertisements through subvertising (adding social commentary to the image to undermine the message of the advertisement). We examined if body image could be enhanced by attaching Photoshop disclaimers or subvertising to thin-ideal media images of swimsuit models. In Study 1 (N=1268), adult women exposed to disclaimers or subvertising did not report higher body state satisfaction or lower drive for thinness than women exposed to unaltered images. In Study 2 (N=820), adult women who were exposed to disclaimers or subvertising did not report higher state body satisfaction or lower state social appearance comparisons than women exposed to unaltered images or to no images. These results raise questions about the effectiveness of disclaimers and subvertising for promoting body satisfaction., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cardiac Arrest (CA) leads to a global hypoxic-ischemic injury in the brain leading to a poor neurological outcome. Understanding the mechanisms of functional disruption in various regions of the brain may be essential for the development of improved diagnostic and therapeutic solutions. Using controlled laboratory experiment with animal models of CA, our primary focus here is on understanding the functional changes in the thalamus and the cortex, associated with the injury and acute recovery upon resuscitation. Specifically, to study the changes in thalamocortical synchrony through these periods, we acquired local field potentials (LFPs) from the ventroposterior lateral (VPL) nucleus of the thalamus and the forelimb somatosensory cortex (S1FL) in rats after asphyxial CA. Band-specific relative Hilbert phases were used to analyze synchrony between the LFPs. We observed that the CA induced global ischemia changes the local phase-relationships by introducing a phase-lag in both the thalamus and the cortex, while the synchrony between the two regions is nearly completely lost after CA.