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The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study's objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T-related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration., (© 2021 by The American Society of Hematology.)

Introduction: Paraneoplastic cerebellar degeneration (PCD) is a rare set of neurological disorders arising from tumor-associated autoimmunity against antigens within the cerebellum. Anti-Purkinje cell cytoplasmic antibody 1 (PCA-1), or anti-Yo, is the most commonly linked antibody and is classically associated with breast and ovarian cancers., Methods: Medical records of patients at our institution who developed PCA-1 associated PCD were reviewed. Clinical information, including cancer history, cancer-directed treatment, and serum and CSF titers of PCA-1 antibody were extracted., Cases: We report a series of cases of PCA-1 associated PCD in patients with known breast or ovarian cancer diagnosis not receiving immunotherapy. These cases highlight aspects of PCA-1 paraneoplastic syndrome such as triggering by cytotoxic chemotherapy or surgery, the possibility of tumor recurrence and the association with development of a second cancer., Discussion: Diagnosis of the syndrome requires neurological workup with lumbar puncture (LP) with cerebrospinal fluids (CSF) studies, serum and CSF paraneoplastic antibody panel, and neuroimaging. Inpatient admission for prompt workup and initiation of treatment is recommended. Treatment most commonly includes immunosuppression with corticosteroids, plasmapheresis, and/or intravenous immune globulin (IVIG); however, we postulate that other immune modulating treatments may warrant consideration., Conclusion: These cases highlight the need for early recognition of the syndrome in patients receiving nonimmune based chemotherapy, for prompt workup and treatment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction:  Preserving the integrity of the corticospinal tract (CST) while maximizing the extent of tumor resection is one of the key principles of brain tumor surgery to prevent new neurologic deficits. Our goal was to determine the impact of the use of perioperative diffusion tensor imaging (DTI) fiber-tracking protocols for location of the CSTs, in conjunction with intraoperative direct electrical stimulation (DES) on patient neurologic outcomes. The role of combining DES and CST shift in intraoperative magnetic resonance imaging (iMRI) to enhance extent of resection (EOR) has not been studied previously., Methods:  A total of 53 patients underwent resection of tumors adjacent to the motor gyrus and the underlying CST between June 5, 2009, and April 16, 2013. All cases were performed in the iMRI (BrainSuite 1.5 T). Preoperative DTI mapping and intraoperative cortical and subcortical DES including postoperative DTI mapping were performed in all patients. There were 32 men and 21 women with 40 high-grade gliomas (76%), 4 low-grade gliomas (8%), and 9 (17%) metastases. Thirty-four patients (64%) were newly diagnosed, and 19 (36%) had a previous resection. There were 31 (59%) right-sided and 22 (42%) left-sided tumors. Eighteen patients (34%) had a re-resection after the first intraoperative scan. Most patients had motor-only mapping, and one patient had both speech and motor mapping. Relative to the resection margin, the CST after the first iMRI was designated as having an outward shift (OS), inward shift (IS), or no shift (NS)., Results:  A gross total resection (GTR) was achieved in 41 patients (77%), subtotal resection in 4 (7.5%), and a partial resection in 8 (15%). Eighteen patients had a re-resection, and the mean EOR increased from 84% to 95% ( p  = 0.002). Of the 18 patients, 7 had an IS, 8 an OS, and in 3 NS was noted. More patients in the OS group had a GTR compared with the IS or NS groups ( p  = 0.004). Patients were divided into four groups based on the proximity of the tumor to the CST as measured from the preoperative scan. Group 1 (32%) included patients whose tumors were 0 to 5 mm from the CST based on preoperative scans; group 2 (28%), 6 to 10 mm; group 3 (13%), 11 to 15 mm; and group 4 (26%), 16 to 20 mm, respectively. Patients in group 4 had fewer neurologic complications compared with other groups at 1 and 3 months postoperatively ( p  = 0.001 and p  = 0.007, respectively) despite achieving a similar degree of resection ( p  = 0.61). Furthermore, the current of intraoperative DES was correlated to the distance of the tumor to the CST, and the regression equation showed a close linear relationship between the two parameters., Conclusions:  Combining information about intraoperative CST and DES in the iMRI can enhance resection in brain tumors (77% had a GTR). The relative relationship between the positions of the CST to the resection cavity can be a dynamic process that could further influence the surgeon's decision about the stimulation parameters and EOR. Also, the patients with an OS of the CST relative to the resection cavity had a GTR comparable with the other groups., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: The COVID-19 pandemic has caused over 1,250,000 deaths worldwide. With limited therapeutic options, proning nonintubated patients emerged as a safe and affordable intervention to manage hypoxemia., Methods: A proning protocol to identify and prone eligible patients was implemented. Patients were encouraged to self-prone for 2-3 hours, 3 times daily. Investigators created educational materials for nurses and patients and developed a COVID-19-specific proning order within the electronic health record (EHR). Investigators completed an 800-person retrospective chart review to study the implementation of this protocol., Results: From March 22, 2020, to June 5, 2020, 586 patients were admitted to the COVID-19 floor. Of these patients, 42.8% were eligible for proning. Common contraindications were lack of hypoxia, altered mental status, and fall risk. The proning protocol led to a significant improvement in provider awareness of patients appropriate for proning, increasing from 12% to 83%, as measured by placement of a proning order into the EHR. There was a significant improvement in all appropriate patients documented as proned, increasing from 18% to 45% of eligible patients., Conclusions: The creation of an effective hospital-wide proning protocol to address the exigencies of the COVID-19 pandemic is possible and may be accomplished in a short period of time., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 National Association for Healthcare Quality.)

Objective: To estimate the incidence of immune checkpoint inhibitor-related myositis (ICI-myositis) in cancer patients receiving ICIs, and to report associated clinical manifestations, patterns of care, and outcomes., Methods: We identified a retrospective cohort of patients receiving ICIs between 2016 and 2019 seen at the University of Texas MD Anderson Cancer Center. Cases of ICI-myositis were identified using International Classification of Disease codes and confirmed by reviewing medical records and pathology, as available., Results: A total of 9,088 patients received an ICI. Thirty-six patients (0.40%) were identified as having ICI-myositis: 17 patients (47%) with ICI-myositis alone and 19 (53%) with overlap manifestations (5 patients with myocarditis, 5 with myasthenia gravis, and 9 with both). The incidence of ICI-myositis was 0.31% in those receiving ICI monotherapy and 0.94% in those receiving combination ICI therapy (relative risk 3.1 [95% confidence interval 1.5-6.1]). Twenty-five patients (69%) received ≥1 treatment in addition to glucocorticoids: plasmapheresis in 17 patients (47%), intravenous immunoglobulin in 12 (33%), and biologics in 11 (31%). Patients with overlap conditions had worse outcomes than those with myositis alone, and 79% of them developed respiratory failure. Eight patients died as a result of ICI-myositis, and all had overlap syndrome with myasthenia gravis or myocarditis (P < 0.05); 75% of these patients had a concomitant infection., Conclusion: ICI-myositis is a rare but severe adverse event. More than half of the patients presented with overlap manifestations and had deleterious outcomes, including respiratory failure and death. None of the patients with ICI-myositis alone died as a result of adverse events. Optimal treatment strategies have yet to be determined., (© 2020, American College of Rheumatology.)

Objective. Somatosensory evoked potentials (SSEPs) recorded with electrocorticography (ECoG) for central sulcus (CS) identification is a widely accepted procedure in routine intraoperative neurophysiological monitoring. Clinical practices test the short-latency SSEPs for the phase reversal over strip electrodes. However, assessments based on waveform morphology are susceptible to variations in interpretations due to the hand area's localized nature and usually require multiple electrode placements or electrode relocation. We investigated the feasibility of unsupervised delineation of the CS by using the spatiotemporal patterns of the SSEP captured with the ECoG grid. Approach . Intraoperatively, SSEPs were recorded from eight patients using ECoG grids placed over the sensorimotor cortex. Neurosurgeons blinded to the electrophysiology identified the sensory and motor gyri using neuronavigation based on sulcal anatomy. We quantified the most discriminatory time points in SSEPs temporal profile between the primary motor (M1) and somatosensory (S1) cortex using the Fisher discrimination criterion. We visualized the amplitude gradient of the SSEP over a 2D heat map to provide visual feedback for the delineation of the CS based on electrophysiology. Subsequently, we employed spectral clustering using the entire the SSEP waveform without selecting any time points and grouped ECoG channels in an unsupervised fashion. Main results. Consistently in all patients, two different time points provided almost equal discrimination between anterior and posterior channels, which vividly outlined the CS when we viewed the SSEP amplitude distribution as a spatial 2D heat map. The first discriminative time point was in proximity to the conventionally favored ∼20 ms peak (N20), and the second time point was slightly later than the markedly high ∼30 ms peak (P30). Still, the location of these time points varied noticeably across subjects. Unsupervised clustering approach separated the anterior and posterior channels with an accuracy of 96.3% based on the time derivative of the SSEP trace without the need for a subject-specific time point selection. In contrast, the raw trace resulted in an accuracy of 88.0%. Significance . We show that the unsupervised clustering of the SSEP trace assessed with subdural electrode grids can delineate the CS automatically with high precision, and the constructed heat maps can localize the motor cortex. We anticipate that the spatiotemporal patterns of SSEP fused with machine learning can serve as a useful tool to assist in surgical planning., (Creative Commons Attribution license.)

Boron and nitrogen co-doped carbon dots (B, N-CDs) were fabricated through a simple, one-step hydrothermal reaction of citric acid, boric acid, and tris base. The obtained B, N-CDs exhibit excitation-dependent fluorescence, high quantum yield (QY), biocompatibility, photostability, and aqueous solubility. The QY was substantially increased to 57% by doping boron atoms. Furthermore, the fluorescence intensity of B, N-CDs was temperature-dependent and decreased linearly from 283 to 333 K. The prepared B, N-CDs were used as a fluorescence probe for the detection of para -nitrophenol (p-NP) and Fe (III) ions with low detection limits of 0.17 μ M and 0.30 μ M, respectively. Moreover, the presence of p-NP could be further confirmed by a colorimetric assay. The fluorescent probe has been applied to determine p-NP and Fe (III) in a spiked serum sample and spiked water samples (lake and tap water). Moreover, the as-prepared B, N-CDs were of low toxicity and capable of bioimaging., (© 2021 IOP Publishing Ltd.)

Background: Proning intubated intensive care unit patients for the management of acute respiratory distress syndrome is an accepted standard of practice. We examined the nursing climate in 4 units and its impact on implementing a novel self-proning protocol to treat COVID-19 patients outside the intensive care unit., Local Problem: Nursing units previously designated for medical/surgical populations had to adjust quickly to provide evidence-based care for COVID-19 patients attempting self-proning., Methods: Nurses from 4 nursing units were surveyed about the implementation process on the self-proning protocol. Their perception of unit implementation was assessed via the Implementation Climate Scale., Interventions: A new self-proning nursing protocol was implemented outside the intensive care unit., Results: Consistent education on the protocol, belief in the effectiveness of the intervention, and a strong unit-based climate of evidence-based practice contributed to greater implementation of the protocol., Conclusions: Implementation of a new nursing protocol is possible with strong unit-based support, even during a pandemic., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX 2 R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX 2 R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX 2 R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX 2 R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX 2 R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

Oxidative stress resulting from reactive oxygen species (ROS) is known to play a key role in numerous neurological disorders, including neuropathic pain. Morphine is one of the commonly used opioids for pain management. However, long-term administration of morphine results in morphine antinociceptive tolerance (MAT) through elevation of ROS and suppression of natural antioxidant defense mechanisms. Recently, mesoporous polydopamine (MPDA) nanoparticles (NPS) have been known to possess strong antioxidant properties. We speculated that morphine delivery through an antioxidant nanocarrier might be a reasonable strategy to alleviate MAT. MPDAs showed a high drug loading efficiency of ∼50%, which was much higher than conventional NPS. Spectral and in vitro studies suggest a superior ROS scavenging ability of NPS. Results from a rat neuropathic pain model demonstrate that MPDA-loaded morphine (MPDA@Mor) is efficient in minimizing MAT with prolonged analgesic effect and suppression of pro-inflammatory cytokines. Additionally, serum levels of liver enzymes and levels of endogenous antioxidants were measured in the liver. Treatment with free morphine resulted in elevated levels of liver enzymes and significantly lowered the activities of endogenous antioxidant enzymes in comparison with the control and MPDA@Mor-treated group. Histopathological examination of the liver revealed that MPDA@Mor can significantly reduce the hepatotoxic effects of morphine. Taken together, our current work will provide an important insight into the development of safe and effective nano-antioxidant platforms for neuropathic pain management.

Immunotherapy has revolutionized treatment of cancer over the past two decades. The antitumor effects of immunotherapy approaches are at the expense of growing spectrum of immune-related adverse events (irAEs) due to cross-reactivity between the tumor and normal host tissue. These adverse events can happen in any organ and range from mild to severe and even life-threatening conditions. While neurological irAEs associated with immune checkpoint inhibitors (CPIs) are rare, they pose a significant challenge in management as the clinical phenotypes are heterogenous and frequently necessitate cessation of therapy and systemic immune suppression and lead to transient functional decline. On the other hand, immune effector cell-associated neurotoxicity (ICANS) is common, frequently occurs in conjunction with cytokine release syndrome (CRS), and poses a significant clinical challenge to the development and widespread use of these effective therapies. Early recognition of these neurological syndromes, timely diagnosis, and thoughtful management are key for further clinical development of these effective therapies in cancer patients. Here, we describe clinical phenotypes of CPI-induced neurological complications and ICANS and discuss steps in clinical monitoring, diagnosis, and effective management., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

We present a sensitive and rapid screening method for the determination of β-lactamase activity of antibiotic-resistant bacteria, by designing a pH-sensitive fluorescent dye-doped mesoporous silica nanoparticle encapsulated with penicillin G as a substrate. When penicillin G was hydrolysed by β-lactamase and converted into penicilloic acid, the acidic environment resulted in fluorescence quenching of the dye. The dye-doped mesoporous nanoparticles not only enhanced the β-lactamase-catalyzed reaction rate but also stablized the substrate, penicillin G, which degrades into penicilloic acid in a water solution without β-lactamase. Twentyfive clinical bacterial samples were tested and the antibiotic resistant and susceptible strains were identified. The proposed method may detect the presence of β -lactamases of clinically relevant samples in less than 1 hour. Moreover, the detection limit of β-lactamase activity was as low as 7.8×10 -4  U/mL, which was determined within two hours., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

Background: To study the clinical, radiological, electroencephalographic, and cerebrospinal fluid (CSF) features of Human Herpes Virus 6 (HHV-6) encephalitis in leukemia patients underwent allogeneic hematopoietic stem cell transplantation (HSCT)., Methods: We retrospectively reviewed all leukemia patients who underwent allogeneic HSCT between January 2010 and December 2018. The clinical, radiological, electroencephalographic, and CSF features of those with HHV6 encephalitis were recorded., Results: A total of five cases of HHV6 encephalitis were identified. Three patients had Chronic Myelogenous Leukemia, one had Chronic Lymphocytic Leukemia and one had Acute Lymphoblastic Leukemia. All of them presented a few months after transplantation with altered mental status. Comorbidities included pancytopenia, sepsis, graft versus host disease, and multi-organ failure. EEG showed focal seizures originating from temporal lobes in two patients, generalized or focal periodic discharges in three patients, focal slowing in two patients, and diffuse slowing in three patients. MRI brain showed T2/FLAIR hyper-intensities in four patients; two of them in bilateral temporal lobes, one in the thalamus/hypothalamus/brainstem/cerebellum/basal ganglia, and one in the periventricular areas. CSF showed pleocytosis, high protein, and positive HHV-6 PCR. Foscarnet was used as an anti-viral agent. Anti-epileptics used were phenytoin, levetiracetam, and valproic acid. Four patients died in a few months, whereas one recovered completely., Conclusions: HHV-6 encephalitis can add significant morbidity and mortality to leukemic patients following allogeneic HSCT. Patients present with typical clinical features of encephalitis. Salient EEG characteristics include periodic discharges or overt temporal lobe seizures. MRI findings are T2/FLAIR signal hyperintensities, mainly in the temporal lobes., Competing Interests: The authors declare that they have no competing interests., (© 2020 The Authors.)

Critical limb ischemia (CLI) is defined as chronic rest pain and/or the presence of tissue loss (ulcers or gangrene) in the lower extremities secondary to ischemia. CLI is a limb and potentially life-threatening disease associated with a poor prognosis with only 50% of patients being able to preserve both limbs within 12 months of diagnosis. CLI related to diabetes is often more extensive with multi-level long segmental arterial disease resulting in a 5-30-fold increased rate of amputation. As the incidence and prevalence of diabetes mellitus increases within our aging society, the rate of infrapopliteal artery occlusive disease (IPOD) and the need for intervention rises with it. The aim of this manuscript is to provide the reader with an overview of the various devices available for vessel preparation (VP) and treatment of IPOD in order to optimize patency rates, symptom resolution, healing of wounds, and minimize complications.

Objective: B vitamins are essential for the functioning of the nervous system. Vitamin B1 (thiamine) deficiency is associated with neuropsychiatric syndromes such as Wernicke's encephalopathy (WE), which, if untreated, has an estimated mortality of 17-20%. Although the prevalence of thiamine deficiency in the general population is difficult to estimate, it is being increasingly recognized in oncology, especially in the inpatient setting. We describe three cases of thiamine deficiency (TD) in the outpatient psychiatric oncology setting., Method: Retrospective chart review of three adult patients, who were seen in the psychiatric oncology clinic and found to have TD on laboratory testing, was done. Patient, disease, and thiamine treatment-related information were obtained, and descriptive statistics were used to analyze the data., Results: The average age was 59 years, mean body mass index (BMI) was 22.00 ± 4.58 (mean ± SD), and mean thiamine level was 59.10 ± 7.69 that ranged from 45 to 68 nmol/L (normal thiamine level reference: 70-180 nmol/L). None of the patients had brain imaging nor cerebrospinal fluid analysis. Risk factors such as unbalanced nutrition, prior GI surgery, renal disease, and chemotherapy were noted., Significance of Results: TD can have a multifactorial etiology in oncology. Identification of TD in both inpatient and outpatient setting is important. Our report highlights how early identification of TD in the outpatient setting can help prevent further clinical progression.

Identification of the prostatic arteries (PAs) is one of the most challenging aspects of prostate artery embolization for treatment of benign prostatic hyperplasia-associated lower urinary tract symptoms. Operators require a detailed understanding of the prostate arterial anatomy to ensure technical and clinical success with minimal complications. Due to substantial variability in internal iliac artery branch patterns and specifically the origin of the PA, we focus on 3 clinically relevant classification systems used to categorize the pelvic vasculature. These include classification systems to understand the internal iliac artery branching pattern, PA origin variation, and intraprostatic branching., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients., (© 2020 by The American Society of Hematology.)

Varicella-zoster virus (VZV) encephalitis typically occurs in immunosuppressed populations such as in patients with HIV/AIDS, transplantation and autoimmune disease. However, it can also occur in healthy hosts. We present the case of an immunocompetent patient who presented with a clinical picture of VZV encephalitis with the sole precipitating factor of advanced age. We want to stress the importance of including VZV in the differential diagnosis for encephalitis in healthy elderly hosts. In patients with a clinical diagnosis of encephalitis, the presence of herpes zoster rash increases the likelihood of VZV encephalitis. However, the absence of a skin rash may not exclude the diagnosis. In general, there is an elevated risk of transient ischaemic attack and stroke associated with the diagnosis of herpes zoster infection. Early treatment is essential to prevent complications, including death., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: This review provides clinical characterization and approach to management of neurotoxicities associated with checkpoint inhibitor therapy and chimeric antigen receptor T cell (CAR T cell) therapy., Recent Findings: Immuno-oncology has revolutionized cancer treatment. The immunomodulatory effect of these treatments extends beyond the targeted cancers; however, with a range of immune-mediated toxicities being associated with these therapies. Both the peripheral and central nervous system are vulnerable to these toxicities, with several distinct clinical syndromes strongly associated with specific immunotherapies. Neurologic immune-related adverse events are significant sequelae of both checkpoint inhibitors and CAR T cell therapy. In addition to clinical characterization of these syndromes, an understanding of the biologic underpinnings of these sequelae is essential. This will facilitate identification of patients at risk of these toxicities, develop treatments to prevent them and identify more effective clinical treatment when they occur.

Neuropathic pain, resulting from the dysfunction of the peripheral and central nervous system, occurs in a variety of pathological conditions including trauma, diabetes, cancer, HIV, surgery, multiple sclerosis, ischemic attack, alcoholism, spinal cord damage, and many others. Despite the availability of various treatment strategies, the percentage of patients achieving adequate pain relief remains low. The clinical failure of most effective drugs is often not due to a lack of drug efficacy but due to the dose-limiting central nervous system (CNS) toxicity of the drugs that preclude dose escalation. There is a need for cross-disciplinary collaborations to meet these challenges. In this regard, the integration of nanotechnology with neuroscience is one of the most important fields. In recent years, promising preclinical research has been reported in this field. This review highlights the current challenges associated with conventional neuropathic pain treatments, the scope for nanomaterials in delivering drugs across the blood-brain barrier, and the state and prospects of nanomaterials for the management of neuropathic pain.

It is well-known that motor cortical oscillatory components are modulated in their amplitude during voluntary and imagined movements. These patterns have been used to develop brain-machine interfaces (BMI) which focused mostly on movement kinematics. In contrast, there have been only a few studies on the relation between brain oscillatory activity and the control of force, in particular, grasping force, which is of primary importance for common daily activities. In this study, we recorded intraoperative high-density electrocorticography (ECoG) from the sensorimotor cortex of four patients while they executed a voluntary isometric hand grasp following verbal instruction. The grasp was held for 2 to 3 s before being instructed to relax. We studied the power modulations of neural oscillations during the whole time-course of the grasp (onset, hold, and offset phases). Phasic event-related desynchronization (ERD) in the low-frequency band (LFB) from 8 to 32 Hz and event-related synchronization (ERS) in the high-frequency band (HFB) from 60 to 200 Hz were observed at grasp onset and offset. However, during the grasp holding period, the magnitude of LFB-ERD and HFB-ERS decreased near or at the baseline level. Overall, LFB-ERD and HFB-ERS show phasic characteristics related to the changes of grasp force (onset/offset) in all four patients. More precisely, the fluctuations of HFB-ERS primarily, and of LFB-ERD to a lesser extent, correlated with the time-course of the first time-derivative of force (yank), rather than with force itself. To the best of our knowledge, this is the first study that establishes such a correlation. These results have fundamental implications for the decoding of grasp in brain oscillatory activity-based neuroprosthetics., (Copyright © 2020 Jiang, Pellizzer, Asman, Bastos, Bhavsar, Tummala, Prabhu and Ince.)

Background: Hip and groin injuries are common in competitive soccer players and have been shown to be significant sources of time loss. There are few studies describing the epidemiology of hip and groin injuries in female National Collegiate Athletic Association (NCAA) soccer players., Purpose: To describe the epidemiology of hip and groin injuries in women's collegiate soccer players., Study Design: Descriptive epidemiology study., Methods: The NCAA Injury Surveillance System/Program (ISS/ISP) was analyzed from 2004 through 2014 for data related to hip and groin injuries in female collegiate soccer players. Injuries and athlete-exposures (AEs) were reported by athletic trainers. Data were stratified by time of season, event type, injury type, treatment outcome, time loss, and player field position., Results: Between 2004 and 2014, there were 439 recorded hip or groin injuries in female soccer players and an overall rate of injury of 0.57 per 1000 AEs. Injuries were 12.0 times more likely to occur during the preseason (4.41/1000 AEs) as opposed to during the regular season (0.37/1000 AEs) (injury rate ratio [IRR], 12.01; 95% confidence interval [CI], 9.92-14.55) or postseason (0.38/1000 AEs) (IRR, 11.55; 95% CI, 7.06-18.91). Rates of injury were similar during the regular season and postseason (IRR, 0.96; 95% CI, 0.59-1.58). Rates of injury were higher during competition (0.69/1000 AEs) than during practice (0.52/1000 AEs) (IRR, 1.33; 95% CI, 1.08-1.63). Most injuries were new (87.5%; n = 384) and unlikely to recur (12.5%; n = 55)., Conclusion: Hip and groin injuries in female NCAA soccer players are uncommon, and fortunately, most players return to play quickly without recurrence. Future prospective studies should evaluate the effectiveness of strength and conditioning programs in preventing these injuries., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: J.A. has received educational support from Goode Surgical, grant support from Stryker, and hospitality payments from Stryker. J.L.M. has received educational support from Arthrex and Goode Surgical. J.H. has received educational support from Arthrex. K.P. has received educational support from Arthrex. A.C. has received consulting fees from Arthrex, Trice Medical, and Zimmer Biomet; educational support from Arthrex and Stryker; and hospitality payments from Arthrex. D.H. has received consulting fees from Arthrex; grant support from Arthrex; educational support from Arthrex, Goode Surgical, and Smith & Nephew; and hospitality payments from Smith & Nephew and Stryker. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2020.)

Background: Non-convulsive status epilepticus (NCSE) is present in 10-30% of ICU patients with altered mental status (AMS) and is associated to poor outcomes. To our knowledge, there is no data describing the prevalence and outcomes of critically ill cancer patients with AMS associated to non-convulsive seizures (NCS) or NCSE. We aim to describe the outcomes and risk factors of critically ill cancer patients with encephalopathy associated with non-convulsive seizures (NCS)., Methods: This is a 3-year prospective observational study in a mixed oncological ICU at MD Anderson Cancer Center. Data of ICU patients with moderate to severe encephalopathy (Glasgow Coma Score < 13) that underwent EEG monitoring to rule out NCS were collected. Multivariate logistic regression was performed to identify risk factors and outcomes., Results: Of the 317 patients with encephalopathy who underwent EEG monitoring, 14.5% had NCS. Known risk factors such as sepsis, CNS infection, antibiotics, and cardiac arrest were not associated with increased risk of NCS. Patients with NCS were more likely to have received recent chemotherapy (41.3% vs 21.4%; p = 0.0036), have a CNS disease (39% vs 24.4%; p = 0.035), and abnormal brain imaging (60.9% vs 44.6%; p = 0.041). Patients with lower SOFA scores, normal renal function, and absence of shock were likely to have NCS as the cause of their encephalopathy ( p < 0.03). After multivariate analysis, only abnormal brain imaging and absence of renal failure were associated with NCS. Mortality was significantly lower in patients with non-convulsive seizures when compared to those without seizures (45.7% vs 64%; p = 0.022); however, there was no significant association of seizures and mortality on a multivariable logistic regression analysis., Conclusions: NCS in critically ill cancer patients is associated with abnormalities on brain imaging and lower prevalence of organ failure. Diagnosis and treatment of NCS should be a priority in encephalopathic cancer patients, as they can have lower mortality than non-seizing patients. Opposite to other populations, NCS should not be considered a poor prognostic factor in critically ill encephalopathic cancer patients as they reflect a reversible cause for altered mentation., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Technological advances in passive digital phenotyping present the opportunity to quantify neurological diseases using new approaches that may complement clinical assessments. Here, we studied multiple sclerosis (MS) as a model neurological disease for investigating physiometric and environmental signals. The objective of this study was to assess the feasibility and correlation of wearable biosensors with traditional clinical measures of disability both in clinic and in free-living in MS patients. This is a single site observational cohort study conducted at an academic neurological center specializing in MS. A cohort of 25 MS patients with varying disability scores were recruited. Patients were monitored in clinic while wearing biosensors at nine body locations at three separate visits. Biosensor-derived features including aspects of gait (stance time, turn angle, mean turn velocity) and balance were collected, along with standardized disability scores assessed by a neurologist. Participants also wore up to three sensors on the wrist, ankle, and sternum for 8 weeks as they went about their daily lives. The primary outcomes were feasibility, adherence, as well as correlation of biosensor-derived metrics with traditional neurologist-assessed clinical measures of disability. We used machine-learning algorithms to extract multiple features of motion and dexterity and correlated these measures with more traditional measures of neurological disability, including the expanded disability status scale (EDSS) and the MS functional composite-4 (MSFC-4). In free-living, sleep measures were additionally collected. Twenty-three subjects completed the first two of three in-clinic study visits and the 8-week free-living biosensor period. Several biosensor-derived features significantly correlated with EDSS and MSFC-4 scores derived at visit two, including mobility stance time with MSFC-4 z-score (Spearman correlation -0.546; p  = 0.0070), several aspects of turning including turn angle (0.437; p  = 0.0372), and maximum angular velocity (0.653; p  = 0.0007). Similar correlations were observed at subsequent clinic visits, and in the free-living setting. We also found other passively collected signals, including measures of sleep, that correlated with disease severity. These findings demonstrate the feasibility of applying passive biosensor measurement techniques to monitor disability in MS patients both in clinic and in the free-living setting., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

Background: Myasthenia gravis (MG) is a rare but life-threatening adverse event of immune checkpoint inhibitors (ICI). Given the limited evidence, data from a large cohort of patients is needed to aid in recognition and management of this fatal complication., Methods: We reviewed our institutional databases to identify patients who had cancer and MG in the setting of ICI. We systematically reviewed the literature through August 2018 to identify all similar reported patients. We collected data on clinical and diagnostic features, management, and outcomes of these cases., Results: Sixty-five patients were identified. Median age was 73 years; 42 (65%) were males, 31 (48%) had metastatic melanoma, and 13 (20%) had a preexisting MG before ICI initiation. Most patients received anti-PD-1 (82%). Sixty-three patients (97%) developed ICI-related MG (new onset or disease flare) after a median of 4 weeks (1 to 16 weeks) of ICI initiation. Twenty-four patients (37%) experienced concurrent myositis, and respiratory failure occurred in 29 (45%). ICI was discontinued in 61 patients (97%). Death was reported in 24 patients (38%); 15 (23%) due to MG complication. A better outcome was observed in patients who received intravenous immunoglobulin (IVIG) or plasmapheresis (PLEX) as first-line therapy than in those who received steroids alone (95% vs 63% improvement of MG symptoms, p = 0.011)., Conclusions: MG is a life-threatening adverse event of acute onset and rapid progression after ICI initiation. Early use of IVIG or PLEX, regardless of initial symptoms severity, may lead to better outcomes than steroids alone. Our data suggest the need to reassess the current recommendations for management of ICI-related MG until prospective longitudinal studies are conducted to establish the ideal management approach for these patients.

A 46-year-old man with no significant medical history presented to haematology with symptoms of fatigue, dyspnoea on exertion and weight loss. Physical examination revealed a lesion on the right shin and splenomegaly. Labs were significant for leucocytosis with immature components, thrombocytosis and 3% peripheral blasts on smear. A bone marrow biopsy confirmed a diagnosis of myelofibrosis (MF). Dynamic International Prognosis Scoring system was 2. He was started on ruxolitnib, with decitabine added subsequently prior to definitive therapy with an allogenic haematopoietic stem cell transplant. His course with decitabine was complicated with febrile neutropaenia with multiple tender erythematous plaques unresponsive to antibacterial and antifungal coverage. A skin biopsy showed neutrophilic dermatitis, consistent with a diagnosis of Sweet's syndrome (SS) and empirical treatment with glucocorticoids was initiated resulting in resolution of symptoms. This report reviews the literature for cases of SS in the setting of MF., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

With the advances in affordable three-dimensional (3D) printing technology, 3D reconstruction and patient-specific 3D printed models are establishing a crucial role in the field of medicine for both educational purposes and procedural planning. 3D printed models provide physicians with increased 3D perception and tactile feedback, and enable a team-based approach to operational planning. However, performing an effective 3D reconstruction requires an in-depth understanding of the software features to accurately segment and reconstruct the human anatomy of interest from preacquired image data from multiple modalities such as computer tomography, 3D angiography and magnetic resonance imaging, and the different 3D printers/materials available in the market today. Increased understanding of this technology may benefit radiologists by developing techniques and tricks specific to interventional radiology and establishing a criterion to determine when to use these. Thus, the purpose of this manuscript is to provide physicians with an update on currently available 3D reconstruction software as well as printers and materials. Our initial experience using this technology is introduced based on a specific case of developing a 3D printed aorta for a patient with severe stenosis of the abdominal aorta., (Copyright © 2018. Published by Elsevier Inc.)

Lower extremity peripheral arterial disease (PAD) is the manifestation of atherosclerotic disease within the lower extremities. The presentation of PAD is diverse ranging from asymptomatic disease to claudication or to debilitating rest pain, nonhealing ulcers, and gangrene. PAD is associated with significant morbidity, mortality, and healthcare costs. Proper diagnosis and management of PAD is important so as to maintain quality of life and reduce the risk of cardiovascular disease and adverse limb events such as amputation. This document provides a comprehensive outpatient approach to the clinical assessment of PAD that includes risk factors, diagnosis, treatment, and follow-up options.

JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo-expanded, partially HLA-matched, third-party-produced, cryopreserved BK virus-specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials.gov number, NCT02479698 .).

Background and Purpose: Whole-brain atrophy is a standard outcome measure in multiple sclerosis (MS) clinical trials as assessed by various software tools. The effect of processing method on the validity of such data obtained from high-resolution 3T MRI is not known. We compared two commonly used methods of quantifying whole-brain atrophy., Methods: Three-dimensional T1-weighted and FLAIR images were obtained at 3T in MS (n = 61) and normal control (NC, n = 30) groups. Whole-brain atrophy was assessed by two automated pipelines: (a) SPM8 to derive brain parenchymal fraction (BPF, proportional-based method); (b) SIENAX to derive normalized brain parenchymal volume (BPV, registration method). We assessed agreement between BPF and BPV, as well their relationship to Expanded Disability Status Scale (EDSS) score, timed 25-foot walk (T25FW), cognition, and cerebral T2 (FLAIR) lesion volume (T2LV)., Results: Brain parenchymal fraction and BPV showed only partial agreement (r = 0.73) in the MS group, and r = 0.28 in NC. Both methods showed atrophy in MS versus NC (BPF p < 0.01, BPV p < 0.05). Within MS group comparisons, BPF (p < 0.05) but not BPV (p > 0.05) correlated with EDSS score. BPV (p = 0.03) but not BPF (p = 0.08) correlated with T25FW. Both metrics correlated with T2LV (p < 0.05) and cognitive subscales. BPF (p < 0.05) but not BPV (p > 0.05) showed lower brain volume in cognitively impaired (n = 23) versus cognitively preserved (n = 38) patients. However, direct comparisons of BPF and BPV sensitivities to atrophy and clinical correlations were not statistically significant., Conclusion: Whole-brain atrophy metrics may not be interchangeable between proportional- and registration-based automated pipelines from 3T MRI in patients with MS., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

High-frequency oscillations in local field potentials recorded with intracranial EEG are putative biomarkers of seizure onset zones in epileptic brain. However, localized 80-500 Hz oscillations can also be recorded from normal and non-epileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones, which limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 epilepsy patients and five control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified by using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent from the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step towards the translation of these signature events into valid clinical biomarkers.awx374media15721572971001.

Purpose: To explore (i) the variability of upper cervical cord area (UCCA) measurements from volumetric brain 3D T 1 -weighted scans related to gradient nonlinearity (GNL) and subject positioning; (ii) the effect of vendor-implemented GNL corrections; and (iii) easily applicable methods that can be used to retrospectively correct data., Methods: A multiple sclerosis patient was scanned at seven sites using 3T MRI scanners with the same 3D T 1 -weighted protocol without GNL-distortion correction. Two healthy subjects and a phantom were additionally scanned at a single site with varying table positions. The 2D and 3D vendor-implemented GNL-correction algorithms and retrospective methods based on (i) phantom data fit, (ii) normalization with C2 vertebral body diameters, and (iii) the Jacobian determinant of nonlinear registrations to a template were tested., Results: Depending on the positioning of the subject, GNL introduced up to 15% variability in UCCA measurements from volumetric brain T 1 -weighted scans when no distortion corrections were used. The 3D vendor-implemented correction methods and the three proposed methods reduced this variability to less than 3%., Conclusions: Our results raise awareness of the significant impact that GNL can have on quantitative UCCA studies, and point the way to prospectively and retrospectively managing GNL distortions in a variety of settings, including clinical environments. Magn Reson Med 79:1595-1601, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

In the present study, we have demonstrated receptor for advanced glycation endproducts (RAGE) as a target for delivery of drugs specifically to triple negative breast cancer cells. We have prepared solid lipid nanoparticle formulation of cytotoxic agent di-allyl-disulfide (DADS) to overcome its bioavailability issues. Then, we have surface modified DADS-loaded solid lipid nanoparticles (DADS-SLN) with RAGE antibody to achieve site-specific delivery of DADS to TNBC cells. We found a significant cellular internalization of RAGE surface modified DADS-SLN (DADS-RAGE-SLN) when compared to DADS-SLN. The cytotoxic effect of DADS was also significantly improved with DADS-RAGE-SLN by downregulating anti-apoptotic proteins and upregulating pro-apoptotic proteins as observed by western blot analysis. RAGE-targeted delivery of cytotoxic agents can be, therefore, a promising approach for improving antitumour activity and reducing off-target effects.

During the last two decades, MRI has been increasingly used for providing valuable quantitative information about spinal cord morphometry, such as quantification of the spinal cord atrophy in various diseases. However, despite the significant improvement of MR sequences adapted to the spinal cord, automatic image processing tools for spinal cord MRI data are not yet as developed as for the brain. There is nonetheless great interest in fully automatic and fast processing methods to be able to propose quantitative analysis pipelines on large datasets without user bias. The first step of most of these analysis pipelines is to detect the spinal cord, which is challenging to achieve automatically across the broad range of MRI contrasts, field of view, resolutions and pathologies. In this paper, a fully automated, robust and fast method for detecting the spinal cord centerline on MRI volumes is introduced. The algorithm uses a global optimization scheme that attempts to strike a balance between a probabilistic localization map of the spinal cord center point and the overall spatial consistency of the spinal cord centerline (i.e. the rostro-caudal continuity of the spinal cord). Additionally, a new post-processing feature, which aims to automatically split brain and spine regions is introduced, to be able to detect a consistent spinal cord centerline, independently from the field of view. We present data on the validation of the proposed algorithm, known as "OptiC", from a large dataset involving 20 centers, 4 contrasts (T 2 -weighted n = 287, T 1 -weighted n = 120, T 2 ∗ -weighted n = 307, diffusion-weighted n = 90), 501 subjects including 173 patients with a variety of neurologic diseases. Validation involved the gold-standard centerline coverage, the mean square error between the true and predicted centerlines and the ability to accurately separate brain and spine regions. Overall, OptiC was able to cover 98.77% of the gold-standard centerline, with a mean square error of 1.02 mm. OptiC achieved superior results compared to a state-of-the-art spinal cord localization technique based on the Hough transform, especially on pathological cases with an averaged mean square error of 1.08 mm vs. 13.16 mm (Wilcoxon signed-rank test p-value < .01). Images containing brain regions were identified with a 99% precision, on which brain and spine regions were separated with a distance error of 9.37 mm compared to ground-truth. Validation results on a challenging dataset suggest that OptiC could reliably be used for subsequent quantitative analyses tasks, opening the door to more robust analysis on pathological cases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: A pipeline for fully automated segmentation of 3T brain MRI scans in multiple sclerosis (MS) is presented. This 3T morphometry (3TM) pipeline provides indicators of MS disease progression from multichannel datasets with high-resolution 3-dimensional T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery (FLAIR) contrast. 3TM segments white (WM) and gray matter (GM) and cerebrospinal fluid (CSF) to assess atrophy and provides WM lesion (WML) volume., Methods: To address nonuniform distribution of noise/contrast (eg, posterior fossa in 3D-FLAIR) of 3T magnetic resonance imaging, the method employs dual sensitivity (different sensitivities for lesion detection in predefined regions). We tested this approach by assigning different sensitivities to supratentorial and infratentorial regions, and validated the segmentation for accuracy against manual delineation, and for precision in scan-rescans., Results: Intraclass correlation coefficients of .95, .91, and .86 were observed for WML and CSF segmentation accuracy and brain parenchymal fraction (BPF). Dual sensitivity significantly reduced infratentorial false-positive WMLs, affording increases in global sensitivity without decreasing specificity. Scan-rescan yielded coefficients of variation (COVs) of 8% and .4% for WMLs and BPF and COVs of .8%, 1%, and 2% for GM, WM, and CSF volumes. WML volume difference/precision was .49 ± .72 mL over a range of 0-24 mL. Correlation between BPF and age was r = .62 (P = .0004), and effect size for detecting brain atrophy was Cohen's d = 1.26 (standardized mean difference vs. healthy controls)., Conclusions: This pipeline produces probability maps for brain lesions and tissue classes, facilitating expert review/correction and may provide high throughput, efficient characterization of MS in large datasets., (© 2017 The Authors. Journal of Neuroimaging published by Wiley Periodicals, Inc. on behalf of American Society of Neuroimaging.)

Objective Gender is a risk factor in the onset of osteoarthritis (OA). The aim of the study was to investigate gender differences in contact area (CA) and congruity index (CI) in the medial tibiofemoral (MTF) joint in 2 different cohorts, quantified automatically from magnetic resonance imaging (MRI). Design The CA and CI markers were validated on 2 different data sets from Center for Clinical and Basic Research (CCBR) and Osteoarthritis Initiative (OAI). The CCBR cohort consisted of 159 subjects and the OAI subcohort consisted of 1,436 subjects. From the MTF joint, the contact area was located and quantified using Euclidean distance transform. Furthermore, the CI was quantified over the contact area by assessing agreement of the first- and second-order general surface features. Then, the gender differences between CA and CI values were evaluated at different stages of radiographic OA. Results Female CAs were significantly higher than male CAs after normalization, male CIs were significantly higher than female CIs after correcting with age and body mass index ( P < 0.05), consistent across the 2 data sets. For the OAI data set, the gender differences were present at all stages of radiographic OA. Conclusion This study demonstrated the gender differences in CA and CI in MTF joints. The higher normalized CA and lower CI values in female knees may be linked with the increased risk of incidence of radiographic OA in females. These differences may help further understand the gender differences and/or to establish gender specific treatment strategies.

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

Background: Cerebral gray matter (GM) atrophy has clinical relevance in multiple sclerosis (MS). Fingolimod has known efficacy on clinical and conventional MRI findings in MS; the effect on GM is unknown., Objective: To explore fingolimod's treatment effect on cerebral GM atrophy over two years in patients with relapsing forms of MS., Design/methods: Patients starting fingolimod [n=24, age (mean±SD) 41.2±11.6years, Expanded Disability Status Scale (EDSS) score 1.1±1.4; 58% women] were compared to untreated patients [n=29, age 45.7±8.4years, EDSS 1.0±1.2; 93% women]. Baseline, one and two year MRI was applied to an SPM12 pipeline to assess brain parenchymal fraction (BPF) and cortical GM fraction (cGMF). T2 lesion volume (T2LV) and gadolinium-enhancing lesions were assessed. Change was modeled using a mixed effects linear regression with a random intercept and fixed effects for time, group, and the time-by-group interaction. The group slope difference was assessed using the interaction term., Results: Over two years, cGMF remained stable in the fingolimod group (p>0.05), but decreased in the untreated group (p<0.001) (group difference p<0.001). BPF change did not differ between groups (all time-points p>0.05). T2LV increased over two years in the untreated group (p<0.001) but not in the fingolimod group (p≥0.44) (group difference p<0.001)., Conclusion: These results suggest a treatment effect of fingolimod on cerebral GM atrophy in the first two years. GM atrophy is more sensitive to such effects than whole brain atrophy. However, due to the non-randomized, retrospective design, heterogeneous between-group characteristics, and small sample size, these results require confirmation in future studies., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: MR imaging can be used to measure structural changes in the brains of individuals with multiple sclerosis and is essential for diagnosis, longitudinal monitoring, and therapy evaluation. The North American Imaging in Multiple Sclerosis Cooperative steering committee developed a uniform high-resolution 3T MR imaging protocol relevant to the quantification of cerebral lesions and atrophy and implemented it at 7 sites across the United States. To assess intersite variability in scan data, we imaged a volunteer with relapsing-remitting MS with a scan-rescan at each site., Materials and Methods: All imaging was acquired on Siemens scanners (4 Skyra, 2 Tim Trio, and 1 Verio). Expert segmentations were manually obtained for T1-hypointense and T2 (FLAIR) hyperintense lesions. Several automated lesion-detection and whole-brain, cortical, and deep gray matter volumetric pipelines were applied. Statistical analyses were conducted to assess variability across sites, as well as systematic biases in the volumetric measurements that were site-related., Results: Systematic biases due to site differences in expert-traced lesion measurements were significant ( P < .01 for both T1 and T2 lesion volumes), with site explaining >90% of the variation (range, 13.0-16.4 mL in T1 and 15.9-20.1 mL in T2) in lesion volumes. Site also explained >80% of the variation in most automated volumetric measurements. Output measures clustered according to scanner models, with similar results from the Skyra versus the other 2 units., Conclusions: Even in multicenter studies with consistent scanner field strength and manufacturer after protocol harmonization, systematic differences can lead to severe biases in volumetric analyses., (© 2017 by American Journal of Neuroradiology.)

Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.

Background: Monitoring patients with multiple sclerosis (MS) for “no evidence of disease activity” (NEDA) may help guide disease-modifying therapy (DMT) management decisions. Whereas surveillance brain magnetic resonance imaging (MRI) is common, the role of spinal cord monitoring for NEDA is unknown., Objective: To evaluate the role of brain and spinal cord 3T MRI in the 1-year evaluation of NEDA., Methods: Of 61 study patients (3 clinically isolated syndrome, 56 relapsing-remitting, 2 secondary progressive), 56 (91.8%) were receiving DMT. The MRI included brain fluid-attenuated inversion recovery and cervical/thoracic T2-weighted fast spin echo images. On MRI, NEDA was defined as the absence of new or enlarging T2 lesions at 1 year., Results: Thirty-nine patients (63.9%) achieved NEDA by brain MRI, only one of whom had spinal cord activity. This translates to a false-positive rate for NEDA based on the brain of 2.6% (95% CI, 0.1%–13.5%). Thirty-eight patients (62.3%) had NEDA by brain and spinal cord MRI. Fifty-five patients (90.2%) had NEDA by spinal cord MRI, 17 of whom had brain activity. Of the 22 patients (36.1%) with brain changes, 5 had spinal cord changes. No evidence of disease activity was sustained in 48.3% of patients at 1 year and was the same with the addition of spinal cord MRI. Patients with MRI activity in either the brain or the spinal cord only were more likely to have activity in the brain (P = .0001)., Conclusions: Spinal cord MRI had a low diagnostic yield as an adjunct to brain MRI at 3T in monitoring patients with MS for NEDA over 1 year. Studies with larger data sets are needed to confirm these findings., Competing Interests: Financial Disclosures: Dr. Healy has received research support from Genzyme, Merck Serono, Novartis, and Verily Life Sciences. Dr. Bakshi has received consulting fees from AbbVie, Alkermes, Biogen, Novartis, and Questcor and has received research support from Biogen, Genzyme, Merck Serono, Novartis, and Teva. Dr. Bakshi's spouse owns stock in Biogen. The other authors have no conflicts of interest to disclose.

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic encephalopathic state associated with reversible cerebral vasogenic edema. Seizures are a common clinical presentation in PRES, however its electroencephalographic and radiologic pattern correlation is limited in this subset of patients. The aim of this study is to analyze the origin of electrographic dysfunction according to the radiologic pattern in patients with PRES and seizures., Methods: We retrospectively identified 46 cancer patients who developed PRES and seizures at The University of Texas MD Anderson Cancer Center between January 2006 and June 2012. Clinical, radiographic and electroencephalographic data were abstracted from their records and reviewed for our analysis., Results: The average age at presentation was 49.9±19.7years. Thirty-four (73.9%) patients were women. Twenty-two (47.8%) patients had a primary hematological malignancy whereas the rest had a solid tumor. Thirty-three (71.7%) patients had received some form of chemotherapy. The mean systolic blood pressure (SBP) variation was 23.7±16.4mmHg at onset of symptoms. On brain MRI, 32 (69.6%) patients had typical pattern while 14 (30.4%) had an atypical pattern. Thirty-seven (80.4%) patients had scalp electroencephalogram (EEG) evaluation. Thirty-three (89.2%) had abnormal EEG findings: diffuse theta/delta slowing (N=12, 36.4%), followed by diffuse slowing with focal dysfunction (N=8, 24.2%), focal dysfunction with epileptiform discharges (N=4, 12.1%), non-convulsive status epilepticus (N=4, 12.1%), focal seizure activity and burst suppression (N=2, 6.1% each). Lateralized Periodic Discharges (LPDs) were recorded in 1 case. Four patients had focal dysfunction localized to areas without conventional MRI signal changes. Four patients had recurrent seizures, of which 3 had an atypical PRES pattern., Conclusion: PRES appears to be a diffuse neurotoxic encephalopathic state. Origin of seizures seen on scalp EEG may not correlate with the location of vasogenic edema/MRI signal changes raising the possibility of greater degree of dysfunction which may exist beyond those areas., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Obstructive sleep apnea (OSA) is accompanied by brain changes in areas that regulate autonomic, cognitive, and mood functions, which were initially examined by Gaussian-based diffusion tensor imaging measures, but can be better assessed with non-Gaussian measures. We aimed to evaluate axonal and myelin changes in OSA using axial (AK) and radial kurtosis (RK) measures., Materials and Methods: We acquired diffusion kurtosis imaging data from 22 OSA and 26 controls; AK and RK maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance., Results: Increased AK, indicating axonal changes, emerged in the insula, hippocampus, amygdala, dorsolateral pons, and cerebellar peduncles and showed more axonal injury over previously identified damage. Higher RK, showing myelin changes, appeared in the hippocampus, amygdala, temporal and frontal lobes, insula, midline pons, and cerebellar peduncles and showed more widespread myelin damage over previously identified injury., Conclusions: Axial kurtosis and RK measures showed widespread changes over Gaussian-based techniques, suggesting a more sensitive nature of kurtoses to injury.

Importance: MicroRNAs (miRNAs) are promising multiple sclerosis (MS) biomarkers. Establishing the association between miRNAs and magnetic resonance imaging (MRI) measures of disease severity will help define their significance and potential impact., Objective: To correlate circulating miRNAs in the serum of patients with MS to brain and spinal MRI., Design, Setting, and Participants: A cross-sectional study comparing serum miRNA samples with MRI metrics was conducted at a tertiary MS referral center. Two independent cohorts (41 and 79 patients) were retrospectively identified from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital. Expression of miRNA was determined by locked nucleic acid-based quantitative real-time polymerase chain reaction. Spearman correlation coefficients were used to test the association between miRNA and brain lesions (T2 hyperintense lesion volume [T2LV]), the ratio of T1 hypointense lesion volume [T1LV] to T2LV [T1:T2]), brain atrophy (whole brain and gray matter), and cervical spinal cord lesions (T2LV) and atrophy. The study was conducted from December 2013 to April 2016., Main Outcomes and Measures: miRNA expression., Results: Of the 120 patients included in the study, cohort 1 included 41 participants (7 [17.1%] men), with mean (SD) age of 47.7 (9.5) years; cohort 2 had 79 participants (26 [32.9%] men) with a mean (SD) age of 43.0 (7.5) years. Associations between miRNAs and MRIs were both protective and pathogenic. Regarding miRNA signatures, a topographic specificity differed for the brain vs the spinal cord, and the signature differed between T2LV and atrophy/destructive measures. Four miRNAs showed similar significant protective correlations with T1:T2 in both cohorts, with the highest for hsa.miR.143.3p (cohort 1: Spearman correlation coefficient rs = -0.452, P = .003; cohort 2: rs = -0.225, P = .046); the others included hsa.miR.142.5p (cohort 1: rs = -0.424, P = .006; cohort 2: rs = -0.226, P = .045), hsa.miR.181c.3p (cohort 1: rs = -0.383, P = .01; cohort 2: rs = -0.222, P = .049), and hsa.miR.181c.5p (cohort 1: rs = -0.433, P = .005; cohort 2: rs = -0.231, P = .04). In the 2 cohorts, hsa.miR.486.5p (cohort 1: rs = 0.348, P = .03; cohort 2: rs = 0.254, P = .02) and hsa.miR.92a.3p (cohort 1: rs = 0.392, P = .01; cohort 2: rs = 0.222, P = .049) showed similar significant pathogenic correlations with T1:T2; hsa.miR.375 (cohort 1: rs = -0.345, P = .03; cohort 2: rs = -0.257, P = .022) and hsa.miR.629.5p (cohort 1: rs = -0.350, P = .03; cohort 2: rs = -0.269, P = .02) showed significant pathogenic correlations with brain atrophy. Although we found several miRNAs associated with MRI outcomes, none of these associations remained significant when correcting for multiple comparisons, suggesting that further validation of our findings is needed., Conclusions and Relevance: Serum miRNAs may serve as MS biomarkers for monitoring disease progression and act as surrogate markers to identify underlying disease processes.