Study design and methods: U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER).

INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.

Cbl-b Is Upregulated and Plays a Negative Role in Activated Human NK Cells.

The E3 ubiquitin ligase Cbl-b has been characterized as an intracellular checkpoint in T cells; however, the function of Cbl-b in primary human NK cells, an innate immune anti-tumor effector cell, is not well defined. In this study, we show that the expression of Cbl-b is significantly upregulated in primary human NK cells activated by IL-15, IL-2, and the human NK cell-sensitive tumor cell line K562 that lacks MHC class I expression. Pretreatment with JAK or AKT inhibitors prior to IL-15 stimulation reversed Cbl-b upregulation. Downregulation of Cbl-b resulted in significant increases in granzyme B and perforin expression, IFN-γ production, and cytotoxic activity against tumor cells. Collectively, we demonstrate upregulation of Cbl-b and its inhibitory effects in IL-15/IL-2/K562-activated human NK cells, suggesting that Cbl-b plays a negative feedback role in human NK cells.

Comparison of Commercial Versus Homemade Models for Teaching Ultrasound-Guided Peripheral I.V. Placement.

BACKGROUND: Various commercially available and do-it-yourself (DIY) models are used to teach emergency medicine (EM) residents and medical students ultrasound (US)-guided i.v. insertion. Expensive commercial models degrade over time, but DIY models are inexpensive, easily prepared, and readily discarded. OBJECTIVE: We tested the hypothesis that DIY models are equally effective as commercial models for teaching US-guided i.v. insertion, and using a controlled trial to subjectively evaluate how well DIY models and commercially manufactured models compare with human tissue both tactilely and sonographically. METHODS: We tested three models for US-guided i.v. teaching-a commercially available model US training block model, a homemade tofu model, and a homemade gelatin model. All three models were compared with US-guided i.v. insertion involving human tissue. Study participants were EM residents and EM attendings experienced in US-guided i.v. placement in real patients. After practicing peripheral i.v. placement under US guidance using the three media, participants at various levels of training and experience with US-guided i.v. insertion subjectively described how each media compared tactilely and sonographically, which model was most similar to a live human overall, and which model was best for instructing learners. RESULTS: The overall score (sum of visual and sonographic scores) for the gelatin model was significantly higher than either of the other models, indicating that the gelatin model was evaluated as most approximate to the anatomy of a human compared with the other models. CONCLUSIONS: Inexpensive homemade alternatives to commercial simulators can be realistic and effective surrogates for learning US-guided peripheral i.v.

Ultrasound-Guided Retroclavicular Approach to the Infraclavicular Region (RAPTIR) Brachial Plexus Block for Anterior Shoulder Reduction.

BACKGROUND: Shoulder dislocations are a common presenting injury to the emergency department (ED), with anterior dislocations comprising the majority of these cases. Some patients may tolerate gentle manipulation and reduction, but many require analgesia of some type. Oral or parenteral pain medication is often used alone or in combination with procedural sedation if gentle manipulation fails to achieve reduction. Recently, this treatment algorithm has grown to include regional anesthesia as a mode of analgesia for reduction of shoulder dislocations in the form of brachial plexus blocks. It has been well described that the interscalene and supraclavicular approach to the brachial plexus can be used to assist in reduction of anterior shoulder dislocations; however, there has yet to be any published literature regarding the use of ultrasound-guided retroclavicular approach to the infraclavicular region (RAPTIR) brachial plexus blocks for shoulder reduction. CASE REPORT: We describe three patients who presented to the ED with anterior shoulder dislocations. The RAPTIR block was performed, provided effective analgesia, and facilitated successful shoulder reduction in all three patients.Why Should an Emergency Physician Be Aware of This? The RAPTIR nerve block is a safe and effective option for analgesia in the patient with an anterior shoulder dislocation. It may have advantages over other brachial nerve blocks and avoids the risks and disadvantages of procedural sedation and opioids.

Cognitive Function Remains Associated With Functional Impairment in Profound Dementia: Alzheimer Disease and Dementia With Lewy Bodies.

Background and Objectives: The Baylor Profound Mental Status Examination (BPMSE) was developed to assess cognitive function in the profound stage of dementia. The Clinical Dementia Rating (CDR) scale has been widely used in measuring functional performance in dementia. We aimed to determine whether cognitive function is related to overall functional impairment in profound dementia. Methods: We selected 864 patients with probable Alzheimer disease (AD) and 25 patients with possible dementia with Lewy Bodies (DLB) cases with profound dementia by Mini-Mental Status Examination or/and clinical global impression. We used BPMSE to measure cognitive function and the CDR sum-of-boxes (CDR-SB) score to determine overall functional status. We used Spearman rank order correlation to examine the univariate association between CDR-SB and BPMSE in the 2 diagnostic groups separately and multivariable regression analysis to investigate whether BPMSE remained associated with functional status after adjustment for age, sex, education, and APOE ε4 genotype. We expected to see an inverse correlation between BPMSE and CDR-SB scores based on the directionality of the rating scale scoring. Results: In both AD and DLB, total BPMSE scores had a significant inverse correlation with CDR-SB scores (AD: r = -0.453, p < 0.001; DLB: r = -0.489, p = 0.013). It is of interest that in DLB, the "attention" domain of BPMSE had the strongest association with CDR-SB (r = -0.700, p < 0.001) compared with other domains. The multivariable regression models showed that higher BPMSE scores (i.e., better cognitive function) remained significantly correlated with lower CDR-SB scores (i.e., better global function) in AD (CDR-SB: ß = -0.340, p < 0.001), but the regression coefficient for BPMSE did not reach significance in the DLB model (CDR-SB: ß = -0.298, p = 0.174). Discussion: In patients with AD and DLB who enter the profound dementia stage, cognitive function is associated with the severity of functional impairment. The lack of significance for DLB in multivariable regression could be due to small sample size because the correlation magnitude is similar to that in AD.

Cerebello-Parietal Functional Connectivity in Amnestic Mild Cognitive Impairment.

The role of the cerebellum in amnestic mild cognitive impairment (aMCI), typically a prodromal stage of Alzheimer's disease, is not fully understood. We studied the lobule-specific cerebello-cerebral connectivity in 15 cognitively normal and 16 aMCI using resting-state functional MRI. Our analysis revealed weaker connectivity between the cognitive cerebellar lobules and parietal lobe in aMCI. However, stronger connectivity was observed in the cognitive cerebellar lobules with certain brain regions, including the precuneus cortex, posterior cingulate gyrus, and caudate nucleus in participants with worse cognition. Leveraging these measurable changes in cerebello-parietal functional networks in aMCI could offer avenues for future therapeutic interventions.

Evaluation of the gap in delivery of opioid agonist therapy among individuals with opioid-related health problems: a population-based retrospective cohort study.

AIMS: Although opioid-related harms have reached new heights across North America, the size of the gap in opioid agonist therapy (OAT) delivery for opioid-related health problems is unknown in most jurisdictions. This study sought to characterize the gap in OAT treatment using a cascade of care framework, and determine factors associated with engagement and retention in treatment. DESIGN: A population-based retrospective cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Individuals who sought medical care for opioid-related health problems or died from an opioid-related cause between 2005 and 2019. MEASUREMENTS: Monthly treatment status for buprenorphine/naloxone or methadone OAT between 2013 and 2019 (i.e. 'off OAT', 'retained on OAT < 6 months', 'retained on OAT ≥ 6 months'). FINDINGS: Of 122 811 individuals in the cohort, 97 516 (79.4%) received OAT at least once during the study period. There was decreasing 6-month treatment retention over time. Model results indicated that males had higher odds of being on OAT each month [odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.23-1.28] but lower odds of OAT retention (OR = 0.90, 95% CI = 0.88-0.92), while the reverse was observed for older individuals (monthly: OR = 0.76 per 10-year increase, 95% CI = 0.76-0.77; retention: OR = 1.36 per 10-year increase, 95% CI = 1.34-1.38) and individuals with higher neighbourhood income (e.g. highest income quintile, monthly: OR = 0.79, 95% CI = 0.77-0.82; highest income quintile, retention: OR = 1.15, 95% CI = 1.11-1.20). Individuals residing in rural areas and with a history of mental health diagnoses had poorer outcomes overall, including lower odds of being on OAT each month (rural: OR = 0.75, 95% CI = 0.73-0.78; mental health: OR = 0.89, 95% CI = 0.87-0.92) and OAT retention (rural: OR = 0.79, 95% CI = 0.77-0.82; mental health: OR = 0.81, 95% CI = 0.78-0.83), as well as higher risk of starting/stopping OAT [rural, starting OAT: hazard ratio (HR) = 1.07, 95% CI = 1.05-1.10; mental health, starting OAT: HR = 1.20, 95% CI: 1.18-1.23; rural, stopping OAT: HR = 1.24, 95% CI: = 1.22-1.26; mental health, stopping OAT: HR = 1.11, 95% CI = 1.09-1.13]. Individuals with a history of mental health diagnoses also had a higher risk of death, regardless of OAT status (off OAT death: HR = 1.49, 95% CI = 1.33-1.66; on OAT death: HR = 1.20, 95% CI = 1.09-1.31). CONCLUSIONS: Factors influencing engagement and declining retention in treatment with opioid agonist therapy in Ontario's health system include age, sex and neighbourhood income, as well as mental health diagnoses or residing in rural regions.

Practical Considerations in the Administration of Aducanumab for the Neurologist.

Aducanumab (Aduhelm), developed by the biotechnology firm Biogen in Cambridge, MA, was approved using the less common accelerated approval pathway by the Federal Drug Administration (FDA) reserved for treatments that fill a significant unmet need.1 Its approval on June 7, 2021, has been met with an outpouring of opinions from prescribers, insurers, advocacy groups, and hospital systems regarding its risk-benefit profile.2-4 Originally approved for all forms of Alzheimer disease (AD), the FDA updated aducanumab's labeling on July 8, 2021, for "treatment in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials."5 With 6 million people nationally in the United States who suffer from AD and an anticipated one-third of those who may now fulfill the criteria under the revised labeling, the implications of aducanumab's approval continue to generate national interest.6.

Gender Discrepancies in Neurologist Compensation.

BACKGROUND AND OBJECTIVES: Previous studies have shown gender disparities in physician pay in various specialties. This retrospective, cross-sectional study evaluated data from the American Academy of Neurology (AAN) Compensation and Productivity Survey for differences in neurologist compensation by gender. METHODS: Of the 3,268 completed surveys submitted, 2,719 were from neurologists and 1,466 had sufficient data for analysis (551 women, 951 men respondents). We calculated an hourly wage from full-time equivalent (FTE) status and weeks worked per year. We evaluated differences in men and women neurologist compensation with multivariable generalized linear models adjusting for race, ethnicity, geographic region, practice setting, years in practice, call status, leadership role, straight salary, and subspecialty. RESULTS: Baseline characteristics for men and women neurologists were similar with the exception of subspecialty distribution. More men were practicing in higher-wage subspecialties compared to women (p < 0.05). Mean FTE annual salary for all neurologists was $280,315, and mean standardized hourly compensation was $131. Estimated annual salary for women was 10.7% less (p ≤ 0.001, 95% confidence interval -4% to -16%) after controlling for race, region, years of practice, practice setting, call status, leadership role, and subspecialty-wage category. FTE annual salary for women neurologists in high-compensation specialties ($281,838) was lower than the mean annual salary for men neurologists in both high-compensation ($365,751) and low-compensation subspecialties ($282,813). When broken down by years of practice, the highest earning women neurologists' mean hourly wage (11-20 years of practice, $128/h) was less than that of all men neurologists except those with 0 to 5 years of practice ($125/h). DISCUSSION: This study, using convenience sample data, adds to the existing body of evidence demonstrating that, despite adjustment for multiple confounding variables, ongoing disparities exist in physician compensation. Despite efforts by professional societies such as the AAN, ongoing systemic issues and barriers exist. Further research into underlying causes and mitigation strategies is recommended; use of probability sampling methods in future research will be important to decrease potential bias and to increase generalizability.

The tight junction protein claudin-3 shows conserved expression in the nephric duct and ureteric bud and promotes tubulogenesis in vitro.

The claudin family of proteins is required for the formation of tight junctions that are contact points between epithelial cells. Although little is known of the cellular events by which epithelial cells of the ureteric bud form tubules and branch, tubule formation is critical for kidney development. We hypothesize that if claudin-3 (Cldn3) is expressed within tight junctions of the ureteric bud, this will affect ureteric bud cell shape and tubule formation. Using transmission electron microscopy, we identified tight junctions within epithelial cells of the ureteric bud. Whole mount in situ hybridization and immunoassays were performed in the mouse and chick and demonstrated that Cldn3 transcript and protein were expressed in the nephric duct, the ureteric bud, and its derivatives at critical time points during tubule formation and branching. Mouse inner medullary collecting duct cells (mIMCD-3) form tubules when seeded in a type I collagen matrix and were found to coexpress CLDN3 and the tight junction marker zonula occludens-1 in the cell membrane. When these cells were stably transfected with Cldn3 fused to the enhanced green fluorescent protein reporter, multiple clones showed a significant increase in tubule formation compared with controls (P < 0.05) due in part to an increase in cell proliferation (P < 0.01). Cldn3 may therefore promote tubule formation and expansion of the ureteric bud epithelium.

Effects of Fragmentation and the Case for Greater Cohesion in Neurologic Care Delivery.

GOALS: To define fragmentation in neurological care delivery; explain the positive and negative drivers in neurologic practice that contribute to fragmentation; illustrate situations that increase fragmentation risk; emphasize the costs and impact on both patients and providers; propose solutions that allow for more cohesive care. WORK GROUP: The Transforming Leaders Program (TLP) class of 2020 was tasked by American Academy of Neurology (AAN) leadership to identify the leading trends in inpatient and outpatient neurology and to predict their effects on future neurologic practice. METHODS: Research material included AAN data bases, PubMed searches, discussion with topic experts and AAN leadership. RESULTS: Trends in care delivery are driven by changes in the work force, shifts in health care delivery, care costs, changes in evidence-based care and patient factors. These trends can contribute to care fragmentation. Potential solutions to these problems are proposed based on care models developed in oncology and medicine. LIMITATIONS: This paper shares our opinions as there is a lack of evidence-based guidelines as to optimal neurological care delivery.

An Oncolytic Virus Expressing IL15/IL15Rα Combined with Off-the-Shelf EGFR-CAR NK Cells Targets Glioblastoma.

IL15 is a pleiotropic cytokine with multiple roles that improve immune responses to tumor cells. Oncolytic viruses (OV) specifically lyse tumors and activate immune responses. Systemic administration of IL15 or its complex with the IL15Rα and chimeric antigen receptor (CAR) natural killer (NK) cells are currently being tested in the clinic. Here, we generated a herpes simplex 1-based OV-expressing human IL15/IL15Rα sushi domain fusion protein (named OV-IL15C), as well as off-the-shelf EGFR-CAR NK cells, and studied their monotherapy and combination efficacy in vitro and in multiple glioblastoma (GBM) mouse models. In vitro, soluble IL15/IL15Rα complex was secreted from OV-IL15C-infected GBM cells, which promoted GBM cytotoxicity and improved survival of NK and CD8+ T cells. Frozen, readily available off-the-shelf EGFR-CAR NK cells showed enhanced killing of tumor cells compared with empty vector-transduced NK cells. In vivo, OV-IL15C significantly inhibited tumor growth and prolonged survival of GBM-bearing mice in the presence of CD8+ T cells compared with parental OV. OV-IL15C plus EGFR-CAR NK cells synergistically suppressed tumor growth and significantly improved survival compared with either monotherapy, correlating with increased intracranial infiltration and activation of NK and CD8+ T cells and elevated persistence of CAR NK cells in an immunocompetent model. Collectively, OV-IL15C and off-the-shelf EGFR-CAR NK cells represent promising therapeutic strategies for GBM treatment to improve the clinical management of this devastating disease. SIGNIFICANCE: The combination of an oncolytic virus expressing the IL15/IL15Rα complex and frozen, ready-to-use EGFR-CAR NK cells elicits strong antitumor responses in glioblastoma.

Variably protease-sensitive prionopathy: A differential diagnostic consideration for dementia.

PURPOSE OF REVIEW: Prion diseases are rare neurodegenerative diseases that are caused by abnormal pathogenic agents and can affect both humans and animals. These diseases are categorized as sporadic, inherited, or acquired by infection. Clinical manifestations include psychiatric symptoms, cognitive impairment, and parkinsonism, which are similar to those of other prion diseases and frontotemporal dementia variants. RECENT FINDINGS: More recently, scientists discovered a new sporadic prion disease called variably protease-sensitive prionopathy. SUMMARY: The following case discusses a patient presenting with sudden onset and rapid decline in cognitive, neurobehavioral, and motor functioning and his clinical journey including treatment interventions and diagnostic confirmation.

Prospective evaluation of multidetector-row CT angiography for the diagnosis of vasospasm following subarachnoid hemorrhage: a comparison with digital subtraction angiography.

PURPOSE: To evaluate the accuracy of multidetector-row CT angiography (CTA) for the diagnosis of large-vessel vasospasm following subarachnoid hemorrhage by comparison to digital subtraction angiography (DSA). METHODS: Thirty-three patients with acute subarachnoid hemorrhage were enrolled in a prospective study and underwent a total of 40 CTA and DSA examinations within 24 h of each other. Two neuroradiologists reviewed the CTA examinations independently. A third neuroradiologist blinded to the CTA results reviewed the DSA examinations. In each patient, for both techniques, 23 arterial segments were evaluated for their degree of narrowing; the reviewers were asked to attribute every narrowing to 'vasospasm' or 'hypoplasia'. Agreement between CTA and DSA for the degree of narrowing, and agreement between the two CTA readers, were calculated using weighted kappa-coefficients. Sensitivity, specificity, accuracy, positive and negative predictive value (NPV) of CTA to detect large-vessel vasospasm were calculated considering DSA as the gold standard. RESULTS: Substantial correlation (kappa = 0.638) was found between CTA and DSA for the detection of arterial narrowing. Interobserver agreement between the two CTA reviewers for the degree of luminal narrowing was substantial (kappa = 0.712).CTA was 87% accurate for the diagnosis of large-vessel vasospasm; the NPV of CTA was 95%. CTA was more accurate, and interobserver agreement higher, for the proximal arterial segments (basilar and vertebral arteries) than for the distal ones (P2 segments). Using CTA as a screening modality, 83% of unnecessary DSA would have been avoided. CONCLUSION: Compared to the gold standard of DSA, CTA is accurate for the detection of large-vessel vasospasm, and has a very high NPV.

Visual grading system for vasospasm based on perfusion CT imaging: comparisons with conventional angiography and quantitative perfusion CT.

BACKGROUND: The purpose of this study was to compare simple visual grading of perfusion CT (PCT) maps to a more quantitative, threshold-based interpretation of PCT parameters in the characterization of presence and severity of vasospasm. METHODS: Thirty-three patients with acute subarachnoid hemorrhage were enrolled in a prospective study and underwent a total of 40 paired PCT and digital subtraction angiography (DSA) examinations. A neuroradiologist and a neurologist reviewed the PCT mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume maps independently; they evaluated five anatomical regions (frontal, temporal, parietal, occipital/thalami, and basal ganglia/insula) and graded them for abnormality (0 if normal, 1 if abnormal in <50% of the region, and 2 if abnormal in >or=50% of the region). A third neuroradiologist blinded to the PCT results reviewed the DSA examinations and assessed 19 segments for the presence or absence of vasospasm. Correlation between PCT and DSA scores was assessed, as well as the sensitivity and specificity of PCT compared to DSA used as a gold standard. RESULTS: MTT (R(2) = 0.939) and CBF (R(2) = 0.907) scores correlated best with DSA scores (p < 0.001). MTT scoring had a sensitivity of 92% and a specificity of 86% compared to DSA; CBF scoring had a sensitivity of 75% and a specificity of 95%. The interobserver agreement between neuroradiologist and neurologist was found to have kappa = 0.789 for MTT and 0.658 for CBF. CONCLUSION: We propose a user-friendly visual grading system for PCT maps in patients with suspected vasospasm. This visual approach compares favorably to the results of DSA. Sensitive MTT maps should be used for screening, and specific CBF maps for confirmation of vasospasm.

Coding for Medication-related Poisoning and Adverse Effects.

Accurate coding is important for proper reimbursement and documentation of care provided. This article provides an overview of coding considerations for patient encounters associated with medication use, abuse, or poisoning.

Sharing notes with patients: A review of current practice and considerations for neurologists.

Improved patient engagement is a critical consideration in the new payment climate. Releasing progress notes for patients to view may improve patient involvement and engagement in their care. Patients perceive benefit from viewing physician progress notes. As initial studies involved only primary care physicians, specialist physicians may have specific considerations when releasing notes to patients. This article provides a framework for neurologists to implement a note release policy in their practice.

Monolithic Chip for High-throughput Blood Cell Depletion to Sort Rare Circulating Tumor Cells.

Circulating tumor cells (CTCs) are a treasure trove of information regarding the location, type and stage of cancer and are being pursued as both a diagnostic target and a means of guiding personalized treatment. Most isolation technologies utilize properties of the CTCs themselves such as surface antigens (e.g., epithelial cell adhesion molecule or EpCAM) or size to separate them from blood cell populations. We present an automated monolithic chip with 128 multiplexed deterministic lateral displacement devices containing ~1.5 million microfabricated features (12 µm-50 µm) used to first deplete red blood cells and platelets. The outputs from these devices are serially integrated with an inertial focusing system to line up all nucleated cells for multi-stage magnetophoresis to remove magnetically-labeled white blood cells. The monolithic CTC-iChip enables debulking of blood samples at 15-20 million cells per second while yielding an output of highly purified CTCs. We quantified the size and EpCAM expression of over 2,500 CTCs from 38 patient samples obtained from breast, prostate, lung cancers, and melanoma. The results show significant heterogeneity between and within single patients. Unbiased, rapid, and automated isolation of CTCs using monolithic CTC-iChip will enable the detailed measurement of their physicochemical and biological properties and their role in metastasis.

Human growth hormone-related iatrogenic Creutzfeldt-Jakob disease with abnormal imaging.

BACKGROUND: Although more than 160 cases of iatrogenic Creutzfeldt-Jakob disease (iCJD) from human growth hormone (hGH) treatment have been documented, to our knowledge abnormal cerebellar findings on magnetic resonance imaging (MRI) have not been reported. OBJECTIVE: To report a case of hGH-related iCJD with abnormal cerebellar MRI findings on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted MRI (DWI). DESIGN: Case report. SETTING: Outpatient neurology clinic at a university medical center. PATIENT: A 33-year old man who had subacute gait ataxia and blurred vision. RESULTS: Beginning 19 years prior, this patient had received cadaveric pituitary-derived hGH treatment for at least 5 years. Magnetic resonance imaging revealed FLAIR and DWI abnormalities, particularly in the cerebellum. He died 7 months after disease onset of autopsy-confirmed iCJD. Pathological changes corresponded largely to MRI findings. CONCLUSIONS: To our knowledge, this is the first case of hGH-related iCJD with FLAIR and DWI abnormalities within the cerebellum. As symptoms referable to the cerebellum occur early in iCJD, it suggests that these MRI sequences may allow earlier diagnosis of this form of prion disease.