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Aging increases the risk of neurodegeneration, cognitive decline, and Alzheimer's disease (AD). Currently no means exist to measure neuronal cell death during life or to prevent it. Here we show that cross-sectional measures of human plasma proteins released from dying/damaged neurons (ubiquitin C-terminal hydrolase-L1/UCH-L1 and neurofilament light/NfL) become exponentially higher from age 2-85; UCH-L1 rises faster in females. Glial fibrillary acidic protein (GFAP) concentrations, indicating astrogliosis/inflammation, increase exponentially after age 40. Treatment with human granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim) halted neuronal cell death, as evidenced by reduced plasma UCH-L1 concentrations, in AD participants to levels equivalent to those of five-year-old healthy controls. The ability of GM-CSF treatment to reduce neuronal apoptosis was confirmed in a rat model of AD. These findings suggest that the exponential increase in neurodegeneration with age, accelerated by neuroinflammation, may underlie the contribution of aging to cognitive decline and AD and can be halted by GM-CSF/sargramostim treatment.

Background: Seborrheic dermatitis (SD) affects 18.6%-59% of persons with Parkinson disease (PD), and recent studies provide evidence that oral cannabidiol (CBD) therapy could reduce sebum production in addition to improving motor and psychiatric symptoms in PD. Therefore, oral CBD could be useful for improving symptoms of both commonly co-occurring conditions., Objective: This study investigates whether oral CBD therapy is associated with a decrease in SD severity in PD., Methods: Facial photographs were collected as a component of a randomized (1:1 CBD vs placebo), parallel, double-blind, placebo-controlled trial assessing the efficacy of a short-term 2.5 mg per kg per day oral sesame solution CBD-rich cannabis extract (formulated to 100 mg/mL CBD and 3.3 mg/mL THC) for reducing motor symptoms in PD. Participants took 1.25 mg per kg per day each morning for 4 ±1 days and then twice daily for 10 ±4 days. Reviewers analyzed the photographs independently and provided a severity ranking based on the Seborrheic Dermatitis Area and Severity Index (SEDASI) scale. Baseline demographic and disease characteristics, as well as posttreatment SEDASI averages and the presence of SD, were analyzed with 2-tailed t tests and Pearson χ 2 tests. SEDASI was analyzed with longitudinal regression, and SD was analyzed with generalized estimating equations., Results: A total of 27 participants received a placebo and 26 received CBD for 16 days. SD severity was low in both groups at baseline, and there was no treatment effect. The risk ratio for patients receiving CBD, post versus pre, was 0.69 (95% CI 0.41-1.18; P=.15), compared to 1.20 (95% CI 0.88-1.65; P=.26) for the patients receiving the placebo. The within-group pre-post change was not statistically significant for either group, but they differed from each other (P=.07) because there was an estimated improvement for the CBD group and an estimated worsening for the placebo group., Conclusions: This study does not provide solid evidence that oral CBD therapy reduces the presence of SD among patients with PD. While this study was sufficiently powered to detect the primary outcome (efficacy of CBD on PD motor symptoms), it was underpowered for the secondary outcomes of detecting changes in the presence and severity of SD. Multiple mechanisms exist through which CBD can exert beneficial effects on SD pathogenesis. Larger studies, including participants with increased disease severity and longer treatment periods, may better elucidate treatment effects and are needed to determine CBD's true efficacy for affecting SD severity., Trial Registration: ClinicalTrials.gov NCT03582137; https://clinicaltrials.gov/ct2/show/NCT03582137., (©Isaac Weber, Caterina Zagona-Prizio, Torunn E Sivesind, Madeline Adelman, Mindy D Szeto, Ying Liu, Stefan H Sillau, Jacquelyn Bainbridge, Jost Klawitter, Cristina Sempio, Cory A Dunnick, Maureen A Leehey, Robert P Dellavalle. Originally published in JMIR Dermatology (http://derma.jmir.org), 11.03.2024.)

Purpose of the Study: Posterior cortical atrophy is a clinico-radiographical syndrome that presents with higher-order visual dysfunction and is most commonly due to Alzheimer's disease. Understanding factors associated with atypical presentations of Alzheimer's disease, such as posterior cortical atrophy (PCA), holds promise to shape our understanding of AD pathophysiology. Thus, we aimed to compare MRI evidence of lobar microbleeds (LMBs) in posterior cortical atrophy (PCA) syndrome to typical AD (tAD) and to assess and compare MRI evidence of cerebral amyloid angiopathy (CAA) in each group., Findings: We retrospectively collected clinical and MRI data from participants with PCA (n = 26), identified from an institutional PCA registry, and participants with tAD (n = 46) identified from electronic health records from a single institution. LMBs were identified on susceptibility-weighted imaging (SWI); the Fazekas grade of white matter disease was assessed using FLAIR images, and Boston criteria version 2.0 for cerebral amyloid angiopathy were applied to all data. The proportion of participants with PCA and LMB (7.7%) was lower than for tAD (47.8%) (p = 0.005). The frequency of "probable" CAA was similar in both groups, while "possible" CAA was more frequent in tAD (30.4%) than PCA (0%) (p = 0.001). The Fazekas grades were not different between groups. Lobar microbleeds on SWI were not more common in PCA than in typical AD. Clinicopathological investigations are necessary to confirm these findings. The factors that contribute to the posterior cortical atrophy phenotype are unknown., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Parkinson disease and related disorders (PDRD) are the fastest growing neurodegenerative illness in terms of prevalence and mortality. As evidence builds to support palliative care (PC) for PDRD, studies are needed to guide implementation., Objective: To determine whether PC training for neurologists and remote access to a PC team improves outcomes in patients with PDRD in community settings., Design, Setting, and Participants: This pragmatic, stepped-wedge comparative effectiveness trial enrolled and observed participants from 19 community neurology practices supported by PC teams at 2 academic centers from March 8, 2017, to December 31, 2020. Participants were eligible if they had PDRD and moderate to high PC needs. A total of 612 persons with PDRD were referred; 253 were excluded. Patients were excluded if they had another diagnosis meriting PC, were receiving PC, or were unable or unwilling to follow study procedures. Patients received usual care or the intervention based on when their community neurologist was randomized to start the intervention. Data were analyzed from January 2021 to September 2023., Intervention: The intervention included (1) PC education for community neurologists and (2) team-based PC support via telehealth., Main Outcomes and Measures: The primary outcomes were differences at 6 months in patient quality of life (QOL; measured by the Quality of Life in Alzheimer Disease Scale [QOL-AD]) and caregiver burden (Zarit Burden Interview) between the intervention and usual care., Results: A total of 359 patients with PDRD (233 men [64.9%]; mean [SD] age, 74.0 [8.8] years) and 300 caregivers were enrolled. At 6 months, compared with usual care, participants receiving the intervention had better QOL (QOL-AD score, 0.09 [95% CI, -0.63 to 0.82] vs -0.88 [95% CI, -1.62 to -0.13]; treatment effect estimate, 0.97; 95% CI, 0.07-1.86; P = .03). No significant difference was observed in caregiver burden (Zarit Burden Interview score, 1.19 [95% CI, 0.16 to 2.23] vs 0.55 [95%, -0.44 to 1.54]; treatment effect estimate, 0.64; 95% CI, -0.62 to 1.90; P = .32). Advance directive completion was higher under the intervention (19 of 38 [50%] vs 6 of 31 [19%] among those without directives at the beginning of the study; P = .008). There were no differences in other outcomes., Conclusions and Relevance: PC education for community neurologists and provision of team-based PC via telehealth is feasible and may improve QOL and advance care planning. Overall treatment effects were small and suggest opportunities to improve both the intervention and implementation., Trial Registration: ClinicalTrials.gov Identifier: NCT03076671.

Introduction: Memory-associated neural circuits produce oscillatory events including theta bursts (TBs), sleep spindles (SPs), and slow waves (SWs) in sleep electroencephalography (EEG). Changes in the "coupling" of these events may indicate early Alzheimer's disease (AD) pathogenesis., Methods: We analyzed 205 aging adults using single-channel sleep EEG, cerebrospinal fluid (CSF) AD biomarkers, and Clinical Dementia Rating® (CDR®) scale. We mapped SW-TB and SW-SP neural circuit coupling precision to amyloid positivity, cognitive impairment, and CSF AD biomarkers., Results: Cognitive impairment correlated with lower TB spectral power in SW-TB coupling. Cognitively unimpaired, amyloid positive individuals demonstrated lower precision in SW-TB and SW-SP coupling compared to amyloid negative individuals. Significant biomarker correlations were found in oscillatory event coupling with CSF Aβ 42 /Aβ 40 , phosphorylated- tau 181 , and total-tau., Discussion: Sleep-dependent memory processing integrity in neural circuits can be measured for both SW-TB and SW-SP coupling. This breakdown associates with amyloid positivity, increased AD pathology, and cognitive impairment., Highlights: At-home sleep EEG is a potential biomarker of neural circuits linked to memory. Circuit precision is associated with amyloid positivity in asymptomatic aging adults. Levels of CSF amyloid and tau also correlate with circuit precision in sleep EEG. Theta burst EEG power is decreased in very early mild cognitive impairment. This technique may enable inexpensive wearable EEGs for monitoring brain health., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Aggression is one manifestation of behavioral disturbances in neurodegenerative disease with emerging literature suggesting a high prevalence in Parkinson's disease and related disorders (PDRD)., Objectives: Our aim was to describe characteristics, associated factors, and consequences of aggression towards caregivers in PDRD., Methods: This is a convergent mixed methods study, leveraging data from 296 PDRD patient-caregiver dyads in a clinical trial of palliative care and semi-structured interviews with a subgroup of 14 caregivers who reported aggression. The primary outcome was baseline caregiver-reported aggression. Using multivariate linear regression, baseline dyad characteristics (eg, measures of disease, psychosocial issues, caregiver strain) were examined to identify factors associated with aggression. Thematic analysis of interviews was used to augment these findings., Results: Associated variables included disease duration ( r  = 0.15, P  < 0.05), patient grief ( r  = 0.22, P < 0.001), symptom burden ( r  = 0.18, r  < 0.01), resistance to care ( r  = 0.40, P  < 0.01), caregivers' depression ( r  = 0.16, P  < 0.05), and caregiving burden ( r  = 0.34, P  < 0.001). We identified five themes: (1) Aggressive behaviors range from verbal abuse to threats of physical violence; (2) Caregivers believe that aggressive behaviors result from the difficulty patients experience in coping with disease progression and related losses; (3) Caregivers' stress and mental health are worsened by aggressive behaviors; (4) Aggressive behaviors negatively affect patient-caregiver relationships; (5) Caregivers are ill-prepared to manage aggressive behaviors and cope with the consequences on their own., Conclusions: Aggression in PDRD is driven by diverse factors (eg, grief, fluctuations in cognition) with serious consequences for caregivers. Neurologists and movement specialists should consider screening for aggression while prioritizing caregiver education and wellbeing., Competing Interests: Study funding provided by the National Institute on Aging's (NIA) Multidisciplinary Research Training in Palliative Care and Aging award number T32AG044296. The authors declare there are no conflicts of interest relevant to this work., (© 2022 International Parkinson and Movement Disorder Society.)

Slow wave activity (SWA) during sleep is associated with synaptic regulation and memory processing functions. Each cycle of non-rapid-eye-movement (NREM) sleep demonstrates a waxing and waning amount of SWA during the transitions between stages N2 and N3 sleep, and the deeper N3 sleep is associated with an increased density of SWA. Further, SWA is an amalgam of different types of slow waves, each identifiable by their temporal coupling to spindle subtypes with distinct physiological features. The objectives of this study were to better understand the neurobiological properties that distinguish different slow wave and spindle subtypes, and to examine the composition of SWA across cycles of NREM sleep. We further sought to explore changes in the composition of NREM cycles that occur among aging adults. To address these goals, we analyzed subsets of data from two well-characterized cohorts of healthy adults: (1) The DREAMS Subjects Database ( n = 20), and (2) The Cleveland Family Study ( n = 60). Our analyses indicate that slow wave/spindle coupled events can be characterized as frontal vs. central in their relative distribution between electroencephalography (EEG) channels. The frontal predominant slow waves are identifiable by their coupling to late-fast spindles and occur more frequently during stage N3 sleep. Conversely, the central-associated slow waves are identified by coupling to early-fast spindles and favor occurrence during stage N2 sleep. Together, both types of slow wave/spindle coupled events form the composite of SWA, and their relative contribution to the SWA rises and falls across cycles of NREM sleep in accordance with depth of sleep. Exploratory analyses indicated that older adults produce a different composition of SWA, with a shift toward the N3, frontal subtype, which becomes increasingly predominant during cycles of NREM sleep. Overall, these data demonstrate that subtypes of slow wave/spindle events have distinct cortical propagation patterns and differ in their distribution across lighter vs. deeper NREM sleep. Future efforts to understand how slow wave sleep and slow wave/spindle coupling impact memory performance and neurological disease may benefit from examining the composition of SWA to avoid potential confounds that may occur when comparing dissimilar neurophysiological events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McConnell, Kronberg, Medenblik, Kheyfets, Ramos, Sillau, Pulver and Bettcher.)

Background: To determine gender differences in rates of sexual and physical abuse in functional movement disorders compared to controls and evaluate if the gender disparity of functional movement disorders is associated with abuse history., Methods: We performed a retrospective case-control study of self-reported trauma data from 696 patients (512 women) with functional movement disorders from six clinical sites compared to 141 controls (98 women) and population data. Chi-square was used to assess gender and disorder associations; logistic regression was used to model additive effects of abuse and calculate the attributable fraction of abuse to disorder prevalence., Results: Higher rates of sexual abuse were reported by women (35.3%) and men (11.5%) with functional movement disorders compared to controls (10.6% of women; 5.6% of men). History of sexual abuse increased the likelihood of functional movement disorders among women by an odds ratio of 4.57 (95% confidence interval 2.31-9.07; p < 0.0001) and physical abuse by an odds ratio of 2.80 (95% confidence interval 1.53-5.12; p = 0.0007). Population attributable fraction of childhood sexual abuse to functional movement disorders in women was 0.12 (0.05-0.19). No statistically significant associations were found in men, but our cohort of men was underpowered despite including multiple sites., Conclusions: Our study suggests that violence against women may account for some of the gender disparity in rates of functional movement disorders. Most people with functional movement disorders do not report a history of abuse, so it remains just one among many relevant risk factors to consider., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Parkinson's disease (PD) is a common neurodegenerative illness that causes disability through both motor and nonmotor symptoms. Family caregivers provide substantial care to persons living with PD, often at great personal cost. While spiritual well-being and spirituality have been suggested to promote resiliency in caregivers of persons living with cancer and dementia, this issue has not been explored in PD. Objective: The aim of this study was to identify predictors of spiritual well-being in PD patients' caregivers. Design: A cross-sectional analysis was performed. Our primary outcome measure, the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp), was measured in caregivers alongside measures of patient quality of life, symptom burden, global function, grief, and spiritual well-being and caregiver mood, burden, and perceptions of patient quality of life. Univariate correlation and multiple regression were used to determine associations between predictor variables and caregiver FACIT-Sp. Setting/Subjects: PD patient/caregiver dyads were recruited through three academic medical centers in the United States and Canada and regional community support groups. Results: We recruited 183 dyads. Patient faith, symptom burden, health-related quality of life, depression, motor function, and grief were significant predictors of caregiver spiritual well-being. Predictive caregiver factors included caregiver depression and anxiety. These factors remained significant in combined models, suggesting that both patient and caregiver factors make independent contributions to caregiver spiritual well-being. Conclusions: The present study suggests that both patient and caregiver factors are associated with spiritual well-being in PD. Further study is needed to understand the causal relationship of these factors and whether interventions to support caregiver spiritual well-being improve outcomes for caregivers or patients. Clinicaltrials.gov registration NCT02533921.

Study Objectives: Slow wave and spindle coupling supports memory consolidation, and loss of coupling is linked with cognitive decline and neurodegeneration. Coupling is proposed to be a possible biomarker of neurological disease, yet little is known about the different subtypes of coupling that normally occur throughout human development and aging. Here we identify distinct subtypes of spindles within slow wave upstates and describe their relationships with sleep stage across the human lifespan., Methods: Coupling within a cross-sectional cohort of 582 subjects was quantified from stages N2 and N3 sleep across ages 6-88 years old. Results were analyzed across the study population via mixed model regression. Within a subset of subjects, we further utilized coupling to identify discrete subtypes of slow waves by their coupled spindles., Results: Two different subtypes of spindles were identified during the upstates of (distinct) slow waves: an "early-fast" spindle, more common in stage N2 sleep, and a "late-fast" spindle, more common in stage N3. We further found stages N2 and N3 sleep contain a mixture of discrete subtypes of slow waves, each identified by their unique coupled-spindle timing and frequency. The relative contribution of coupling subtypes shifts across the human lifespan, and a deeper sleep phenotype prevails with increasing age., Conclusions: Distinct subtypes of slow waves and coupled spindles form the composite of slow wave sleep. Our findings support a model of sleep-dependent synaptic regulation via discrete slow wave/spindle coupling subtypes and advance a conceptual framework for the development of coupling-based biomarkers in age-associated neurological disease., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal anti-inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short-term treatment of transgenic AD mice with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM-CSF/sargramostim to safely ameliorate AD symptoms/pathology., Methods: A randomized, double-blind, placebo-controlled trial was conducted in mild-to-moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow-up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments., Results: Sargramostim treatment expectedly changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At end of treatment (EOT), the Mini-Mental State Examination score of the sargramostim group increased compared to baseline ( P  = .0074) and compared to placebo ( P  = .0370); the treatment effect persisted at FU1 ( P  = .0272). Plasma markers of amyloid beta (Aβ40 [decreased in AD]) increased 10% ( P  = .0105); plasma markers of neurodegeneration (total tau and UCH-L1) decreased 24% ( P  = .0174) and 42% ( P  = .0019), respectively, after sargramostim treatment compared to placebo., Discussion: The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long-term safety and efficacy of GM-CSF/sargramostim in AD is warranted., Competing Interests: Drs. Potter and Boyd are two of the inventors on several U.S. patents owned by the University of South Florida, but not licensed. As of Feb.1 2021, Dr. Boyd is an employee of Partner Therapeutics., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Objective: We sought reduce electronic health record (EHR) burden on inpatient clinicians with a 2-week EHR optimization sprint., Materials and Methods: A team led by physician informaticists worked with 19 advanced practice providers (APPs) in 1 specialty unit. Over 2 weeks, the team delivered 21 EHR changes, and provided 39 one-on-one training sessions to APPs, with an average of 2.8 hours per provider. We measured Net Promoter Score, thriving metrics, and time spent in the EHR based on user log data., Results: Of the 19 APPs, 18 completed 2 or more sessions. The EHR Net Promoter Score increased from 6 to 60 postsprint (1.0; 95% confidence interval, 0.3-1.8; P = .01). The NPS for the Sprint itself was 93, a very high rating. The 3-axis emotional thriving, emotional recovery, and emotional exhaustion metrics did not show a significant change. By user log data, time spent in the EHR did not show a significant decrease; however, 40% of the APPs responded that they spent less time in the EHR., Conclusions: This inpatient sprint improved satisfaction with the EHR., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The objective of this study is to investigate whether alterations in the neurotransmission of gamma-aminobutyric acid (GABA) in the thalamus are present in patients with cervical dystonia compared to healthy controls. Methods: GABA magnetic resonance spectroscopy was used to investigate concentration levels of GABA in the thalamus of cervical dystonia patients ( n = 17) compared to healthy controls ( n = 18). Additionally, a focused post hoc analysis of thalamic GABA A receptor availability data in a similar cohort ( n = 15 for both groups) using data from a previously collected 11 C-flumazenil positron emission tomography study was performed. Group comparisons for all evaluations were performed using two-sided t -tests with adjustments for age and sex, and Bonferroni correction for multiple comparisons was applied. Spearman's coefficient was used to test correlations. Results: We found significantly reduced GABA+/Cre levels in the thalamus of cervical dystonia patients compared to controls, and these levels positively correlated with disease duration. Although mean thalamic GABA A receptor availability did not differ between patients and controls, GABA A availability negatively correlated with both disease duration and dystonia severity. Conclusions: These findings support that aberrant inhibitory signaling within the thalamus contributes to the pathophysiology of cervical dystonia. Additionally, these results suggest that an inadequate ability to compensate for the loss of GABA through upregulation of GABA A receptors may underlie more severe symptoms., Competing Interests: CG has received research grant support from the Dystonia Medical Research Foundation. BB has received research grant support from the Dana Foundation, NIH (NIH/NCATS Colorado CTSI Grant Number KL2 TR001080), Dystonia Coalition (receives the majority of its support through NIH grant NS065701 from the Office of Rare Diseases Research in the National Center for Advancing Translational Science and National Institute of Neurological Disorders and Stroke), and from Mary Rossick Kern and Jerome H. Kern. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Groth, Brown, Honce, Shelton, Sillau and Berman.)

Parkinson's disease (PD) is a neurodegenerative disorder associated with multiple comorbidities, including seborrheic dermatitis (SD), which develops in more than half of PD patients. SD in patients with PD can be severe and frequently intractable by traditional topical therapy. Cannabinoids possess anti-inflammatory and neuromodulatory properties working within the intrinsic endocannabinoid system, the activation of which may alleviate the motor symptoms of PD. The effect of cannabinoids on SD is unknown. Here we explore the pathophysiological mechanisms and possible therapeutic role of oral cannabinoids in PD patients with SD, and review speculative mechanisms underlying the association of PD and SD. Current data supporting the use of cannabinoids in both PD and SD, as well as oral cannabinoid safety and tolerability, are presented. Cannabinoids may provide the possibility of simultaneous treatment of both SD and PD. Specific SD studies and additional safety data on oral cannabinoids are needed., (© 2020 S. Karger AG, Basel.)

Introduction: Our understanding of the determinants of quality of life (QOL) in people living with Parkinson's disease and related disorders (PDRD) has grown remarkably in the past decade. However, several areas remain understudied including determinants of general vs. health-related QOL, determinants in high-need patients, drivers of perceptions of caregivers vs. patients, and exploration of potential determinants outside of the traditional medical model., Methods: This was a cross-sectional study of 210 PDRD patients and 175 caregivers who completed a battery of measures regarding general QOL (QOL-Alzheimer's disease; QOL-AD), health-related QOL (Parkinson's disease Questionnaire; PDQ-39), cognitive function, mood, grief, spiritual wellbeing, symptom burden, disease severity, disease stage, overall function, socioeconomic status, and healthcare utilization. Elastic net regularization modeling of variables significantly associated with our outcomes of interest were performed to determine predictors of general QOL, compare predictors of general vs. health-related QOL, and compare predictors of patient and caregiver perspectives on patient general QOL., Results: General QOL was associated with spiritual wellbeing, depression, cognitive function, presence of a caregiver, and recent emergency department visits. In contrast, health-related QOL was associated with grief, symptom burden, income, disease stage, and utilization of counseling services. Caregiver ratings of patient general QOL were associated with patient symptom burden, patient grief, patient global function, caregiver burden, and caregiver spiritual wellbeing., Conclusions: There are notable differences in the predictors of general QOL, health-related QOL and caregiver perspectives on patient general QOL. These differences have important implications for clinical research and models of clinical care., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Neuroimaging studies using functional magnetic resonance imaging (fMRI), which measures brain activity by detecting the changes in blood oxygenation levels, are advancing our understanding of the pathophysiology of dystonia. Neurobiological disturbances in dystonia, however, may affect neurovascular coupling and impact the interpretability of fMRI studies. We evaluated here whether the hemodynamic response patterns during a behaviorally matched motor task are altered in isolated cervical dystonia (CD). Twenty-five CD patients and 25 healthy controls (HCs) underwent fMRI scanning during a paced finger tapping task (nondystonic task in patients). Imaging data were analyzed using a constrained principal component analysis-a statistical method that combines regression analysis and principal component analysis and enables the extraction of task-related functional networks and determination of the spatial and temporal hemodynamic response patterns associated with the task performance. Data from three patients and two controls were removed due to excessive movement. No significant differences in demographics or motor performance were observed. Three task-associated functional brain networks were identified. During task performance, reduced hemodynamic responses were seen in a sensorimotor network and in a network that included key nodes of the default mode, executive control and visual networks. During rest, reductions in hemodynamic responses were seen in the cognitive/visual network. Lower hemodynamic responses within the primary sensorimotor network in patients were correlated with the increased dystonia severity. Pathophysiological disturbances in isolated CD, such as alterations in inhibitory signaling and dopaminergic neurotransmission, may impact neurovascular coupling. Not accounting for hemodynamic response differences in fMRI studies of dystonia could lead to inaccurate results and interpretations., (© 2019 Wiley Periodicals, Inc.)

Background: Parkinson's disease (PD) is a neurodegenerative disorder associated with caregiver burden. Higher rates of burden are associated with adverse outcomes for caregivers and patients. Our aim was to understand patient and caregiver predictors of caregiver burden in PD from a palliative care approach., Methods: We conducted a cross-sectional analysis of baseline data from PD patients and caregivers in a randomized trial of outpatient palliative care at three study sites: University of Colorado, University of Alberta, and University of California San Francisco. The primary outcome measure of caregiver burden, the Zarit Burden Interview (ZBI), was compared against the following patient and caregiver variables: site of care, age, disease/caretaking duration, presence of atypical parkinsonism, race, income, education level, deep brain stimulation status, the Unified Parkinson's Disease Rating Scale (UPDRS) and Edmonton Symptom Assessment System Revised: Parkinson Disease (ESAS) for symptom severity and burden, the Montreal Cognitive Assessment (MoCA) for cognitive function, Quality of Life in Alzheimer's Disease (QOL-AD) scale for patient and caregiver perspectives on patient general quality of life, Parkinson's Disease Questionnaire 39 (PDQ-39) scale for health-related quality of life, Hospital Anxiety and Depression Scale (HADS) for patient and caregiver mood, Prolonged Grief Questionnaire, Functional Assessment of Chronic Illness Therapy- Spiritual Well-Being (FACIT-SP) of patient and caregiver, and Palliative Performance Scale for functional status. A stepwise multivariate linear regression model was used to determine associations with ZBI., Results: A total of 175 patients (70.9% male; average age 70.7±8.1 years; average disease duration 117.2±82.6 months), and 175 caregivers (73.1% female; average age 66.1±11.1 years) were included. Patient spiritual well-being (FACIT-SP Faith subscale, r2=0.024, P=0.0380), patient health-related quality of life (PDQ-39, r2=0.161, P<0.0001), caregiver depression (HADS Depression, r2=0.062, P=0.0014), caregiver anxiety (HADS Anxiety, r2=0.077, P=0.0002), and caregiver perspective on patient quality of life (QOL-AD Caregiver Perspective, r2=0.088, P<0.0001) were significant contributors to ZBI scores., Conclusions: Patient and caregiver factors contribute to caregiver burden in persons living with PD. These results suggest targets for future interventions to improve caregiver support.

Background: The prevalence of functional movement disorders is 2 to 3 times higher in women than in men. Trauma and adverse life events are important risk factors for developing functional movement disorders. On a population level, rates of sexual abuse against women are higher when compared with the rates against men., Objectives: To determine gender differences in rates of sexual abuse in functional movement disorders compared with other neurologic disorders and evaluate if the gender prevalence is influenced by higher rates of sexual abuse against women., Methods: We performed a case-control series including 199 patients with functional movement disorders (149 women) and 95 controls (60 women). We employed chi-squared test to assess gender and sexual abuse associations and Bayes formula to condition on sexual abuse., Results: Our analysis showed an association between sexual abuse and functional movement disorders in women (odds ratio, 4.821; 95% confidence interval, 2.089-12.070; P  < 0.0001), but not men. Bayesian analysis found the functional movement disorder prevalence ratio between women and men conditional on sexual abuse to be 4.87 times the unconditioned ratio., Conclusions: There is a statistically significant association between sexual abuse and functional movement disorders in women and a greater likelihood that women who are sexually abused will develop functional movement disorders than men who are sexually abused. Our findings suggest that the increased prevalence of functional movement disorders in women is associated, at least in part, with sexual abuse and its sequelae; however, further research is needed to explore the role of other traumatic and nontraumatic factors., (© 2019 International Parkinson and Movement Disorder Society.)

Introduction: Quality of life (QOL) assessments allow for more complete evaluation of patients' lived experiences in relation to chronic conditions, such as Parkinson's disease (PD). In palliative care, such instruments are vital to ensure QOL issues are catalogued and addressed for patients. However, little is known regarding the psychometric properties of quality of life scales for use in palliative care for PD, specifically., Methods: 210 participants with parkinsonian disorders, who participated in a larger palliative intervention clinical trial, completed four quality of life scales (PDQ-39, PROMIS-29, QOL-AD, and McGill QOL) at baseline and post-intervention. Psychometric properties, including internal consistency and concurrent validity, were examined. Factor analyses were performed to evaluate relationships between scale items. Minimal clinically important differences (MCID) and responsiveness were calculated for each scale., Results: All scales demonstrated good internal consistency and concurrent validity. Factor analyses revealed few deviations from the defined subdomains of the scales. Mean absolute MCID values were estimated at 12.7, 10.9, 3.9, and 18.9 for PDQ-39, PROMIS-29, QOL-AD, and McGill QOL, respectively. The PDQ-39 and PROMIS-29 demonstrated higher responsiveness to palliative intervention, while the QOL-AD was more responsive in the control group., Conclusions: The PDQ-39, PROMIS-29, QOL-AD, and McGill QOL are all valid for use in PD palliative care, though subdomains of the scales in this population may differ slightly from those initially defined. We recommend the use of PDQ-39 and PROMIS-29 as outcome measures in clinical trials for palliative care in PD, though the QOL-AD may be superior for tracking disease progression., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background Incidence of cardiovascular disease in young adults is unabated. Increased prevalence of self-reported atherosclerotic risk factors may be driving this trend. The goal of this study was to examine whether the prevalence of atherosclerotic risk factors in young adults is increasing over time using both self-report and standard clinical criteria. Methods and Results Data from young adults, aged 20 to 45 years, in the National Health and Nutrition Examination Survey from 1999/2000 to 2013/2014 were analyzed. Risk factor prevalence of hypertension, diabetes mellitus, and hyperlipidemia was measured using clinical criteria and self-report. Smoking was based on self-report only, and obesity was based clinically on body mass index and waist to height ratio. Prevalence by survey was adjusted for age, sex, and race/ethnicity. By clinical criteria, adjusted prevalence of any 3 risk factors (hypertension, diabetes mellitus, and hyperlipidemia) declined slightly from 21.8% to 18.9% ( P for trend=0.05). However, by self-report, the adjusted prevalence of any 3 risk factors increased from 17.8% to 26.5% ( P<0.01). Hypertension was unchanged by clinical criteria ( P=0.32) but increased by self-report ( P<0.08). Diabetes mellitus, by clinical diagnosis and self-report, remained unchanged ( P=0.35 and P=0.29, respectively). Hyperlipidemia, by clinical criteria, declined over time ( P<0.01), but increased by self-report ( P<0.01). Smoking declined ( P<0.01), and obesity increased by both body mass index ( P<0.01) and waist/height ratio ( P<0.01). Conclusions The perception that young adult risk factors are increasing is consistent with increasing self-reported risk factors. However, evidence does not suggest that clinical risk factor prevalence overall has increased in young adults.

Background: The Multiple Sclerosis Severity Score (MSSS), combining the Expanded Disability Status Scale (EDSS) and disease duration, attempts to stratify multiple sclerosis (MS) patients based on their rate of progression. Its prognostic ability in the individual patient remains unproven., Objectives: To assess the stability of MSSS within individual persons with MS in a longitudinal cohort, to evaluate whether certain factors influence MSSS variability, and to explore the ability of MSSS to predict future ambulatory function., Methods: A single-center retrospective review was performed of patients following a single provider for at least 8 years. Mixed model regression modeled MSSS over time. A Kaplan-Meier survival plot was fitted, using change of baseline MSSS by at least one decile as the event. Cox modeling assessed the influence of baseline clinical and demographic factors on the hazard of changing MSSS by at least one decile. Linear models evaluated the impact of baseline EDSS, baseline MSSS, and other factors on the Timed 25-Foot Walk (T25FW)., Results: Out of 122 patients, 68 (55.7%) deviated from baseline MSSS by at least one decile. Final T25FW had slightly weaker correlation to baseline MSSS than to baseline EDSS, which was moderately strongly correlated with future log T25FW., Conclusion: Individual MSSS scores often vary over time. Clinicians should exercise caution when using MSSS to prognosticate.

Background: Outcome measures that capture functional abilities related to cognition offer the potential to demonstrate real-world effectiveness of cognitive-enhancing treatments. However, distinguishing functional disability related to cognition from that attributed to motor symptoms can be difficult in PD. A performance-based functional assessment allows for direct observation of activity of daily living skills and separation of cognitive from motoric disabilities., Objectives: Validate the University of California San Diego Performance-Based Skills Assessment in PD., Methods: One hundred PD participants, ranging from normal cognition to dementia, completed the University of California San Diego Performance-Based Skills Assessment, a performance-based measure of cognitively demanding activities of daily living, as well as a neuropsychological battery and motor examination. Cognitive classification was determined by consensus conference, blinded to University of California San Diego Performance-Based Skills Assessment scores. Psychometric properties of the University of California San Diego Performance-Based Skills Assessment, including internal consistency, test-retest and inter-rater reliability, and discriminant validity for dementia, were examined., Results: The University of California San Diego Performance-Based Skills Assessment demonstrated strong internal consistency (Cronbach's α = 0.82) and test-retest reliability (r = 0.89) and correlated strongly with global cognition (Mattis Dementia Rating Scale: r = 0.80; P < 0.001). University of California San Diego Performance-Based Skills Assessment regression models indicated greater contribution from cognitive explanatory variables (marginal partial: R 2  = 0.33) than motor variables (marginal partial: R 2  = 0.05), controlling for age, education, disease duration, and l-dopa equivalent dose. Additionally, the University of California San Diego Performance-Based Skills Assessment exhibited strong discriminant validity for dementia (area under the curve = 0.91)., Conclusions: The University of California San Diego Performance-Based Skills Assessment is a valid measure of functional abilities related to cognition rather than motor symptoms in PD. Furthermore, it reliably distinguishes demented from nondemented participants. The University of California San Diego Performance-Based Skills Assessment may be considered as an outcome measure that combines cognitive and functional abilities in treatment trials for cognitive impairment in PD. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Objective: To study the effect of subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease (PD) and moderate to severe restless legs syndrome (RLS) on their RLS symptoms., Methods: Patients undergoing STN DBS surgery for PD completed the International RLS Study Group Rating Scale (IRLS) and RLS Quality of Life (QoL) questionnaires preoperatively and postoperatively at 6 months, 1 year, and 2 years. The primary outcome measure was IRLS sum score and subscales (severity and impact) and the secondary measure was RLS QoL scores. Differences among the mean scores over time were analyzed using mixed model regression., Results: Twenty-two patients were enrolled. The preoperative IRLS sum scores were 19.59 ± 6.95, severity subscale 12.91 ± 4.33, impact subscale 4.45 ± 2.72, and transformed RLS QoL score 68.30 ± 20.26. The differences between preoperative and averaged postoperative scores were IRLS sum score -7.80, severity subscale -5.50, impact subscale -1.20, and RLS QoL 4.73. The overall F tests demonstrated differences among the times for the means of the IRLS sum and subscales: p < 0.05. There were no correlations between RLS symptoms improvement and PD motor symptoms improvement or reduction in PD medications. Half of the patients had at least 50% improvement and 27% had resolution of their RLS symptoms (IRLS = 0)., Conclusions: STN DBS significantly decreased RLS symptoms in patients with PD despite a decrease in dopaminergic treatment. This improvement was sustained over a 2-year period., Classification of Evidence: This study provides Class IV evidence that for patients with PD and moderate to severe RLS, STN DBS improves RLS symptoms., (© 2018 American Academy of Neurology.)

Objective: Isolated adult-onset focal dystonia is considered a network disorder with disturbances to the motor basal ganglia and cerebellar circuits playing a pathophysiological role, but why specific body regions become affected remains unknown. We aimed to use diffusion tensor imaging to determine if the two most common phenotypes of focal dystonia are associated with distinguishing microstructural changes affecting the motor network., Methods: Fifteen blepharospasm patients, 20 cervical dystonia patients, and 30 age- and sex-matched healthy controls were recruited. Maps of fractional anisotropy and mean diffusivity were analyzed using a voxel-based approach and an automated region-of-interest technique to evaluate deep gray matter nuclei. Correlations between diffusion measures and dystonia severity were tested, and post hoc discriminant analyses were conducted., Results: Voxel-based analyses revealed significantly reduced fractional anisotropy in the right cerebellum and increased mean diffusivity in the left caudate of cervical dystonia patients compared to controls, as well as lower fractional anisotropy in the right cerebellum in cervical dystonia patients relative to blepharospasm patients. In addition to reduced fractional anisotropy in the bilateral caudate nucleus of cervical dystonia patients relative to controls and blepharospasm patients, region-of-interest analyses revealed significantly reduced fractional anisotropy in the right globus pallidus internus and left red nucleus of blepharospasm patients compared to both controls and cervical dystonia patients. Diffusivity measures in the red nucleus of blepharospasm patients correlated with disease severity. In a three-group discriminant analysis, participants were correctly classified with only modest reliability (67-75%), but in a two-group discriminant analysis, patients could be distinguished from each other with high reliability (83-100%)., Conclusions: Different focal dystonia phenotypes are associated with distinct patterns of altered microstructure within constituent regions of basal ganglia and cerebellar circuits.

OBJECTIVE Prophylactic use of antiepileptic drugs (AEDs) in seizure-naïve brain tumor patients remains a topic of debate. This study aimed to characterize a subset of patients at highest risk for new-onset perioperative seizures (i.e., intraoperative and postoperative seizures occurring within 30 days of surgery) who may benefit from prophylactic AEDs. METHODS The authors conducted a retrospective case-control study of all adults who had undergone tumor resection or biopsy at the authors' institution between January 1, 2004, and June 31, 2015. All patients with a history of preoperative seizures, posterior fossa tumors, pituitary tumors, and parasellar tumors were excluded. A control group was matched to the seizure patients according to age (± 0 years). Demographic data, clinical status, operative data, and postoperative course data were collected and analyzed. RESULTS Among 1693 patients who underwent tumor resection or biopsy, 549 (32.4%) had never had a preoperative seizure. Of these 549 patients, 25 (4.6%) suffered a perioperative seizure (Group 1). A total of 524 patients (95.4%) who remained seizure free were matched to Group 1 according to age (± 0 years), resulting in 132 control patients (Group 2), at an approximate ratio of 1:5. There were no differences between the patient groups in terms of age, sex, race, relationship status, and neurological deficits on presentation. Histological subtype (infiltrating glioma vs meningioma vs other, p = 0.041), intradural tumor location (p < 0.001), intraoperative cortical stimulation (p = 0.004), and extent of resection (less than gross total, p = 0.002) were associated with the occurrence of perioperative seizures. CONCLUSIONS While most seizure-naïve brain tumor patients do not benefit from perioperative seizure prophylaxis, such treatment should be considered in high-risk patients with supratentorial intradural tumors, in patients undergoing intraoperative cortical stimulation, and in patients in whom subtotal resection is likely.

Background: The objective of this study was to characterize hypoxic-ischemic injury and seizures in abusive head trauma., Methods: We studied 58 children with moderate or severe traumatic brain injury due to abusive head trauma. Continuous electroencephalograms and magnetic resonance images were scored., Results: Electrographic seizures (51.2%) and hypoxic-ischemic injury (77.4%) were common in our cohort. Younger age was associated with electrographic seizures (no seizures: median age 13.5 months, interquartile range five to 25 months, versus seizures: 4.5 months, interquartile range 3 to 9.5 months; P = 0.001). Severity of hypoxic-ischemic injury was also associated with seizures (no seizures: median injury score 1.0, interquartile range 0 to 3, versus seizures: 4.5, interquartile range 3 to 8; P = 0.01), but traumatic injury severity was not associated with seizures (no seizures: mean injury score 3.78 ± 1.68 versus seizures: mean injury score 3.83 ± 0.95, P = 0.89). There was a correlation between hypoxic-ischemic injury severity and seizure burden when controlling for patient age (r s =0.61, P < 0.001). The ratio of restricted diffusion volume to total brain volume (restricted diffusion ratio) was smaller on magnetic resonance imaging done early (median restricted diffusion ratio 0.03, interquartile range 0 to 0.23 on magnetic resonance imaging done within two days versus median restricted diffusion ratio 0.13, interquartile range 0.01 to 0.43 on magnetic resonance imaging done after two days, P = 0.03)., Conclusions: Electrographic seizures are common in children with moderate to severe traumatic brain injury from abusive head trauma, and therefore children with suspected abusive head trauma should be monitored with continuous electroencephalogram. Severity of hypoxic-ischemic brain injury is correlated with severity of seizures, and evidence of hypoxic-ischemic injury on magnetic resonance imaging may evolve over time. Therefore children with a high seizure burden should be reimaged to evaluate for evolving hypoxic-ischemic injury., (Published by Elsevier Inc.)

Background: The Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UDPRS) is a commonly used tool to measure Parkinson disease (PD) progression. Longitudinal changes in MDS-UPDRS scores in de novo PD have not been established., Objective: Determine progression rates of MDS-UPDRS scores in de novo PD., Methods: 362 participants from the Parkinson's Progression Markers Initiative, a multicenter longitudinal cohort study of de novo PD, were included. Longitudinal progression of MDS-UPDRS total and subscale scores were modeled using mixed model regression., Results: MDS-UPDRS scores increased in a linear fashion over five years in de novo PD. MDS-UPDRS total score increased an estimated 4.0 points/year, Part I 0.25 points/year, Part II 1.0 points/year, and Part III 2.4 points/year., Conclusions: The expected average progression of MDS-UPDRS scores in de novo PD from this study can assist in clinical monitoring and provide comparative data for detection of disease modification in treatment trials.

Background: Fingolimod (FTY) and dimethyl fumarate (DMF) are multiple sclerosis (MS) oral therapies that became available in 2010 and 2013, respectively., Objective: The objective of this article is to compare discontinuation rates, efficacy, and adverse events (AEs) of FTY and DMF over two years., Methods: Patients prescribed FTY or DMF at the Rocky Mountain MS Center at University of Colorado prior to October 2013 were identified. Clinician-reported data were retrospectively collected. Primary outcome was discontinuation of drug by the end of year two. Reasons for discontinuation were evaluated., Results: A total of 271 FTY and 342 DMF patients were evaluated. Patients had a mean age of 42.5 (FTY) and 45.8 (DMF) years and were predominantly female (72.0% FTY; 69.6% DMF) and white (86.3% FTY; 82.2% DMF). At ≤24 months, 93 (34.3%) and 161 (47.1%) discontinued FTY and DMF, respectively, with an unadjusted odds ratio (OR) of 1.70 (1.23-2.37, p  = 0.002), or 1.69 (1.16-2.46, p  = 0.006) for the doubly robust propensity score weighted estimator. Primary reason for discontinuation was AEs, which were less likely for FTY 46 (17.0%) compared to DMF 82 (24.0%) (OR 1.54, 1.03-2.31, p  = 0.035). Discontinuation due to disease activity (FTY (10%) DMF (11.1%); OR 1.13, 0.67-1.90, p  = 0.647) and breakthrough disease activity, regardless of discontinuation (FTY (34.7%) DMF (33.6%); OR 0.95, 0.68-1.34, p  = 0.783), were similar., Conclusions: The odds of discontinuation were less for FTY than DMF, and were driven by AEs for both drugs.

Objective: We describe long-term functional, neurodiagnostic, and psychosocial outcomes of a cohort of 12 children from Colorado diagnosed with acute flaccid myelitis (AFM) in 2014., Methods: Children were assessed every 3 months for 1 year or until clinical resolution. Assessments included neurologic examination, MRI, EMG/nerve conduction studies (NCS), functional measures (Assisting Hand Assessment, Hammersmith Functional Motor Scale), and Patient-Reported Outcomes Measurement Information System questionnaires., Results: Eight of 12 children completed the study. Six of 8 had persistent motor deficits at 1 year; 2 demonstrated full recovery. Four were not enrolled, 2 of whom reported full recovery. The 6 affected were weakest in proximal muscles, showing minimal to no improvement and significant atrophy at 1 year. All patients improved in distal muscle groups. Cranial nerve dysfunction resolved in 2 of 5 and improved in all. Four of 5 showed progressive functional improvement at 6 and 12 months. Two of 8 reported pain at 1 year. Three of 8 reported depressive symptoms. Repeat MRI was performed in 7 of 8 children a median of 7 months after onset and showed significant improvement or normalization in all but one child. Repeat EMG/NCS was performed on 4 children a median of 8 months after onset and showed ongoing denervation and chronic reinnervation in 3 children with persistent deficits., Conclusions: At 1 year, children with AFM demonstrated functional gains but weakness persisted. EMG changes correlated with persistent deficits better than imaging. Despite improvements, AFM had substantial long-term functional effects on affected children., (© 2017 American Academy of Neurology.)

Background: Depression and anxiety frequently accompany the motor manifestations of isolated adult-onset focal dystonias. Whether the body region affected when this type of dystonia first presents is associated with the severity of these neuropsychiatric symptoms is unknown., Objectives: The aim of this study was to determine whether depression, anxiety and social anxiety vary by dystonia onset site and evaluate whether pain and dystonia severity account for any differences., Methods: Patients with isolated focal dystonia evaluated within 5 years from symptom onset, enrolled in the Natural History Project of the Dystonia Coalition, were included in the analysis. Individual onset sites were grouped into five body regions: cervical, laryngeal, limb, lower cranial and upper cranial. Neuropsychiatric symptoms were rated using the Beck Depression Inventory, Hospital Anxiety and Depression Scale and Liebowitz Social Anxiety Scale. Pain was estimated using the 36-Item Short Form Survey., Results: Four hundred and seventy-eight subjects met our inclusion criteria. High levels of depression, anxiety and social anxiety occurred in all groups; however, the severity of anxiety and social anxiety symptoms varied by onset site group. The most pronounced differences were higher anxiety in cervical and laryngeal, lower anxiety in upper cranial and higher social anxiety in laryngeal. Increases in pain were associated with worse neuropsychiatric symptom scores within all groups. Higher anxiety and social anxiety in laryngeal and lower anxiety in upper cranial persisted after correcting for pain and dystonia severity., Conclusion: Anxiety and social anxiety severity vary by onset site of focal dystonia, and this variation is not explained by differences in pain and dystonia severity., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: (1) Describe clinical and histopathologic findings in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). (2) Determine if tissue and serum eosinophilia predicts disease severity in CRSwNP., Study Design: Case series with chart review., Setting: Academic hospital specializing in respiratory and allergic disease., Subjects: Patients with CRSwNP treated from 2008 to 2010., Methods: Clinical data were collected; sinus computed tomography (CT) scans were scored according to the Lund-Mackay system; and surgical specimens were evaluated for degree of tissue eosinophilia. Statistical analysis was performed to compare eosinophilia with indicators of disease severity., Results: Seventy CRSwNP patients were included, with a mean Lund-Mackay score of 16.7; 62.1% of patients had severe asthma, and 62.9% were aspirin sensitive. Elevated tissue eosinophil level did not correlate with medication usage, olfactory symptoms, or Lund-Mackay scores, nor did it correlate with presence of asthma or aspirin-sensitivity (P = .09). Patients with mild asthma had significantly more tissue eosinophils versus patients with severe asthma, possibly because of the high amount of chronic corticosteroid use in severe asthmatics. There was no correlation between tissue and serum eosinophil counts (P = .97), but there was a significant positive correlation between CT score and peripheral eosinophil level (P < .05)., Conclusions: Higher serum eosinophil levels may indicate more extensive mucosal disease as measured on CT scan. Neither serum nor tissue eosinophilia predicted disease severity in our retrospective analysis of CRSwNP patients, and serum eosinophil level did not serve as a marker of tissue eosinophilia., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Diffusion tensor imaging (DTI) of the substantia nigra has shown promise in detecting and quantifying neurodegeneration in Parkinson disease (PD). It remains unknown, however, whether differences in microstructural changes within the basal ganglia underlie PD motor subtypes. We investigated microstructural changes within the basal ganglia of mild to moderately affected PD patients using DTI and sought to determine if microstructural changes differ between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes. Fractional anisotropy, mean diffusivity, radial, and axial diffusivity were obtained from bilateral caudate, putamen, globus pallidus, and substantia nigra of 21 PD patients (12 TD and 9 PIGD) and 20 age-matched healthy controls. T-tests and ANOVA methods were used to compare PD patients, subtypes, and controls, and Spearman correlations tested for relationships between DTI and clinical measures. We found our cohort of PD patients had reduced fractional anisotropy within the substantia nigra and increased mean and radial diffusivity within the substantia nigra and globus pallidus compared to controls, and that changes within those structures were largely driven by the PIGD subtype. Across all PD patients fractional anisotropy within the substantia nigra correlated with disease stage, while in PIGD patients increased diffusivity within the globus pallidus correlated with disease stage and motor severity. We conclude that PIGD patients have more severely affected microstructural changes within the substantia nigra compared to TD, and that microstructural changes within the globus pallidus may be particularly relevant for the manifestation of the PIGD subtype.

Objectives: We sought to describe the prevalence of restrictive lung function in structural congenital heart disease and to determine the effect of cardiothoracic surgical intervention., Methods: The data from a retrospective review of the spirometry findings from pediatric patients with structural congenital heart disease were compared with the data from 220 matched controls. Restrictive lung function was defined as a forced vital capacity of <80%, with a preserved ratio of the forced expiratory volume in the first second to forced vital capacity of >80%., Results: Of the children with congenital heart disease, 20% met the criteria for restrictive lung function compared with 13.2% of the controls (P = .03). The prevalence in those with congenital heart disease without a surgical history was similar to that of the controls (odds ratio, 0.62; 95% confidence interval, 0.34-1.13). Restrictive lung function was more likely if surgical intervention had occurred within the first year of life (odds ratio, 1.96; 95% confidence interval, 1.08-3.55; P < .0001). Those who had undergone both sternotomy and thoracotomy had a greater prevalence of restrictive lung function than those who had undergone sternotomy or thoracotomy alone (54.2% vs 25.6% and 23.5%, respectively; P < .0001). The prevalence of restrictive lung function increased significantly with each additional surgical intervention (odds ratio, 1.61; 95% confidence interval, 1.29-2.01; P < .0001)., Conclusions: Restrictive lung function was more prevalent in those with congenital heart disease after cardiothoracic surgical intervention than in the controls or patients without surgical intervention. The prevalence was also greater with surgical intervention at an earlier age. The risk was equivalent when sternotomy alone was compared with thoracotomy alone but was significantly greater when both sternotomy and thoracotomy were performed. The risk increased with each additional surgery performed., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Integrated primary care, a health care delivery model that combines medical and behavioral health services, provides better patient access to care at a lower cost, with better outcomes compared with usual nonintegrated care models. The perspectives of primary care providers (PCPs) and behavioral health care providers (BHPs) toward integration are especially valuable because their input and endorsement are key to successful and sustained integration. However, there is little research assessing or comparing PCP and BHP perspectives on integration, especially in rural areas. The objective of this study was to identify rural PCP and BHP perspectives on integration., Methods: Written and electronic surveys were distributed to PCPs and BHPs in the High Plains Research Network in rural eastern Colorado. Items included perspectives on improving behavioral health care, barriers to integration, and confidence in the ability to integrate primary and behavioral care., Results: Surveys were completed by 88 PCPs (60%), and 49 BHPs (63%), for an overall response rate of 61%. PCPs were significantly more likely than BHPs to prefer improving referral methods (odds ratio [OR], 2.2; P = .03) and significantly less likely to prefer colocation (OR, 0.2; P < .0001), warm hand-offs (OR, 0.3; P < .01), improved behavioral health training for PCPs (OR, 0.4; P < .01), and shared visits (OR, 0.4; P =.03) as ways to improve health care. Lack of sufficient methods of payment for behavioral health care services was the most commonly selected barrier to integration by both groups. PCPs were significantly more likely than BHPs to select recruitment (OR, 3.8; P < .001) and retention (OR, 2.7; P < .01) of behavioral health care staff as a major barrier. BHPs were slightly more optimistic than PCPs about the achievability of integration., Conclusions: Important differences of perspective exist between rural PCPs and BHPs regarding the best ways to improve behavioral health care, barriers to integration, and the achievability of integration. These differences may have important implications for rural communities and health care systems considering a transition to an integrated primary care model.

Background: Patients with chronic rhinosinusitis (CRS) and nasal polyps (NPs) may be subdivided into aspirin-sensitive (AS) and aspirin-tolerant (AT) populations. These cohorts are not well characterized., Objective: To examine phenotypic characteristics and determine the extent of medical/surgical interventions in patients with CRS+NP and to compare the AS with the AT subset in the CRS+NP sample., Methods: Retrospective chart review was performed at a tertiary academic respiratory hospital. Data included patient demographics, asthma severity, peripheral eosinophilia, Lund-Mackay computed tomographic score, symptomatic dysosmia, and therapeutic interventions., Results: Of the 182 patients included, 81 had aspirin sensitivity (45%) and 101 had aspirin tolerance (55%). Asthma was present in 94% of patients with CRS+NP (100% in AS subgroup vs 89% in AT subgroup, P = .001). Eighty-eight percent of the CRS+NP sample had moderate to severe persistent asthma. In the AS and AT subgroups, asthma severity was similar (P > .6). The CRS+NP sample showed a mean computed tomographic score of 14.0 (44% with eosinophilia and 46% with dysosmia). More severe sinus disease was noted in the AS group (Lund-Mackay computed tomographic scores, P = .002; olfactory symptoms, P = .001). Serum eosinophil levels were not statistically different between groups (51% in AS group, 39% in AT group, P > .1)., Conclusion: This study is one of the broadest reviews of patients with CRS+NP, with unique findings in the high prevalence of asthma in AS and AT patients, greater olfactory dysfunction in AS patients, and a minority of patients with CRS+NP and circulating eosinophils. Most AS patients do not have increased circulating eosinophils, as is often believed. These results shed further light on the association between asthma and upper respiratory tract disease in those with nasal polyposis., (Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Despite the numerous disease conditions associated with vitamin D deficiency in the general population, the relationship of this deficiency to outcome in critically ill patients remains unclear. The objective of this study is to determine the burden of vitamin D deficiency in intensive care unit (ICU) patients and determine if it is associated with poor patient outcomes., Methods: The authors conducted an analysis of samples collected from a prospective study of 196 patients admitted to a medical/surgical ICU in a tertiary care hospital. They measured serum 25-hydroxyvitamin D at admission and up to 10 days following admission and followed patients prospectively for 28-day outcomes., Results: Of analyzable patients, 50 (26%) were deficient (≤30 nmol/L) and 109 (56%) were insufficient (>30 and ≤60 nmol/L). Baseline 25(OH)D levels decreased significantly in all patients after 3 days in the ICU and remained significantly lower through 10 days (P < .001). 25(OH)D status was not significantly associated with 28-day all-cause mortality (hazard ratio [HR], 0.89; 95% confidence interval, [CI] 0.37-2.24). Higher levels of 25(OH)D were associated with a shorter time-to-alive ICU discharge (HR, 2.11; 95% CI, 1.27-3.51). 25(OH)D-deficient patients showed a nonstatistically significant trend toward a higher infection rate (odds ratio [OR], 3.20; 95% CI, 0.784-13.07; P = .11) compared with patients with sufficient levels of 25(OH)D., Conclusions: This study demonstrates significant decreases in vitamin D status over the duration of the patient's ICU stay. Low levels of vitamin D are associated with longer time to ICU discharge alive and a trend toward increased risk of ICU-acquired infection.

A Web-based electronic health record (EHR) system was compared with traditional paper-based documentation and vaccination tracking during the 2009 H1N1 influenza pandemic. In a cohort of 8,411 healthcare network employees, EHRs improved completeness of self-reported contraindication data and reduced medical discrepancies. Vaccination program quality and accuracy are enhanced by EHRs.